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PSE 5755 Regulação do comportamento por agentes químicos 2o. semestre 2008 Docentes: Maria Teresa Araujo Silva ([email protected]) Miriam Garcia Mijares ([email protected]) SEMINÁRIOS 03 e 17/09 Dependência e auto-administração 1. Nestler, E. J. (2004). Molecular mechanisms of drug addiction. Neuropharmacology, 47 Suppl 1, 24-32. RESUMO: Regulation of gene expression is one mechanism by which drugs of abuse can induce relatively longlasting changes in the brain to cause a state of addiction. Here, we focus on two transcription factors, CREB (cAMP response element binding protein) and DeltaFosB, which contribute to drug-induced changes in gene expression. Both are activated in the nucleus accumbens, a major brain reward region, but mediate different aspects of the addicted state. CREB mediates a form of tolerance and dependence, which dampens an individual's sensitivity to subsequent drug exposure and contributes to a negative emotional state during early phases of withdrawal. In contrast, DeltaFosB mediates a state of relatively prolonged sensitization to drug exposure and may contribute to the increased drive and motivation for drug, which is a core symptom of addictive disorders. A major goal of current research is to identify the many target genes through which CREB and DeltaFosB mediate these behavioral states. In addition, future work needs to understand how CREB and DeltaFosB, acting in concert with numerous other druginduced molecular changes in nucleus accumbens and many other brain regions, interact with one another to produce the complex behavioral phenotype that defines addiction. 2. Spiga, R., Martinetti, M. P., Meisch, R. A., Cowan, K., & Hursh, S. (2005). Methadone and nicotine selfadministration in humans: a behavioral economic analysis. Psychopharmacology (Berl), 178, 223-231. RESUMO: RATIONALE: Prior research has revealed inconsistencies in the behavioral relations between nicotine and opiates among methadone-maintained patients.OBJECTIVES: The current study examined whether the drug reinforcers cigarette puffs and methadone were economic complements or substitutes.METHODS: Five methadonemaintained, nicotine-dependent participants were trained to self-administer methadone, cigarette puffs, or concurrently available methadone and puffs. Following training, the fixed ratio (FR) value ("price") was increased across sessions (FR 32, 64, 128, 256, and 512), first for methadone and then for puffs. Subsequently, methadone and puffs were concurrently available, and the price of each drug was increased independently, while the price of the alternative (puffs or methadone) remained constant at FR 32.RESULTS: Demand for methadone and cigarette puffs decreased as a function of increases in methadone and cigarette puff prices, respectively. When methadone and puffs were concurrently available, an increase in methadone's price decreased puff consumption, and demand for methadone was less elastic than when puffs were not concurrently available. An increase in puff price decreased puff and methadone demand, but the elasticity of puff demand was unaffected. The concurrent presence of methadone had no effect on the elasticity of demand for cigarette puffs.CONCLUSIONS: Methadone and cigarette puffs appear to be asymmetric economic complements 3. Siegel, S. (1999). Drug anticipation and drug addiction. The 1998 H. David Archibald Lecture. Addiction, 94, 1113-1124. RESUMO: Environmental cues associated with drug use become capable of eliciting withdrawal symptoms, craving and relapse to drug self-administration. The phenomenon, although noted almost 150 years ago, has repeatedly been confirmed in epidemiological and experimental studies. Drug tolerance, which is closely correlated with withdrawal symptoms and craving, is also modulated by drug-associated environmental cues. The contribution of predrug cues to withdrawal and tolerance is emphasized in a Pavlovian conditioning analysis of drug administration. Drug-induced disturbances are modulated by homeostatic responses elicited by pharmacological stimulation. According to the conditioning analysis, we learn to anticipate the drug effect; corrective response (conditional compensatory responses) occur in the presence of situations and events that have been associated with the drug in the past. These conditional responses, seen in anticipation of drugs, importantly contribute to drug tolerance, failures of tolerance (enigmatic overdoses), and withdrawal symptoms. I review evidence indicating that a complete analysis of drug withdrawal and tolerance requires an appreciation of the contribution of Pavlovian conditioning. 4. Winger, G., Woods, J. H., Galuska, C. M., & Wade-Galuska, T. (2005). Behavioral perspectives on the neuroscience of drug addiction. J Exp Anal Behav, 84, 667-681. RESUMO: Neuroscientific approaches to drug addiction traditionally have been based on the premise that addiction is a process that results from brain changes that in turn result from chronic administration of drugs of abuse. An alternative approach views drug addiction as a behavioral disorder in which drugs function as preeminent reinforcers. Although there is a fundamental discrepancy between these two approaches, the emerging neuroscience of reinforcement and choice behavior eventually may shed light on the brain mechanisms involved in excessive drug use. Behavioral scientists could assist in this understanding by devoting more attention to the assessment of differences in the reinforcing strength of drugs and by attempting to develop and validate behavioral models of addiction. 5. Winsauer, P. J., Moerschbaecher, J. M., Molina, P. E., & Roussell, A. M. (2003). Contingent and noncontingent cocaine administration in rhesus monkeys: a comparison of the effects on the acquisition and performance of response sequences. Behav Pharmacol, 14, 295-306. RESUMO: Previous studies have suggested that the effects of contingent (response dependent) and noncontingent (response independent) cocaine administration may differ, which could limit the generality and validity of laboratory studies that use only noncontingent administration. Therefore, two separate three-component multiple schedules of operant responding were used to examine the effects of both types of cocaine administration on the acquisition and performance of response sequences, in four rhesus monkeys. In one multiple schedule, responding under a fixed-ratio (FR) 60 schedule was followed by intravenous (i.v.) saline or cocaine (0.0032-0.32 mg/kg per infusion), whereas responding in the other two components (i.e. acquisition and performance) was followed by food presentation. In the second multiple schedule, the cocaine administration component consisted of a variable-time (VT) schedule that mimicked each subject's pattern of self-administration. When compared to saline administration, increasing infusion doses of cocaine decreased overall response rates comparably in both food-maintained components, irrespective of the cocaine contingency. The 0.1-0.32 mg/kg infusion doses also increased the percentage of errors in 2 of 4 subjects; however, these disruptions in accuracy were not differentially associated with the type of cocaine administration and generally occurred at doses that produced large rate-decreasing effects. Taken together, these data suggest that the effects of cocaine on complex operant behavior in monkeys may not differ substantially as a function of contingent or noncontingent administration 6. Sarnyai, Z., & Kovacs, G. L. (1994). Role of oxytocin in the neuroadaptation to drugs of abuse. Psychoneuroendocrinology, 19, 85-117. RESUMO: Oxytocin (OXT), a neurohypophyseal hormone, has a wide range of behavioral effects outside its classic peripheral endocrine functions. OXT involvement in adaptive central nervous system processes has been demonstrated as an inhibitory, amnestic action on learning and memory in different paradigms. Because adaptation and learning are likely to be involved in the neural events leading to drug tolerance and dependence, the question logically arose whether OXT is able to influence the development of tolerance of and dependence on abused drugs. In this review, we summarize our results on the effects of OXT on opiate (including morphine, heroin, and the endogenous opiates beta-endorphin and enkephalin) tolerance and dependence, heroin self-administration, psychostimulant-induced behavioral changes, and behavioral tolerance and sensitization. The sites and mechanisms of action and the possible physiological role of OXT are also discussed. In the first part of this review the effects of exogenously administered OXT on both the acute and chronic behavioral effects of opiates and psychostimulants have been summarized. OXT inhibited the development of tolerance to morphine, heroin, beta-endorphin, and enkephalin, OXT also inhibited the development of cross-tolerance between the predominantly mu-agonist heroin and the predominantly delta-agonist enkephalin in mice. Naloxone-precipitated morphine withdrawal syndrome was also attenuated by OXT. Heroin self-administration was decreased by OXT administration in heroin-tolerant rats. OXT inhibited cocaine-induced exploratory activity, locomotor hyperactivity, and stereotyped behavior in rats and in mice. Behavioral tolerance to cocaine was also attenuated by OXT. On the contrary, OXT stimulated the development of behavioral sensitization to cocaine. OXT did not alter the stereotyped behavior induced by amphetamine. In the second series of experiments, the sites of action of OXT on drug-related behavior were investigated. Intracerebro-ventricular (ICV) and intracerebral (IC) administration of an OXT-receptor antagonist inhibited the effects of peripherally administered OXT on morphine tolerance, heroin self-administration, and cocaine-induced sniffing behavior. This suggests the central, intracerebral location of OXT target sites. Local IC microinjection of OXT in physiological doses into the posterior olfactory nucleus, tuberculum olfactorium, nucleus accumbens, central amygdaloid nucleus, and the hippocampus inhibited the development of tolerance to and dependence on morphine as well as cocaine-induced sniffing behavior and tolerance to cocaine. The physiological role of endogenous OXT in acute morphine tolerance has also been demonstrated, since OXT antiserum (ICV) and OXT-receptor antagonist (injected into the basal forebrain structures) potentiated the development of morphine tolerance. Finally, we investigated the possible mechanisms of action of OXT on drug related behavior. Both morphine tolerance and dependence, and cocaine administration, increased dopamine utilization in the mesencephalon and in the nucleus accumbens, respectively. OXT treatment decreased the alphamethylparatyrosine-induced dopamine utilization in the mesencephalon and in the nucleus accumbens-septal complex. Chronic OXT treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum. In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine. This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction. 