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Drug and Alcohol Dependence 51 Ž1998. 13]22 Drug-activation of brain reward pathways Roy A. Wise Intramural Research Program, National Institute on Drug Abuse, PO Box 5180, Baltimore, MD 21224, USA 1. Introduction A wide variety of biologically important stimuli can serve as rewards and establish adaptive behavior patterns in higher animals. Such stimuli act through brain mechanisms that evolved long before the human invention of the hypodermic syringe, the human harnessing of fire, or the human development of methods for refining and concentrating psychoactive substances that occur in nature. These brain mechanisms utilize endogenous neurotransmitters that are blocked or mimicked by a variety of addictive exogenous substances. The brain mechanisms for feeding, for example, have depended on endogenous opioid peptide neurotransmitters from the earliest stages of our evolutionary history ŽJosefsson and Johansson, 1979; Kavaliers and Hirst, 1987.. A complete understanding of the brain mechanisms of addiction will require an understanding of the anatomy and normal functions of brain pathways that evolved because they served basic adaptive functions. Our current understanding of the brain circuitry through which various rewards gain control over behavior has developed from studies of brain stimulation reward ŽOlds and Milner, 1954.. Rewarding brain stimulation is useful in anatomical localization of reward-relevant circuit elements because focal electrical stimulation of the brain only activates nerve fibers passing within a fraction of a millimetre of the electrode tip ŽFouriezos and Wise, 1984.. However, while stimulation differentially activates fibers of different sizes, the stimulation is indiscriminate with respect to the neurotransmitter a given set of fibers carry. Thus our knowledge of the neurochemical subtypes of reward-relevant neurons derives primarily from pharmacological studies; the rewarding effects of brain stimulation can be attenuated or augmented by drugs that are selective for various neurotransmitter systems ŽWise and Rompre, ´ 1989., and neurochemically selective drugs can be rewarding in their own right ŽWise, 1978.. Moreover, laboratory animals can be 0376-8716r98r$19.00 Elsevier Science Ireland Ltd. PII S0376-8716Ž98.00063-5 trained to self-administer drugs injected directly into the brain ŽBozarth and Wise, 1981.; such injections are, to a significant degree, both anatomically and neurochemically selective. 2. Activation of reward circuitry by direct brain stimulation Olds and Milner Ž1954. first discovered that direct electrical stimulation of the brain can be powerfully rewarding. The initial finding was that rats would return to places where they received stimulation of the septal area ŽOlds and Milner, 1954.. Subsequent mapping studies showed that stimulation of many other, seemingly disparate ŽPhillips, 1984., brain regions was rewarding ŽOlds and Olds, 1963.; these included structures with presumed sensory ŽPhillips, 1970., motor ŽVan Der Kooy and Phillips, 1977., and associational ŽRouttenberg and Sloan, 1972. functions. The most sensitive sites were along the medial forebrain bundle, particularly at its lateral hypothalamic, posterior hypothalamic, and ventral tegmental levels ŽFig. 1.. The lateral hypothalamic medial forebrain bundle has been the most frequently studied brain stimulation reward site, particularly in studies of the effects of drugs on brain stimulation reward. Olds and Olds Ž1965. hypothesized that the medial forebrain bundle was a final common path for reward messages involving a variety of forebrain reward sites. Unfortunately, over 50 fiber systems pass through this region of the brain ŽNieuwenhuys et al., 1982., and only a few of them are likely to contribute to the fact that stimulation of this region is rewarding. The sub-population of directly activated fibers that play a role in the fact that the stimulation is rewarding are designated the reward-rele¨ ant fibers; a similar distinction between reward-relevant and reward-irrelevant circuitry is also useful when considering the multiple actions of rewarding drugs. By administering stimulation in trains of paired 14 R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 Fig. 1. Drug reward circuitry Žapprox. 