Download 28/03 - Instituto de Psicologia da USP

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.