7. Contreras, M, Ceric, F, Torrealba, F. Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 2007;318:655-658. RESUMO: Addiction profoundly alters motivational circuits so that drugs become powerful reinforcers of behavior. The interoceptive system continuously updates homeostatic and emotional information that are important elements in motivational decisions. We tested the idea that interoceptive information is essential in drug craving and in the behavioral signs of malaise. We inactivated the primary interoceptive cortex in amphetamine-experienced rats, which prevented the urge to seek amphetamine in a place preference task. Interoceptive insula inactivation also blunted the signs of malaise induced by acute lithium administration. Drug-seeking and malaise both induced Fos expression, a marker of neuronal activation, in the insula. We conclude that the insular cortex is a key structure in the perception of bodily needs that provides direction to motivated behaviors. 24/09 Nicotina e Cafeína 1. Soderstrom, K., Qin, W., Williams, H., Taylor, D. A., & McMillen, B. A. (2007). Nicotine increases FosB expression within a subset of reward- and memory-related brain regions during both peri- and postadolescence. Psychopharmacology (Berl), 191, 891-897. RESUMO: INTRODUCTION: Periadolescent nicotine exposure is associated with increased consumption and rewarding properties of abused drugs. In the case of peribut not post-adolescent animals, these effects are persistent and last to adulthood, suggesting that early nicotine treatment may alter postnatal CNS development in ways that contribute to long-term problems with drug abuse. MATERIALS AND METHODS: To begin to identify brain regions that may be altered by developmental nicotine exposure, we have measured expression of a transcription factor, FosB, within a series of reward- and memoryrelated brain regions of Sprague-Dawley rats. RESULTS: FosB expression is known to acutely and cumulatively increase within a subset of brain regions, particularly nucleus accumbens, after exposure to many classes of abused drugs. Our results demonstrate that FosB is increased within nucleus accumbens and also the granule cell layer of hippocampal dentate gyrus after both peri- and post-adolescent nicotine exposure (0.4 mg kg(-1) day(-1) from days 34 to 43 and 60 to 69, respectively). In periadolescents, expression increases were detected 2 days after nicotine exposure, and persisted for weeks, through at least early adulthood at 80 days of age. In post-adolescents, expression increases persisted for at least 11 days to postnatal day 80. DISCUSSION: These findings demonstrate that nicotine treatment during both peri- and post-adolescence persistently alters activity of brain regions involved in reward and memory. CONCLUSION: Because this altered gene expression occurs after both peri- and postadolescent treatment, it cannot be directly responsible for increased consumption and rewarding properties of abused drugs previously established to be distinctly associated with periadolescent nicotine exposure. 2. Gallinat, J., Lang, U. E., Jacobsen, L. K., Bajbouj, M., Kalus, P., von Haebler, D., et al. (2007). Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T. J Clin Psychopharmacol, 27, 80-84. RESUMO: OBJECTIVE: In animals, nicotine, the primary psychoactive constituent of tobacco smoke, reduces neurogenesis and increases cell loss in both hippocampus and cortex. Accordingly, tobacco smoking has been linked to reduced performance on cognitive paradigms requiring attention and working memory in humans. However, few prior studies have tested for evidence of structural brain alterations in human tobacco smokers. In this study, proton magnetic resonance spectroscopy was used to assess the effects of chronic smoking on neuronal integrity of the hippocampus and anterior cingulate cortex (ACC). METHODS: Absolute concentrations of N-acetylaspartate, total choline (tCho), and total creatine were measured in the left hippocampus and ACC in 13 chronic tobacco smokers and 13 nonsmokers matched for age, sex, and education. RESULTS: The N-acetylaspartate concentration was significantly reduced in smokers relative to nonsmokers in the left hippocampus but not in the ACC. There were no group differences in the tCho and total creatine concentrations in either voxel. However, ACC tCho concentration was positively correlated with magnitude of lifetime exposure to tobacco smoke (pack-years). CONCLUSION: The results are consistent with prior observations of hippocampal neuronal damage in rodents receiving nicotine and working memory deficits in human tobacco smokers. The positive relationship between tCho and lifetime tobacco exposure suggests that a component of tobacco smoke, presumably nicotine, may increase cortical membrane turnover or modify cell density. Together, these results add to growing evidence that nicotine exerts neurotoxic effects in human brain, although an a priori nature of the findings cannot be ruled out. 3. Cohen, C., Perrault, G., Griebel, G., & Soubrie, P. (2005). Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology, 30, 145-155. RESUMO:Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drug-seeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drug-seeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotinerelated stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After selfadministration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to leverpress for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence. 4. Griffiths, R. R., & Vernotica, E. M. (2000). Is caffeine a flavoring agent in cola soft drinks? Arch Fam Med, 9, 727-734. RESUMO: BACKGROUND: Concern has been expressed about the nutrition and health impact of high rates of soft drink consumption. Caffeine is an added ingredient in approximately 70% of soft drinks consumed in the United States. The soft drink manufacturers' justification to regulatory agencies and the public for adding caffeine to soft drinks is that caffeine is a flavoring agent. OBJECTIVE: To examine the claim that caffeine plays an integral role in the flavor profile of soft drinks, by examining the effect of caffeine on the threshold for detection of flavor differences in cola beverages. DESIGN: Double-blind crossover study starting November 1998 and ending July 1999. SETTING: An academic research center. PARTICIPANTS: Twenty-five adult regular consumers of cola soft drinks. Based on a screening session, all were able to detect a flavor difference between cola containing sugar and diet cola. INTERVENTION: A sensitive version of a forced-choice flavor-detection procedure was used to evaluate the effects of a wide range of caffeine concentrations (range, 0.05-1.6 mg/mL) on the ability to detect flavor differences between caffeinated and caffeine-free cola beverages. Repeated tests permitted determination of significant detection at each concentration in individual subjects. MAIN OUTCOME MEASURES: Percentage of subjects significantly detecting a flavor difference and mean percentage of trials correct at each caffeine concentration. RESULTS: Detection of flavor differences increased as a function of caffeine concentration. At the 0.1-mg/mL concentration, which is the approximate concentration in the majority of cola soft drink products, 2 subjects (8%) significantly detected a flavor difference and the mean percentage correct (53%) was at chance levels. CONCLUSIONS: The finding that only 8% of a group of regular cola soft drink consumers could detect the effect of the caffeine concentration found in most cola soft drinks is at variance with the claim made by soft drink manufacturers that caffeine is added to soft drinks because it plays an integral role in the flavor profile. It is valuable for the general public, the medical community, and regulatory agencies to recognize that the high rates of consumption of caffeinated soft drinks more likely reflect the mood-altering and physical dependence-producing effects of caffeine as a central nervous system-active drug than its subtle effects as a flavoring agent. Arch Fam Med. 2000;9:727-734 5. Nehlig, A. (1999). Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev, 23, 563-576. RESUMO: Caffeine is the most widely used psychoactive substance and has been considered occasionally as a drug of abuse. The present paper reviews available data on caffeine dependence, tolerance, reinforcement and withdrawal. After sudden caffeine cessation, withdrawal symptoms develop in a small portion of the population but are moderate and transient. Tolerance to caffeine-induced stimulation of locomotor activity has been shown in animals. In humans, tolerance to some subjective effects of caffeine seems to occur, but most of the time complete tolerance to many effects of caffeine on the central nervous system does not occur. In animals, caffeine can act as a reinforcer, but only in a more limited range of conditions than with classical drugs of dependence. In humans, the reinforcing stimuli functions of caffeine are limited to low or rather moderate doses while high doses are usually avoided. The classical drugs of abuse lead to quite specific increases in cerebral functional activity and dopamine release in the shell of the nucleus accumbens, the key structure for reward, motivation and addiction. However, caffeine doses that reflect the daily human consumption, do not induce a release of dopamine in the shell of the nucleus accumbens but lead to a release of dopamine in the prefrontal cortex, which is consistent with caffeine reinforcing properties. Moreover, caffeine increases glucose utilization in the shell of the nucleus accumbens only at rather high doses that stimulate most brain structures, nonspecifically, and likely reflect the side effects linked to high caffeine ingestion. That dose is also 5-10-fold higher than the one necessary to stimulate the caudate nucleus, which mediates motor activity and the structures regulating the sleep-wake cycle, the two functions the most sensitive to caffeine. In