1998.. Cocaine and amphetamine trigger reward at NAcc Žand perhaps mFCx. where they elevate DA levels and thereby inhibit medium spiny GABA neurons. Nicotine triggers reward at cholinergic synapses in VTA, where it activates DA neurons projecting to NAcc. Morphine and heroin reward by disinhibiting the VTA dopamine cells, inhibiting GABA release for neighboring neurons in SNc and VTA. PCP Žphencyclidine. triggers reward in NAcc, by blocking the excitatory glutamate input to medium spiny neurons, and in mFCx, by an unknown mechanism. Cannabis and ethanol increase dopaminergic cell firing, but the cellular basis of this effect, and its contribution to reward are not yet clear. pulses and varying the interval between the members of each pair, one can determine the distribution of refractory periods of the population of directly activated and reward-relevant fibers. The bulk of rewardrelevant fibers in the medial forebrain bundle have the short refractory periods typical of large myelinated axons ŽYeomans, 1979.. At least two sub-populations appear to be involved; one of these appears to be cholinergic ŽGratton and Wise, 1985.. Paired-pulse stimulation can also be used to determine when the same reward-relevant fibers conduct reward signals between two identified reward sites ŽShizgal et al., 1980.. In this case one pulse of each pulse-pair is delivered through each of two properly aligned stimulating electrodes, and connectivity is inferred from collision-like effects familiar to electrophysiologists. Collision tests have established connectivity between reward sites along much of the length of the medial forebrain bundle ŽShizgal, 1989.. Conduction velocities of the reward-relevant fibers can be estimated from such two-electrode studies; here evidence of collision between the antidromic action potentials triggered at the more efferent site and the orthodromic action potentials triggered at the more afferent site is used to give estimates that are again consistent with large myelinated fibers ŽBielajew and Shizgal, 1982.. Dual-electrode studies can also be used to determine the direction of projection of reward-relevant fibers. Such studies indicate that the large majority of reward-relevant fibers in the medial forebrain bundle project in the rostro-caudal direction ŽBielajew and Shizgal, 1986.. Pharmacological studies first implicated dopamine as an important neurotransmitter in brain reward circuitry ŽWise and Rompre, ´ 1989.. However, dopamine-containing fibers project rostrally from the substantia nigra and ventral tegmental area, have long refractory periods and slow conduction velocities. Moreover, dopaminergic fibers have high thresholds for activation and are not directly depolarized by stimulation at the parameters traditionally used in these studies ŽYeomans et al., 1988.. Thus it is presumed that the dopaminergic link in reward circuitry is trans-synaptically activated by the more sensitive, caudally projecting, first-stage or directly acti¨ ated neurons. ŽThe so-called ‘first-stage’ neurons are, of course, ‘first-stage’ only with respect to brain stimulation reward; they, too, are presumed to be trans-synaptically activated } that is, ‘nth stage’ } when considered with respect to more natural rewards like food and sexual contact.. Little is known as to which other reward sites are ‘wired’ in series ŽWise and Bozarth, 1984. with the medial forebrain bundle elements and which are, on the other hand, part of independent, parallel ŽPhillips, 1984., reward circuits. Midline mesencephalic reward sites ŽRompre ´ and Miliaressis, 1985. appear to be part of the medial forebrain bundle circuit ŽShizgal, 1989.. The rewarding effects of stimulation of this region are augmented or attenuated: Ži. by the same drugs; Žii. in much the same way; and Žiii. to much the same extent R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 as are the rewarding effects of medial forebrain bundle stimulation ŽMiliaressis et al., 1986; Bauco and Wise, 1994., and stimulation in this region