conclusion, it appears that although caffeine fulfils some of the criteria for drug dependence and shares with amphetamines and cocaine a certain specificity of action on the cerebral dopaminergic system, the methylxanthine does not act on the dopaminergic structures related to reward, motivation and addiction 6. Svenningsson, P., Nomikos, G. G., & Fredholm, B. B. (1999). The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J Neurosci, 19, 4011-4022. RESUMO: We sought neurochemical correlates to the stimulatory action of caffeine in rats and to adaptations during development of tolerance. Acute intraperitoneal injections of caffeine (7.5 mg/kg) increased locomotion and NGFI-A mRNA, a marker of neuronal activity, in the hippocampal area CA1, but decreased NGFI-A mRNA in rostral striatum and nucleus accumbens. Rats that received caffeine (0.3 gm/l) in their drinking water for 14 d developed tolerance to the stimulatory effect of a challenge with caffeine (7.5 mg/kg) and responded with a less pronounced decrease of NGFI-A mRNA in rostral striatum and nucleus accumbens. Metabolism of caffeine to its active metabolites was increased in tolerant animals, but the total level of active metabolites in brain was not significantly altered. Thus, there are changes in caffeine metabolism after long-term caffeine treatment, but they cannot explain development of tolerance. Caffeine-tolerant animals had downregulated levels of adenosine A2A receptors and the corresponding mRNA in rostral parts of striatum, but an increased expression of adenosine A1 receptor mRNA in the lateral amygdala. No changes in mesencephalic tyrosine hydroxylase mRNA were found in caffeine-tolerant rats. Thus, we have identified neuronal pathways that are regulated by adenosine A1 and/or A2A receptors and are targets for the stimulatory action of caffeine. Furthermore, adaptive changes in gene expression in these brain areas were associated with the development of locomotor tolerance to caffeine. 7. Antoniou, K, Papadopoulou-Daifoti ,Z., Hyphantis, T., Papathanasiou, G., Bekris, E., Marselos, M., Panlilio, L., Müller, C,E,, Goldberg , S.R.e Ferré S (2005). A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors Psychopharmacology (Berl), 183(2):15462. RESUMO: RATIONALE: There is no consensus on the contribution of adenosine A(1) and A(2A) receptor blockade to motor-activating effects of caffeine. OBJECTIVE: Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A(1) and A(2A) receptor antagonists. METHODS: The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A(1) receptor agonist N (6)-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A(2A) receptor agonist 2-p-(2carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined. RESULTS: The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3. CONCLUSIONS: The results indicate a predominant role for A(1) receptors in the motoractivating effects of acutely administered caffeine. 8. DiFranza, JR. Hooked from the first cigarette. Scientific American 2008;298:82-87. RESUMO: New research has overturned the dogma that cigarette addiction takes years to develop. Studies of adolescent smokers show that symptoms of addiction, such as withdrawal, craving for cigarettes and failed attempts at quitting, can appear within the first weeks of smoking. To account for these findings, scientists have developed a new theory positing that the brain quickly develops adaptations that counter the effects of nicotine. These adaptations lead to withdrawal symptoms when the effects of nicotine wear off. The results highlight the importance of boosting government funding for antismoking campaigns, particularly those aimed at youngsters. 01/10 Estimulantes psicomotores 1. Childress, A. R., Mozley, P. D., McElgin, W., Fitzgerald, J., Reivich, M., & O'Brien, C. P. (1999). Limbic activation during cue-induced cocaine craving. Am J Psychiatry, 156, 11-18. RESUMO: OBJECTIVE: Since signals for cocaine induce limbic brain activation in animals and cocaine craving in humans, the objective of this study was to test whether limbic activation occurs during cue-induced craving in humans. METHOD: Using positron emission tomography, the researchers measured relative regional cerebral blood flow (CBF) in limbic and comparison brain regions of 14 detoxified male cocaine users and six cocaine-naive comparison subjects during exposure to both non-drug-related and cocaine-related videos and during resting baseline conditions. RESULTS: During the cocaine video, the cocaine users experienced craving and showed a pattern of increases in limbic (amygdala and anterior cingulate) CBF and decreases in basal ganglia CBF relative to their responses to the nondrug video. This pattern did not occur in the cocaine-naive comparison subjects, and the two groups did not differ in their responses in the comparison regions (i.e., the dorsolateral prefrontal cortex, cerebellum, thalamus, and visual cortex). CONCLUSIONS: These findings indicate that limbic activation is one component of cue-induced cocaine craving. Limbic activation may be similarly involved in appetitive craving for other drugs and for natural rewards 2. Ferrario, C. R., & Robinson, T. E. (2007). Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsychopharmacol, 17, 352-357. RESUMO: It has been proposed that some neuroadaptations that underlie behavioral sensitization may play a role in the development and persistence of addiction. However, whether or not sensitization facilitates the development of symptoms specific to addiction, such as the escalation of drug intake, is not known. We examined, therefore, the effect of pretreatment with a sensitizing regimen of amphetamine on the escalation of subsequent drug intake in rats given the opportunity to self-administer cocaine. Amphetamine pretreatment produced psychomotor sensitization and also accelerated the subsequent escalation of cocaine intake. This suggests that the neural circuits that are altered as a consequence of repeated amphetamine treatment, and the induction of sensitization, may overlap with those responsible for the development of some addiction-like behaviors 3. Shippenberg, T. S., Chefer, V. I., Zapata, A., & Heidbreder, C. A. (2001). Modulation of the behavioral and neurochemical effects of psychostimulants by kappa-opioid receptor systems. Ann N Y Acad Sci, 937, 5073. RESUMO:The repeated, intermittent use of cocaine and other drugs of abuse produces profound and often long-lasting alterations in behavior and brain chemistry. It has been suggested that these consequences of drug use play a critical role in drug craving and relapse to addiction. This article reviews the effects of psychostimulant administration on dopaminergic and excitatory amino acid neurotransmission in brain regions comprising the brain's motive circuit and provides evidence that the activation of endogenous κ-opioid receptor systems in these regions opposes the behavioral and neurochemical consequences of repeated drug use. The role of this opioid system in mediating alterations in mood and affect that occur during abstinence from repeated psychostimulant use are also discussed. 4. Weiss, F., Ciccocioppo, R., Parsons, L. H., Katner, S., Liu, X., Zorrilla, E. P., et al. (2001). Compulsive drugseeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci, 937, 126. RESUMO: The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5-HT transmission in the nucleus accumbens—neurochemical systems that are activated by cocaine and ethanol self-administration and deficient during withdrawal—as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli. The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans and confirms a significant role of learning factors in the longlasting addictive potential of cocaine. With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug-related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior. Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies. 5. Becker, J. B., Molenda, H., & Hummer, D. L. (2001). Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse. Ann N Y Acad Sci, 937, 172-187. RESUMO: When ovariectomized female rats receive estrogen, the response to the psychomotor stimulants amphetamine or cocaine is enhanced. Estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine release are also noted. Intact female rats exhibit a greater behavioral response to amphetamine on estrus than they do on other days of the cycle. Ovariectomy results in attenuation of amphetamine-induced behavior and the striatal dopamine response to amphetamine. Physiological doses of estrogen given to ovariectomized rats reinstate both of these responses to a level comparable to that in estrous females. Furthermore, a sex difference is noted, in that females tend to exhibit a greater behavioral response to the psychomotor stimulants, and estrogen enhances this sex difference. Repeated treatment with amphetamine or cocaine produces a progressive increase in behavioral responsiveness with subsequent drug administration, a process known as sensitization. In rodents, behavioral sensitization results in increases in both frequency and duration of psychomotor behaviors such as rotational behavior, stereotyped grooming, headbobs, and forelimb movements. Interestingly, females display greater sensitization of behaviors in response to psychomotor stimulants than do males. Previous research results are summarized, and new results are presented, demonstrating that estrogen selectively enhances components of behavior that exhibit sensitization in female rats. Results also indicate gender differences in sensitization independent of gonadal hormones, suggesting that the neural systems that undergo sensitization are sexually dimorphic. 6. Quinones-Jenab, V., Perrotti, L. I., Fabian, S. J., Chin, J., Russo, S. J., & Jenab, S. (2001). Endocrinological basis of sex differences in cocaine-induced behavioral responses. Ann N Y Acad Sci, 937, 140-171. RESUMO:Currently, 1.8 million Americans use cocaine, 30% of whom are females. Sex differences in the pattern of cocaine abuse may reside in neuroendocrinological modulations that affect the use of and/or dependence on cocaine. This review discusses sex differences in cocaine-induced behavioral and molecular alterations in the central nervous system, with emphasis on the role of endocrine responses in the neuronal modulations of this drug. Mechanisms and data supporting the role of the hypothalamic-gonadal axis in the modulation of cocaine-induced behavioral and molecular alterations are also provided. 7. McClung, C. A., & Nestler, E. J. (2003). Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci, 6, 1208-1215. RESUMO:FosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of FosB and the activator protein-1 (AP-1) antagonist cJun. However, unlike CREB, short-term and prolonged FosB induction had opposing effects on gene expression. Gene expression induced by short-term FosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged FosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly FosB dependent. These findings help define the molecular functions of CREB and FosB and identify clusters of genes that contribute to cocaine addiction. 8. Dunn, M. J., & Killcross, S. (2006). Differential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists. Psychopharmacology (Berl), 188, 183-192. RESUMO:Rationale Recent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks. Objective To establish the reversal potential of D1, D2 and 5-HT receptor antagonists acutely, and D1 and D2 receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance. Method A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli. Results d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D1 antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D2 antagonist eticlopride (Eti) and the antipsychotic haloperidol (Hal) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT1A antagonist WAY 100635 and the selective 5HT2A/C antagonist ritanserin. However, Eti and Hal did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, α-flupenthixol and Cloz). Conclusions These results suggest that D1 receptors are involved in tasks that require the use of conditional relationships and that D2 receptor antagonism can come to exert a similar influence after chronic treatment. 9. Ciccocioppo, R., Martin-Fardon, R., & Weiss, F. (2004). Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nature Neuroscience, 7, 495-496. RESUMO: Epidemiological data suggest that cocaine dependence emerges rapidly, and most cocaine addicts meet criteria for dependence within 1-3 years after onset of drug use. Here we show that in rats, environmental stimuli associated with a single cocaine selfadministration experience elicit strong cocaine-seeking that persists for up to one year. In contrast, conditioned stimuli that were associated with a highly palatable non-drug reinforcer elicited modest behavioral responses that extinguished within 3 months. 10. Mameli, M, Balland, B, Lujan, R, Luscher, C. Rapid synthesis and synaptic insertion of GluR2 for mGluRLTD in the ventral tegmental area. Science 2007;317:530-533. RESUMO: The activation of metabotropic glutamate receptors (mGluRs) leads to long-term depression (mGluR-LTD) at many synapses of the brain. The induction of mGluR-LTD is well characterized, whereas the mechanisms underlying its expression remain largely elusive. mGluR-LTD in the ventral tegmental area (VTA) efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. We show that mGluR-LTD is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid messenger RNA translation of GluR2. Regulated synthesis of GluR2 in the VTA is therefore required to reverse cocaine-induced synaptic plasticity. 11. Belin, D, Mar, AC, Dalley, JW, Robbins, TW, Everitt, BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science 2008;320:1352-1355. RESUMO: oth impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity predicts the development of addiction-like behavior in rats, including persistent or compulsive drug-taking in the face of aversive outcomes. This study shows experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, which provides insights into the genesis and neural mechanisms of drug addiction. 08/10 Álcool. Barbitúricos e benzodiazepínicos (Ansiedade) 1. Kalueff, A. V., Wheaton, M., & Murphy, D. L. (2007). What's wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression. Behav Brain Res. Jan 31; [Epub ahead of print] RESUMO: Stress plays a key role in pathogenesis of anxiety and depression. Animal models of these disorders are widely used in behavioral neuroscience to explore stress-evoked brain abnormalities, screen anxiolytic/antidepressant drugs and establish behavioral phenotypes of gene-targeted or transgenic animals. Here we discuss the current situation with these experimental models, and critically evaluate the state of the art in this field. Noting a deficit of fresh ideas and especially new paradigms for animal anxiety and depression models, we review existing challenges and outline important directions for further research in this field. 2. de Castro, P. C., Hoshino, A., Silva, J. C., & Mendes, F. R. (2007). Possible anxiolytic effect of two extracts of Passiflora quadrangularis L. in experimental models. Phytother Res. 2007 Feb 13; [Epub ahead of print] RESUMO:Several species of the genus Passiflora, known in Brazil as 'maracuja', have widespread use in folk medicine as sedatives and anxiolytics. The anxiolytic activities of aqueous and hydroalcohol extracts of Passiflora quadrangularis leaves were evaluated using the elevated plus-maze, open field and holeboard tests. The hydroalcohol extract presented results suggestive of anxiolytic activity in dosages around 100, 250 and 500 mg/kg, as expressed by elevation of the time spent on the open arms in the plus-maze; a decrease of freezing and an increase of deambulation and rearing in the open field test. The hydroalcohol extract showed results similar to diazepam on the holeboard. No positive results were found for the aqueous extract. Copyright (c) 2007 John Wiley & Sons, Ltd 3. Nemeroff, C. B. (2003). The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull, 37, 133-146. RESUMO:Mechanisms underlying the pathological characteristics of the various anxiety disorders have yet to be fully elucidated. One of the most widely accepted mediators known to play a central role in the pathophysiology of anxiety disorders is the g-aminobutyric acid (GABA) system. Evidence supporting the role of a dysfunctional GABA system has resulted from clinical experience with the benzodiazepines, as well as subsequent determination of mechanism of action, genetic engineering, and neuroimaging studies of the GABA receptor. The concatenation of results suggests a relative deficiency in GABA neurotransmission, which can be augmented by agents acting on different components of the GABA system. Agents such as the benzodiazepines, neuroactive steroids, and barbiturates act as allosteric modulators of the GABAA receptor; b-carboline and the barbiturates function as direct GABA agonists. Valproate, gabapentin, pregabalin, and vigabatrin increase brain GABA levels or neurotransmission at least in part by targeting the metabolic pathways of GABA. Tiagabine selectively increases synaptic GABA availability by blocking the reuptake of GABA via transporter inhibition. Evidence exists, to a greater or lesser extent, that all of these agents possess anxiolytic properties, as would be expected by their mechanisms of action. This article reviews the findings implicating the GABA system in the pathophysiology of anxiety disorders and describes the potential role of agents that modulate GABA neurotransmission in the treatment of these disorders. 4. Tambour, S., & Quertemont, E. (2007). Preclinical and clinical pharmacology of alcohol dependence. Fundam Clin Pharmacol, 21, 9-28. RESUMO:In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action 5. Nunez, M. J., Rivas, M., Riveiro, P., Suarez, J., Balboa, J., Nunez, L. A., et al. (2002). Effects of nefazodone on voluntary ethanol consumption induced by isolation stress in young and aged rats. Pharmacol Biochem Behav, 73, 689-696. RESUMO: Late-onset ethanol (EtOH) consumption is related to life and social stressors of aging. The stress system (hypothalamic-pituitary-adrenal, HPA, axis) coordinates the adaptive response of the organism to stressors, but age-related deficits in HPA function seem to be associated with disorders such as lateonset EtOH consumption, anxiety and depression. In the present study, we examined whether HPA dysfunction is associated with stress-related EtOH consumption in aged rats and whether the treatment with nefazodone hydrochloride, a phenylpiperazine antidepressant, partially reverses the adverse effects of isolation (ISOL) stress. The animals were offered two-bottle choice consumption of 0.2% saccharin and 10% EtOH/0.2% saccharin, and then exposed to 4 days of ISOL stress on an irregular, unpredictable schedule. ISOL stress-induced increases in corticosterone secretion and EtOH consumption both during and following the stress (recovery period) in aged rats. Nevertheless, this effect at the recovery period was not evident in young stressed rats. Nefazodone caused a significant decrease in plasma corticosterone levels and EtOH consumption. The attenuation of stress-induced corticosterone by nefazodone was correlated with reduced EtOH consumption. These findings link the effect of ISOL stress to the induction of voluntary EtOH consumption following the end of the stressor and the limitation of aged HPA to down-regulated corticosterone 6. Porrino, L. J., Williams-Hemby, L., Whitlow, C., Bowen, C., & Samson, H. H. (1998). Metabolic mapping of the effects of oral alcohol self-administration in rats. Alcohol Clin Exp Res, 22, 176-182. RESUMO: The functional effects of the voluntary consumption of ethanol in rats were investigated using the quantitative autoradiographic 2[14C]deoxyglucose method for measurement of rates of local cerebral glucose utilization. A modified sucrosesubstitution procedure was used to train three groups of Wistar rats to self-administer water, a 5% sucrose solution, or a 10% ethanol/5% sucrose solution in daily sessions. Once stable rates of consumption were established, the 2[14C]deoxyglucose method was applied immediately after completion of the final test session. Rats received a dose of ethanol equivalent to 0.5 g/kg (n = 6) on the day of the procedure or a comparable volume of sucrose solution (n = 6) or water (n = 5). Rates of local cerebral glucose utilization in rats that ingested water did not differ from those that rats consumed a 5% sucrose solution. In contrast, voluntary ethanol consumption produced a highly discrete pattern of changes in rates of glucose utilization. Ethanol ingestion increased cerebral metabolism, as compared with rates of metabolism in rats that consumed either water or sucrose in the rostral pole and shell of the nucleus accumbens, medial prefrontal cortex, lateral septum, basolateral and central nuclei of the amygdala, substantia nigra, and the ventral tegmental area. This pattern of alterations in functional activity is distinctly different from that observed when equivalent doses of ethanol are administered acutely, emphasizing the importance of selfadministration in determining the changes in glucose utilization. Furthermore, within the nucleus accumbens, glucose utilization was selectively augmented in the rostral pole and shell subterritories, whereas cerebral metabolism in the core was unaffected. Finally, these data demonstrate that it is the simultaneous activation of an interconnected network of limbic brain regions that serves as the substrate of the effects of voluntarily ingested ethanol. 