causes dopamine release in nucleus accumbens much as does medial forebrain bundle stimulation ŽBauco et al., 1994.. Stimulation of the medial or sulcal prefrontal cortex, on the other hand, causes different behavioral side effects than } and has rewarding effects that are different in some ways to the rewarding effects of medial forebrain bundle stimulation ŽMcGregor et al., 1992.. Stimulation of such varied structures as the cerebellum, brainstem, olfactory bulb, and a variety of limbic structures has been shown to be rewarding but has not been studied extensively with respect to drug sensitivity or connectivity with other reward sites. The initial hypothesis as to the second-stage neurons in MFB brain stimulation reward was that the descending first-stage fibers projected directly to the dopaminergic dendrites or cell bodies of the VTA and substantia nigra ŽWise, 1980.. This hypothesis was based on the fact that the MFB reward fibers have the same dorso-ventral and medio]lateral boundaries as the dopaminergic cell groups ŽCorbett and Wise, 1980; Wise, 1981.. More recently, however, it has been shown that at least some MFB reward fibers project caudally beyond the level of the dopaminergic cell bodies ŽShizgal, 1989., and sites caudal to the dopaminergic cells themselves have subsequently been proposed as the direct synaptic targets of the descending first-stage neurons ŽYeomans et al., 1993.. The chemical sub-type of the first stage MFB reward neurons has been surprisingly difficult to determine ŽGallistel et al., 1981.. Cholinergic fibers appear to contribute a minor sub-population to the first stage ŽGratton and Wise, 1985., but there are no rostro-caudal projections of the MFB that utilize acetylcholine as their transmitter. Nonetheless, the search for cholinergic links in brain stimulation reward circuitry has suggested a cholinergic input to the VTA that seems likely to innervate the chemical trigger zone for nicotine’s rewarding actions ŽYeomans et al., 1993.. The cholinergic projection Ža portion of which co-localizes glutamate; Charara et al., 1996. from the pedunculo-pontine and latero-dorsal tegmental nuclei ŽPPTg and LDTg, respectively. to the VTA. Manipulation of PPTg by cholinergic autoreceptor activation or inactivation modulates brain stimulation reward ŽYeomans et al., 1993.. In addition, muscarinic blockade in the VTA attenuates MFB brain stimulation reward ŽKofman et al., 1990.. Yeomans et al. have hypothesized that PPTg is the target of the first-stage MFB reward fibers, and that descending MFB reward signals activate the mesolimbic dopamine system indirectly by activating the cholinergic projection from PPTg to VTA. Muscarinic receptors are thought to transduce this reward input, as 15 nicotinic blockade does not alter the effectiveness of rewarding MFB stimulation in non-drugged animals. An attractive but unproven and counter-intuitive alternative to the Yeomans hypothesis is that the first-stage cholinergic contribution to MFB self-stimulation involves the rostrally projecting cholinergic fibers of LDTg and PPTg. These nuclei send multiply branched long fibers up the medial forebrain bundle ŽWoolf and Butcher, 1986.. Activation of these fibers by rewarding brain stimulation triggers not only orthodromic action potentials propagating toward the forebrain but also antidromic action potentials propagating toward the PPTg and LDTg cell bodies. Antidromic action potentials along the ‘trunk’ of the axonal ‘tree’ could conceivably invade the collaterals that branch off between the electrode tip and the cell body, including the collateral to the VTA. In this view, the ascending cholinergic fibers could carry a rostro-caudal Žantidromic. signal to the branch point and a caudo-rostral Žorthodromic. signal along the collateral from the branch point to its terminals in the VTA. Thus PPTg could be activated both antidromically } by the stimulation itself and trans-synaptically } by the non-cholinergic first-stage MFB reward fibers, i.e. cholinergic neurons might make both first-stage and second-stage contributions to MFB reward. 