7. Zironi, I., Burattini, C., Aicardi, G., & Janak, P. H. (2006). Context is a trigger for relapse to alcohol. Behav Brain Res, 167, 150-155. RESUMO: The environment in which alcohol consumption occurs may trigger later relapse in alcohol abusers. In this study, we tested whether an alcohol-associated environment would induce alcohol-seeking behavior. Male rats were trained to lever press for oral alcohol reinforcement in a distinctive context. Responding was then extinguished in a context with different olfactory, visual and tactile properties. Placement of the rats back into the original context in which they self-administered alcohol induced, in the absence of alcohol availability, a significant increase in lever press responding on the alcohol lever as compared to extinction levels of responding. The ability of the alcohol context to support alcohol-seeking behavior was maintained over 3 weeks, with no significant diminution. A second group of rats was trained to lever press for sucrose reinforcement; this group also demonstrated context-dependent reinstatement, although the degree of reinstatement decreased over repeated tests, returning to extinction values after 3 weeks. These findings indicate that contextual conditioning has a long-term impact on ethanol-seeking behavior after ethanol withdrawal. This animal model may be useful to study the neural mechanisms underlying relapse induced by ethanol-associated contexts in humans. 8. Wilson, A. W., Neill, J. C., & Costall, B. (1998). An investigation into the effects of 5-HT agonists and receptor antagonists on ethanol self-administration in the rat. Alcohol, 16, 249-270. RESUMO: Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague-Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. dFenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol selfadministration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT1A, 5-HT1B, and 5-HT2 receptors reduced ethanol intake and reinforced behaviour in an operant paradigm. 15/10 Antidepressivos (Depressão; TOC; pânico; dor). 1. Lowry, CA, Hollis, JH, de Vries, A, Pan, B, Brunet, LR, Hunt, JR, Paton, JF, van Kampen, E, Knight, DM, Evans, AK, Rook, GA, Lightman, SL. Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience 2007;146:756-772. RESUMO: Peripheral immune activation can have profound physiological and behavioral effects including induction of fever and sickness behavior. One mechanism through which immune activation or immunomodulation may affect physiology and behavior is via actions on brainstem neuromodulatory systems, such as serotonergic systems. We have found that peripheral immune activation with antigens derived from the nonpathogenic, saprophytic bacterium, Mycobacterium vaccae, activated a specific subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus (DRI) of mice, as measured by quantification of c-Fos expression following intratracheal (12 h) or s.c. (6 h) administration of heat-killed, ultrasonically disrupted M. vaccae, or heat-killed, intact M. vaccae, respectively. These effects were apparent after immune activation by M. vaccae or its components but not by ovalbumin, which induces a qualitatively different immune response. The effects of immune activation were associated with increases in serotonin metabolism within the ventromedial prefrontal cortex, consistent with an effect of immune activation on mesolimbocortical serotonergic systems. The effects of M. vaccae administration on serotonergic systems were temporally associated with reductions in immobility in the forced swim test, consistent with the hypothesis that the stimulation of mesolimbocortical serotonergic systems by peripheral immune activation alters stress-related emotional behavior. These findings suggest that the immune-responsive subpopulation of serotonergic neurons in the DRI is likely to play an important role in the neural mechanisms underlying regulation of the physiological and pathophysiological responses to both acute and chronic immune activation, including regulation of mood during health and disease states. Together with previous studies, these findings also raise the possibility that immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors. Consequently, selective activation of specific subsets of serotonergic neurons may have distinct behavioral outcomes. 2. Katz, M. M., Tekell, J. L., Bowden, C. L., Brannan, S., Houston, J. P., Berman, N., et al. (2004). Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology, 29, 566-579. ABSTRACT: This study was aimed at resolving the time course of clinical action of antidepressants (ADs) and the type of early behavioral changes that precede recovery in treatmentresponsive depressed patients. The first goal was to identify, during the first 2 weeks of treatment, the onset of clinical actions of the selective serotonin reuptake inhibitor (SSRI), paroxetine, and the selective noradrenergic reuptake inhibitor, desipramine (DMI). The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients. The design was a randomized, parallel group, placebo-controlled, double-blind study for 6 weeks of treatment following a 1-week washout period. The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity. The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days, averaged 13 days for paroxetine, and was 16-42 days for placebo. Furthermore, as hypothesized, the different types of ADs initially impacted different behavioral aspects of the disorder. After 1 week of treatment, DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo, and this difference persisted at the second week of treatment. Early improvement in depressed mood-motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not. Paroxetine initially reduced anxiety more in responders than in nonresponders, and by the second week, significantly improved depressed mood and distressed expression in responders to a greater extent. Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement. Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs, results that could eventually be applied directly to clinical practice. 3. Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci, 22, 3251-3261. RESUMO: Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment. 4. Cryan, J. F., Markou, A., & Lucki, I. (2002). Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci, 23, 238-245. RESUMO: Animal models are indispensable tools in the search to identify new antidepressant drugs and to provide insights into the neuropathology that underlies the idiopathic disease state of depression. As new targets are developed, both serendipitously and through hypothesis-driven research, existing animal paradigms are being modified and new tests are being developed to detect antidepressant actions of compounds acting on a broad range of neural and genetic targets. This review focuses on recent findings regarding some of the most widely employed animal models used currently to predict antidepressant potential. Emphasis is placed on recent modifications to such paradigms that have increased their utility and reliability. Furthermore, some key issues that need to be addressed for future discovery of novel antidepressant agents are examined, and the available data on genetically altered mice that might lead to the discovery of novel targets for antidepressant action are collated. 5. Petty, F., Davis, L. L., Kabel, D., & Kramer, G. L. (1996). Serotonin dysfunction disorders: a behavioral neurochemistry perspective. J Clin Psychiatry, 57 Suppl 8, 11-16. RESUMO: The spectrum of efficacy of the serotonin selective reuptake inhibitor (SSRI) antidepressant drugs continues to expand. In fact, no psychiatric syndrome seems to worsen with these agents, and few studies fail to demonstrate clinical improvement in some patients, regardless of any nosologic nicety, such as precise DSM diagnosis. This suggests that the biological rubric of psychopathology is dimensional rather than categorical. New research using in vivo microdialysis shows differences in neurochemistry among SSRIs, wherein fluoxetine blocks reuptake of dopamine and norepinephrine, as well as serotonin, in medial prefrontal cortex, and fluvoxamine has a relatively more selective neurochemical profile. In the animal model of learned helplessness, which is a biobehavioral model for stress-induced anxiety causing depression, the SSRIs including fluvoxamine prevent helplessness. From these and other data, a neurotransmitter balance theory of biopsychopathology is formulated. In this hypothetical construct, dopamine, norepinephrine, and GABA modulate thought, anxiety, and mood, respectively. Serotonin is a stabilizing agent, which assists in returning the mind to its homeostatic setpoint 6. Gorman, J. M., & Kent, J. M. (1999). SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry, 60 Suppl 4, 33-38; discussion 39. RESUMO: Originally studied and introduced for the treatment of depression, the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have proven effective for a broad range of psychiatric illnesses, including several anxiety disorders, bulimia, and dysthymia. These drugs have in common important effects on the serotonergic (5-HT) neurotransmission system, which is involved in mediating a substantial number of important functions, including mood, aggression, sexual behavior, and pain. In addition, some of the new antidepressants, like venlafaxine/venlafaxine XR, also have effects on the noradrenergic neurotransmission system, which also appears important in mood and anxiety disorders. These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in addition to being the usual first-line treatments for major depression, they are also first-line for panic disorder, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and bulimia. They may also be the best medication treatments for dysthymia and generalized anxiety disorder. Further advances in psychopharmacology will be driven by discoveries from brain imaging and molecular biological research. 