3. Activation of reward circuitry by drugs of abuse Most psychoactive drugs act in the central nervous system ŽFig. 1. as agonists or antagonists at the receptors for endogenous chemical messengers Žneurotransmitters or neuromodulators.. Opiates act at receptors for endogenous opioid neurotransmitters ŽGoldstein et al., 1971.; nicotine acts at a subclass Žnicotinic. of acetylcholine receptors ŽMarks et al., 1986.; cannabis acts at receptors ŽDevane et al., 1988. for an endogenous cannabanoid ŽDevane et al., 1992.; phencyclidine acts at the N-methyl-D-aspartate subtype of glutamate receptor ŽMaragos et al., 1988.; and caffeine acts at adenosine receptors ŽSnyder et al., 1981.. Some drugs do not act at neurotransmitter receptors per se, but nonetheless have actions selective for particular transmitter systems. For example, cocaine blocks reuptake ŽHeikkila et al., 1975a. of dopamine, norepinephrine, and serotonin by acting at the various monoamine transporters; amphetamine blocks reuptake and causes release ŽHeikkila et al., 1975b. of these monoamines, also by acting at their transporters; alcohol influences many neurotransmitter systems though its strongest effects are thought to be on GABA and glycine receptors ŽMihic et al., 1997.. Just as only a fraction of the fiber systems activated by medial forebrain bundle electrical stimulation play 16 R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 causal roles in the rewarding effects of such stimulation, so do only a fraction of the systems activated by drugs play causal roles in the rewarding effects of those drugs. Just as it is essential for brain stimulation reward specialists to identify which of the directly activated medial forebrain bundle neurons is rewardrele¨ ant, so is it important for the drug reward specialist to identify the reward-relevant targets of drugs of abuse. It is important to realize that most actions of habit-forming drugs contribute little if anything to the rewarding action of the drug; this important goal has only been partially realized, even in the case of the best characterized of habit-forming drugs. The neurotransmitter system that has been most clearly identified with the habit-forming actions of drugs of abuse is the mesolimbic dopamine system. Dopamine was first implicated in the rewarding effects of medial forebrain bundle electrical stimulation ŽLiebman and Butcher, 1973; Fouriezos and Wise, 1976; Mihic et al., 1997. and of the psychomotor stimulants amphetamine ŽYokel and Wise, 1975. and cocaine Žde Wit and Wise, 1977. by pharmacological studies. Amphetamine and cocaine non-selectively elevate synaptic levels of dopamine, noradrenaline, and also serotonin, but the rewarding effects of these agents are attenuated by selective dopamine antagonists and not by selective noradrenergic ŽYokel and Wise, 1975; de Wit and Wise, 1977. or serotonergic ŽLyness and Moore, 1983; Lacosta and Roberts, 1993. antagonists. Dopamine is found in a limited number of systems in the brain, and it is the mesolimbic and mesocortical dopamine systems } which project primarily from the ventral tegmental area to the nucleus accumbens and frontal cortex, respectively } that appear to be involved in psychomotor stimulant reward function. First, lesions of nucleus accumbens block or attenuate the rewarding effects of intravenous cocaine ŽRoberts et al., 1977, 1980. and amphetamine ŽLyness et al., 1979.. Second, rats learn to lever-press for amphetamine microinjections into the nucleus accumbens ŽHoebel et al., 1983.. Third, they learn to approach portions of their environment where they receive such injections ŽCarr and White, 1983.. Rats also learn to lever-press for nucleus accumbens microinjections of nomifensine Ža selective dopamine reuptake inhibitor; Carlezon et al., 1995. and for dopamine itself ŽDworkin et al., 1986., though, perhaps because of side effects ŽCarlezon et al., 1995. they do not so readily learn to lever-press for cocaine into this region ŽGoeders and Smith, 1983; Carlezon et al., 1995.. Rats also learn to lever-press for cocaine injections into the medial prefrontal cortex ŽGoeders and Smith, 1983.. However, the role of medial prefrontal cortex in cocaine reward is not yet completely clear. While rats more readily