7. Beasley, C. M., Masica, D. N., & Potvin, J. H. (1992). Fluoxetine: a review of receptor and functional effects and their clinical implications. Psychopharmacology (Berl), 107, 1-10. RESUMO: Downregulation of serotonin 5-HT1 receptors is the most frequently reported central nervous system neural effect of subchronic exposure to fluoxetine in rodents. However, downregulation of these receptors has not been universally demonstrated. Effects of subchronic exposure on 5-HT2 receptors are mixed. Fluoxetine exposure appears to have no effect on cholinergic muscarinic receptors. Effects on beta-adrenergic receptors are controversial, as only one laboratory has reported downregulation. The majority of studies have failed to show an effect on beta-adrenergic-receptor-stimulated cAMP generation. Electrophysiologic studies support the concept that fluoxetine facilitates net serotonergic transmission through downregulation of presynaptic inhibitory autoreceptors. Data suggest that its subchronic specificity and selectivity distinguish fluoxetine from members of other classes of available antidepressants, making it a distinct therapeutic option. 8. Carrol D'Sa, Ronald S Duman (2002) Antidepressants and neuroplasticity Bipolar Disorders 4 , 183–194. RESUMO: Objective: We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs. Methods: We review results from various clinical and basic research studies. Results: Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants upregulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response elementbinding protein (CREB) and the neurotrophin, brain derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants. Conclusions: These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival. 9. De Vry, J., Maurel, S., Schreiber, R., de Beun, R., & Jentzsch, K. R. (1999). Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism. Eur Neuropsychopharmacol, 9, 461-468. RESUMO: Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John's wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. In addition, hypericum extracts, as well as standard antidepressants such as the tricyclic, impramine, and the selective serotonin reuptake inhibitor, fluoxetine, have been reported to be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients. It was the aim of the present study to compare the effects of hypericum extracts with those of imipramine and fluoxetine in the rat forced swimming test (RFST), a model of depression, as well as in cAA rats, a genetic model of alcoholism. In the RFST, triple i.p. administration of imipramine (3-30 mg/kg) and fluoxetine (3-30 mg/kg) induced a dose-dependent reduction in immobility: the minimal effective dose (MED) being 30 and 10 mg/kg, and the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. In this test, the hypericum extracts Ze 117 (Remotiv) and LI 160 (Jarsin) also induced a statistically significant reduction of immobility when administered under the same application schedule (5-40 mg/kg, i.p., triple application). In the case of the hypericum extracts the dose-response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively. Interestingly, the anti-immobility effects tended to be more pronounced after subacute (1 week, B.I.D.) treatment with 10 mg/kg of imipramine, fluoxetine, or Ze 117, as compared with acute treatment. This phenomenon is in accordance with clinical experience and suggests that repeated treatment is required for full development of antidepressive effects. In the alcohol-preferring cAA rats, acute i.p. administration of imipramine (3-30 mg/kg), fluoxetine (1-10 mg/kg) and Ze 117 (10-40 mg/kg) dose-dependently reduced alcohol intake in a 12-h limited access two-bottle [ethanol 10% (v/v) versus water] choice procedure: with MED values of 30, 5 and 20 mg/kg, respectively. The anti-alcohol effects of fluoxetine and Ze 1-17 appeared to be specific, as reductions in alcohol intake coincided with reductions in alcohol preference. The present study suggests that hypericum extracts have antidepressant-like properties which resemble those of clinically established antidepressants, and that Remotiv may be an interesting adjunct for the treatment of alcoholism 10. Shumake, J., Barrett, D., & Gonzalez-Lima, F. (2005). Behavioral characteristics of rats predisposed to learned helplessness: reduced reward sensitivity, increased novelty seeking, and persistent fear memories. Behav Brain Res, 164, 222-230. RESUMO: The congenitally helpless rat strain, which was selectively bred for increased susceptibility to learned helplessness, may model the predisposition to affective disorders, including depression and post-traumatic stress disorder. Other than the selected trait, the behavior of this strain is not well characterized. In this study, we assessed congenitally helpless rats on several behavioral tests. First, we assessed reward sensitivity by measuring their consumption of a 5% sucrose solution. Next, we assessed exploratory behavior and fearfulness in both a novel and familiar open field, and in a light-dark test. Finally, we assessed fear conditioning by exposing the animals to 4 tone-shock pairs on 1 day (acquisition) and then presenting 60 tones over the next 2 days (extinction). Compared to normal Sprague-Dawley controls, congenitally helpless rats showed less consumption of the sucrose solution and more exploratory behavior in the novel, but not the familiar, open fields. They also showed less fearfulness in the light-dark test, but more conditioned freezing to the tone predicting shock. Moreover, this freezing was resistant to extinction; congenitally helpless rats not only failed to show a fear decrement during extinction, but actually showed increased fear, a phenomenon termed "paradoxical enhancement." Thus, congenitally helpless rats appear to have a behavioral phenotype characterized by reduced sensitivity to reward, increased drive to explore novel environments, and increased propensity to form and maintain fear-associated memories. This behavioral phenotype is discussed as resembling the personality of humans vulnerable to post-traumatic stress disorder. 11. Zhou, Z, Zhen, J, Karpowich, NK, Goetz, RM, Law, CJ, Reith, ME, Wang, DN. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 2007;317:1390-1393.RESUMO: Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters. 12. Maya Vetencourt, JF, Sale, A, Viegi, A, Baroncelli, L, De Pasquale, R, O'Leary, OF, Castren, E, Maffei, L. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 2008;320:385-388. RESUMO: We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders. 22/10 Opiáceos (Dor) 1. Shi, J., Liu, Y. L., Fang, Y. X., Xu, G. Z., Zhai, H. F., & Lu, L. (2006). Traditional Chinese medicine in treatment of opiate addiction. Acta Pharmacol Sin, 27, 1303-1308. RESUMO: Traditional Chinese medicine (TCM) includes Chinese medicine and acupuncture. Chinese medicine consists of natural products including plants, animals and minerals. TCM has been practiced in China for more than 2000 years, and for the past 200 years has been used in treatment of drug addiction. Ten Chinese medicines for the treatment of opiate addiction have been approved by the Chinese State Food and Drug Administration (SFDA), and at least 6 are in clinical trials. The general therapeutic principle of Chinese medicine developed was based on its unique theory of " reinforcing healthy Qi and resolving and removing effects of toxicity". Acupuncture, another essential part of TCM, which was developed based on the principle that " functions of the human body are controlled by the ' Jing-Luo' and 'Qi-Xue'system" , has been used not only in China, but also in Europe, the USA and other countries, for controlling opiate addiction. There are some advantages in using TCM for opiate detoxification, including less harmful side effects, high safety and ideal effects in the inhibition of protracted withdrawal symptoms and relapse. Co-administration of TCM with modern medicine shows some synergistic effects in detoxification. Many TCM for detoxification also have efficacy in the rehabilitation of abnormal body functions induced by chronic drug use, including improving immune function, increasing working memory and preventing neurological disorder. Given that TCM is effective in the prevention of relapse and causes fewer side effects, it may be used widely in the treatment of opiate addiction 2. Ersche, K. D., Fletcher, P. C., Roiser, J. P., Fryer, T. D., London, M., Robbins, T. W., et al. (2006). Differences in orbitofrontal activation during decision-making between methadone-maintained opiate users, heroin users and healthy volunteers. Psychopharmacology (Berl), 188, 364-373. RESUMO: OBJECTIVE: Previously, we reported that opiate users enrolled in methadone treatment made 'risky' choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials. METHODS: We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous [Formula: see text] positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin. RESULTS: We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to 'play risky'. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to 'play safe'. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. 'Playing safe' following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users. CONCLUSION: Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used 3. Kiyatkin, E. A., & Rebec, G. V. (2001). Impulse activity of ventral tegmental area neurons during heroin selfadministration in rats. Neuroscience, 102, 565-580. RESUMO: To assess the pattern of mesocorticolimbic dopamine activity associated with drug-seeking and drug-taking behavior, we recorded impulse activity of ventral tegmental area neurons during intravenous heroin self-administration in trained rats. Although these neurons had considerable variability, two major groups-units with triphasic long-duration spikes and biphasic short-duration spikes-were identified. Relative to a slow and irregular basal activity of long-spike units, the first self-administration of each session was preceded by a phasic neuronal activation and followed by a more sustained drug-induced activation that reached a maximum at the time of the second self-injection. After each subsequent heroin selfinjection, the discharge rate transiently decreased, correlating with the blockade of preceding motor activation and the appearance of freezing, but slowly and gradually increased again in parallel with searching behavior, reaching a maximum at the time of the next self-injection. Passive drug injections in either drug-naive, freely moving or drugexperienced, anesthetized rats caused much smaller, tonic increases in activity of long-spike units; these monophasic increases changed into biphasic responses with repeated injections. Although short-spike units had highly varying discharge rate and showed phasic activation during movement, during heroin self-injections they generally mimicked the activity pattern seen in long-spike units. Our results indicate that in behaving animals indirect "identification" of dopamine cells based on their distinctive electrophysiological features is more complex than in vitro and in anesthetized preparations. With respect to long-spike units, a candidate group of presumed dopamine neurons, our data agree with the view that mesocorticolimbic dopamine activation is important for the activational and/or motivational aspects of heroin-taking behavior and suggest the role of an abrupt termination of dopamine activation for drug reinforcement (reward). Although the neurochemical nature of long- and short-spike units is obviously different, similar changes in their activity may indicate that they are regulated by similar afferent inputs and that these inputs change similarly during drug-taking behavior 4. Shane Darke, Deborah Zador (1996) Fatal heroin 'overdose': a review. Addiction 91 (12), 1765–1772. RESUMO: The current paper examines critically the literature on deaths attributed to heroin overdose, and examines the characteristics and circumstances of such deaths. In particular, the dominance of the widely held belief that heroin-related fatalities are a consequence of overdose is challenged. Deaths attributed to overdose represented in the literature are typically older, heroin-dependent males not in drug treatment at the time of death. Fatalities involving only heroin appear to form a minority of overdose occasions, the presence of other drugs primarily central nervous system depressants such as alcohol and benzodiazepines being commonly detected at autopsy. Furthermore, deaths attributed to overdose are likely to have morphine levels no higher than those who survive, or heroin users who die from other causes. It is concluded that the term overdose is, in many cases, a misleading term, since it implies the same mechanism of death in all cases, an implication that is neither clinically useful nor consistent with published data. Implications for the prevention of heroin-related deaths are discussed. 5. Olive MF, Koenig HN, Nannini MA, Hodge CW (2001) Stimulation of endorphin neurotransmission in the nucleus accumbens by ethanol, cocaine, and amphetamine. J Neurosci 21:RC184 RESUMO: Numerous studies have emonstrated that drugs of abuse activate the mesolimbic dopamine reward pathway, and it is widely held that this activation contributes to the motivational and positive reinforcing properties of these substances. However, there is evidence that endogenous opioid systems within this brain reward circuit also play a role in drug reinforcement and drug-seeking behavior. Using microdialysis in freely moving rats, we sought to determine whether various drugs of abuse (i.e., ethanol, cocaine, D-amphetamine, and nicotine) would increase neurotransmission of endogenous opioid peptides (i.e., endorphins) in the nucleus accumbens. Drugs were administered intraperitoneally twice at 3 h intervals, and the endorphin content of microdialysates was analyzed by a solid-phase radioimmunoassay. Acute administration of ethanol, cocaine, and D-amphetamine transiently elevated extracellular levels of endorphins in the nucleus accumbens, whereas nicotine and saline were without effect. We hypothesize that this drug-induced release of endorphins may contribute to the positive reinforcing and motivating properties of ethanol and psychostimulants 6. Kenny, P. J., Chen, S. A., Kitamura, O., Markou, A., & Koob, G. F. (2006). Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci, 26, 5894-5900. RESUMO: Aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via classical conditioning processes. Nevertheless, the significance of conditioned withdrawal effects in motivating drug intake remains largely unexplored. Here, we investigated the effects of conditioned withdrawal in modulating heroin consumption and brain reward sensitivity in rats. Rats intravenously self-administered heroin (20 microg/infusion) during 0 h (control), 1 h (nondependent), or 23 h (dependent) sessions and had daily intracranial self-stimulation (ICSS) thresholds assessed. ICSS thresholds remained stable and unaltered in control rats. In nondependent rats, heroin selfadministration induced a transient activation of reward systems, reflected in lowering of ICSS thresholds. In dependent rats, heroin intake escalated across sessions and was associated with a gradual decrease in reward sensitivity, reflected in progressively elevated ICSS thresholds. Thus, as dependence develops, heroin may be consumed not only for its acute reward-facilitating effects, but also to counter persistent deficits in reward sensitivity. In nondependent rats, the opioid receptor antagonist naloxone (30 microg/kg) increased heroin consumption and reversed heroin-induced lowering of ICSS thresholds, effects resistant to classical conditioning. In contrast, in dependent rats naloxone (30 microg/kg) increased heroin consumption and also elevated ICSS thresholds above their already elevated baseline levels (i.e., precipitated withdrawal). Most importantly, stimuli repeatedly paired with naloxone-precipitated withdrawal provoked heroin consumption and elevated ICSS thresholds in dependent rats. Thus, conditioned stimuli predicting the onset of heroin withdrawal, and hence the reward deficits coupled with this state, may play a critical role in provoking craving and relapse in human opiate addicts. 7. Benedetti, F, Mayberg, HS, Wager, TD, Stohler, CS, Zubieta, JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25:10390-10402. RESUMO: Any medical treatment is surrounded by a psychosocial context that affects the therapeutic outcome. If we want to study this psychosocial context, we need to eliminate the specific action of a therapy and to simulate a context that is similar in all respects to that of a real treatment. To do this, a sham treatment (the placebo) is given, but the patient believes it is effective and expects a clinical improvement. The placebo effect, or response, is the outcome after the sham treatment. The placebo effect is a psychobiological phenomenon that can be attributable to different mechanisms, including expectation of clinical improvement and pavlovian conditioning. Thus, we have to look for different mechanisms in different conditions, because there is not a single placebo effect but many. So far, most of the neurobiological mechanisms underlying this complex phenomenon have been studied in the field of pain and analgesia, although recent investigations have successfully been performed in the immune system, motor disorders, and depression. Overall, the placebo effect appears to be a very good model to understand how a complex mental activity, such as expectancy, interacts with different neuronal systems (Colloca and Benedetti, 2005; Finniss and Benedetti, 2005)….. 29/10 Antipsicóticos (Esquizofrenia) 1. Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., et al. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med, 353, 1209-1223. RESUMO: Background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. Methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. Conclusions The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism 2. Arnt, j and Skarsfeldt,T (1998) Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence. Neuropsychopharmacology 18, 63-101.RESUMO: the pharmacological properties of the novel antipsychotic drugs (APDs) risperidone, sertindole, olanzapine, quetiapine, ziprasidone, remoxipride, and amperozide are reviewed and compared with haloperidol and clozapine. Focus is made on their receptor profiles, their effects in animal models used for evaluation of antipsychotic activity, and extrapyramidal side effects (EPS). In addition, the contrasting actions of these compounds on animal models of cognition, anxiety, and depression are briefly reviewed. The available evidence indicates that novel APDs and clozapine can be differentiated from haloperidol, particularly in models of EPS and cognitive side effects. However, among the group of novel APDs there are many individual differences in models reflecting limbic versus striatal inhibition of dopamine function: clozapine and sertindole show the largest limbic selectivity, followed by quetiapine, ziprasidone, olanzapine and remoxipride, whereas risperidone in many respects has a profile that resembles haloperidol. To date, the results of clinical studies have confirmed the predictions of lower incidence or absence of EPS after administration of novel APDs in doses which demonstrate antipsychotic efficacy. 3. Barrett, J. E. (1982). Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli. Psychopharmacology (Berl), 77, 1-6. RESUMO: The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001-0.03 mg/kg), haloperidol (0.001-0.01 mg/kg), molindone (0.001-0.03 mg/kg) and thiothixene (0.001-0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01-1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule. 4. Williams, J. H., Wellman, N. A., Geaney, D. P., Cowen, P. J., Feldon, J., & Rawlins, J. N. (1998). Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment. Br J Psychiatry, 172, 243-249. RESUMO: Background People with schizophrenia show impaired attention. This could result from reduced latent inhibition (a measure of ability to filter out irrelevant stimuli). Previous studies have found reduced auditory latent inhibition in people with acute schizophrenia: we tested whether this results from psychosis or from drug treatment. Method We measured auditory latent inhibition in two studies. One compared antipsychotic-naive people with acute schizophrenia with patients within two weeks of starting antipsychotic treatment The second compared healthy volunteers given either saline or 1.0 mg haloperidol, intravenously Results Latent inhibition was absent in treated patients, but was clearly present in patients who were naive to antipsychotics. Latent inhibition was absent in volunteers given haloperidol, but was clearly present in those given saline. Conclusions The reduced auditory latent inhibition seen in acute schizophrenia is more plausibly due to antipsychotic treatment than to the disorder. Unless neuropsychological models ofschizophrenia incorporate evidence from drug-free patients and drugtreated healthy controls, they may be invalid. 5. Alves, C. R., & Silva, M. T. (2001). Facilitation of latent inhibition by the atypical antipsychotic risperidone. Pharmacol Biochem Behav, 68, 503-506. RESUMO: The action of the atypical antipsychotic risperidone on latent inhibition (LI), an animal model of schizophrenia, was investigated. The parameters of the procedure were set at values insufficient to generate LI in control rats. On the first day, rats administered 0.5, 1.0, or 2.0 mg/kg ip risperidone or vehicle were preexposed (PE) to 10 tone presentations. On the second day, they were again injected with drug or vehicle and then submitted to two conditioned stimulus (CS; tone)-unconditioned stimulus (US; shock) pairings. On the third day, suppression of their drinking response under the CS was measured. Nonpreexposed (NPE) animals were submitted to the same procedure except for the tone preexposure. On the suppression test, LI was not observed in control rats as well as in animals given 0.5 mg/kg risperidone. Animals given 1.0 and 2.0 mg risperidone, however, displayed an LI effect. The facilitation of LI by risperidone gives additional support to the LI paradigm as an animal model of schizophrenia. 6. Dunn, L. A., Atwater, G. E., & Kilts, C. D. (1993). Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action. Psychopharmacology (Berl), 112, 315-323. RESUMO:Latent inhibition (L1) of a conditioned emotional response (CER) has been proposed as a quantitative measure of selective attention. We have assessed the parallels of the pharmacology of L1 in rats with the clinical pharmacology of schizophrenia. Drug and vehicle treated rats were divided into groups and preexposed 20 times to cage illumination as a CS, or not preexposed. All groups were conditioned with 2 CS-footshock pairings. The following day CER, as measured by interruption of drinking in response to CS presentation, was recorded. L1 was observed as a decreased CER in preexposed relative to non-preexposed animals. L1 was enhanced by haloperidol 0.3 mg/kg after 7 or 14 daily treatments, but not after a single acute dose 05/11 Alucinógenos. Cannabis. 1. Riba, J., Romero, S., Grasa, E., Mena, E., Carrio, I., & Barbanoj, M. J. (2006). Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology (Berl), 186, 93-98. RESUMO: RATIONALE: Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. OBJECTIVES: To investigate the effects of ayahuasca administration on regional cerebral blood flow. METHODS: Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100-110 min after drug administration by means of single photon emission tomography (SPECT). RESULTS: Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. CONCLUSIONS: The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes 2. Check, E. (2004). Psychedelic drugs: the ups and downs of ecstasy. Nature, 429, 126-128. 3. Nicoll, R. A., & Alger, B. E. (2004). The brain's own marijuana. Sci Am, 291, 68-75. 4. Tanda, G., & Goldberg, S. R. (2003). Cannabinoids: reward, dependence, and underlying neurochemical mechanisms--a review of recent preclinical data. Psychopharmacology (Berl), 169, 115-134. RESUMO: BACKGROUND AND RATIONALE: Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, delta9-tetrahydrocannabinol (THC). OBJECTIVES: The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids. RESULTS AND CONCLUSIONS: Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability. 5. De Vries, T. J., Homberg, J. R., Binnekade, R., Raaso, H., & Schoffelmeer, A. N. (2003). Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl), 168, 164-169. RESUMO: RATIONALE: Recently, we provided evidence for a cannabinoid mechanism in relapse to cocaine seeking in rats. There is also increasing evidence for functional crosstalk between cannabinoid and opioid systems in several physiological processes. OBJECTIVES: This study was designed to evaluate whether the cannabinoid system plays a role in mediating the reinforcing and motivational effects of heroin and heroin-paired stimuli. METHODS: Male Wistar rats were trained to self-administer heroin (50 microg/kg per infusion) on fixed (FR5) or progressive ratio schedules of reinforcement in the presence of a discriminative and discrete heroin-associated cue. The selective cannabinoid CB1 antagonist SR141716A was given 30 min before the session to determine its effect on responding for heroin. Separate groups of rats were subjected to extinction training during which heroin-associated cues were absent and no heroin was delivered. During subsequent reinstatement tests, the effects of the cannabinoid agonist HU210 and the antagonist SR141716A on reinstatement of heroin seeking were evaluated. RESULTS: The cannabinoid antagonist dosedependently reduced responding for heroin on the FR5 schedule and to a greater extent on the progressive ratio schedule. HU210 (20 microg/kg) reinstated heroin seeking behaviour following a 2-week extinction period, whereas SR141716A dose-dependently attenuated heroin seeking that was provoked by a priming injection of heroin (0.25 mg/kg) and heroin seeking that was triggered by re-exposure to heroin paired stimuli. CONCLUSIONS: The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction. 6. Rubino, T., Sala, M., Vigano, D., Braida, D., Castiglioni, C., Limonta, V., et al. (2007). Cellular Mechanisms Underlying the Anxiolytic Effect of Low Doses of Peripheral Delta(9)-Tetrahydrocannabinol in Rats. Neuropsychopharmacology advance online publication 7 February 2007. RESUMO: We investigated the effect of low doses of intraperitoneal Delta(9)-tetrahydrocannabinol (THC) on anxiety behavior in rats using the elevated plus maze (EPM). An anxiolytic effect was obtained in a range of doses between 0.075 and 1.5 mg/kg, the 0.75 dose being the most effective. Pretreatment with the CB1 receptor antagonist AM251 fully reversed THC's effect, suggesting CB1 receptors were involved. In order to elucidate the neuroanatomical substrates underlying the effect of the maximal effective dose of THC, we investigated cFos expression in anxiety-related brain regions (prefrontal cortex, nucleus accumbens, amygdala, and hippocampus) of rats exposed to the EPM. THC significantly lowered the amount of cFos in prefrontal cortex and amygdala without affecting the other cerebral areas. As there is increasing evidence that CREB function regulates anxiety-like behavior in rats, the second biochemical parameter we measured was phosphorylated CREB in the same brain areas. Rats treated with THC showed a significant increase in CREB activation in the prefrontal cortex and hippocampus. In the prefrontal cortex this increased activation was linked to an increase in ERK activation, whereas in the hippocampus there was a drop in the activity of CAMKII, a kinase with inhibitory effect on CREB activation. All these effects were reversed by AM251 pretreatment, suggesting that stimulation of CB1 receptors is fundamental for triggering the biochemical events. Our results suggest that the stimulation of these receptors in the prefrontal cortex, amygdala, and hippocampus with the subsequent activation of different signaling pathways is the first event underlying the effects of cannabinoids on anxious states. 7. Stone, A. L., O'Brien M, S., De La Torre, A., & Anthony, J. C. (2007). Who is becoming hallucinogen dependent soon after hallucinogen use starts? Drug Alcohol Depend, 87, 153-163. RESUMO: This study, based upon epidemiological survey data from the United States (U.S.) National Household Surveys on Drug Abuse (NHSDA) from 2000 to 2001, presents new estimates for the risk of developing a hallucinogen dependence syndrome within 24 months after first use of any hallucinogen (median elapsed time approximately 12 months). Subgroup variations in risk of becoming hallucinogen dependent also are explored. Estimates are derived from the NHSDA representative samples of non-institutionalized U.S. residents ages 12 and older (n=114,241). A total of 2035 respondents had used hallucinogens for the first time within 24 months prior to assessment. An estimated 23% of these recent-onset hallucinogen users had become dependent on hallucinogens, according to the NHSDA DSM-IV computerized diagnostic algorithm. Controlling for sociodemographic and other drug use covariates, very early first use of hallucinogens (age 10-11 years) is associated with increased risk of hallucinogen dependence (p<0.01). Excess risk of developing hallucinogen dependence was found in association with recent-onset use of mescaline; excess risk also was found for recent-onset users of ecstasy and of PCP. This study's evidence is consistent with prior evidence on a tangible but quite infrequent dependence syndrome soon after the start of hallucinogen use; it offers leads that can be confirmed or disconfirmed in future investigations. 8. Almeida, SP; Silva MTA. (2003) Ecstasy (MDMA): Effects and patterns of use reported by users in São Paulo. Revista Brasileira de Psiquiatria, 25(1):11-7. RESUMO: OBJECTIVE: As there are no studies about the use of ecstasy in Brazil, our aim was to identify the effects and patterns of use of this substance among users in the city of São Paulo. METHODS: Subjects were recruited through the snowball technique. Fifty-two subjects of both genders who had been using ecstasy frequently and recently were interviewed. The instrument was a self-reported and anonymous questionnaire. RESULTS: The sample's mean age was 24 years, mostly composed by single, college graduated middle-class subjects. Among the interviewed users, 61.6% used ecstasy at least once per week and 50% of them took one pill per episode of use and 46% more than one. Drug taking was usually performed in company of several people (63%) in contexts related to night leisure, such as rave parties (78.8%), dancing clubs (69.2%) and parties (53.8%). Ecstasy pills were mainly purchased from friends or acquaintances in order to favor a dancing mood in those places. Most subjects used ecstasy associated to other psychoactive drugs (93.3%), mainly Cannabis, followed by tobacco and LSD. The effects attributed to ecstasy were mainly positive. DISCUSSION: The use of ecstasy in São Paulo has had a recreational pattern quite similar to those described in previous studies. The assessment of the use of ecstasy as positive also agrees with the findings of the literature. 9. Marsa, L. Could an Acid Trip Cure Your OCD? (2008) Discovery Magazine REPORTAGEM EM: http://discovermagazine.com/2008/jun/16-could-an-acid-trip-cure-your-ocd Researchers are again using mindbending drugs as a means of treating mental disorders.