learn to lever-press for mPFC cocaine than for NAS cocaine ŽGoeders and Smith, 1983; Carlezon et al., 1995., lesions of mPFC do not affect lever-pressing for intravenous cocaine in trained animals ŽMartin-Iverson et al., 1986.. Such lesions appear, paradoxically, to make untrained animals more rather than less sensitive to the rewarding effects of cocaine ŽSchenk et al., 1991.. Cocaine injections into mPFC increase dopamine turnover in nucleus accumbens, which suggests at least one hypothesis as to why cocaine is rewarding when injected into this region ŽGoeders and Smith, 1993.. Both NAS and mPFC are implicated in the habitforming effects of phencyclidine. Rats will learn to lever-press for injections of PCP-as well as for the more selective NMDA antagonists MK-801 and CPPinto either mPFC or the shell of NAS ŽCarlezon and Wise, 1996.. Whereas the rewarding effects of nomifensine in NAS are blocked by co-injections of the dopamine antagonist sulpiride, the rewarding effects of PCP, MK-801, and CPP are not. Thus it appears that PCP is habit-forming primarily because of its action as an NMDA antagonist, and not because of its ability to block dopamine reuptake ŽPCP blocks NMDA receptors at an order of magnitude lower concentrations than are necessary for it to inhibit dopamine uptake.. It seems most likely that PCP is habit forming in NAS because it decreases excitatory input to the medium spiny output neurons of NAS; decreased output of medium spiny neurons is also caused by the elevations of NAS dopamine that result from rewarding cocaine and amphetamine injections. Thus decreased medium spiny neuron output appears to be a common consequence of PCP, cocaine, and amphetamine reward. Rewarding opiate treatments also share the ability to inhibit the output of NAS medium spiny neurons. Opiates appear to have more than one site of rewarding action; proposed sites of rewarding action include the ventral tegmental area ŽPhillips and LePiane, 1980; Bozarth and Wise, 1981., NAS ŽOlds, 1982., lateral hypothalamus ŽOlds, 1979; but see Britt and Wise, 1981., hippocampus ŽStevens et al., 1991., and periaqueductal gray Žvan der Kooy et al., 1982; Corrigall and Vaccarino, 1988.. Of these, the VTA and NAS are the most clearly implicated ŽWise, 1989.. Rewarding opiate injections into the VTA ŽBozarth and Wise, 1981; Devine and Wise, 1994. elevate NAS dopamine ŽDevine et al., 1993. by disinhibiting dopaminergic cell firing ŽJohnson and North, 1992.. Ventral tegmental dopaminergic neurons are tonically inhibited by neighboring GABAergic neighbors that express m opioid receptors and are inhibited by morphine ŽJohnson and North, 1992.. It is not clear whether the GABAergic inhibitors of dopaminergic activity are interneurons ŽGrace and Bunney, 1979., R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 projection neurons with collaterals to their dopaminergic neighbors ŽTepper et al., 1995., or GABAergic projection neurons that inhibit dopaminergic cell firing simply through local dendritic GABA release. D opioids are also capable of elevating NAS dopamine ŽDevine et al., 1993. and are rewarding in proportion to their ability to do so ŽDevine and Wise, 1994.. Early evidence suggested that VTA GABAergic neurons have m but not d receptors, but more recent evidence involving hippocampal GABAergic interneurons that are sensitive to both m and d agonists ŽLupica, 1995. raises the possibility that d opioid actions on VTA GABAergic neurons should be sought more closely. The medium spiny neurons of NAS, like the opiate target neurons of VTA, are GABAergic. They express m receptors ŽGracy et al., 1997. and are inhibited by morphine ŽJiang and North, 1992.. Opioid injections into NAS are rewarding ŽOlds, 1982; van der Kooy et al., 1982., and have psychomotor stimulant actions similar to those associated with VTA morphine injections Žalthough doses an order of magnitude higher are generally needed in NAS; Bozarth and Wise, 1981; Kalivas et al., 1983.. Thus opiates have at least two mechanisms through which they can be rewarding and through which they inhibit NAS medium spiny neurons. This adds to the evidence suggesting inhibition of medium spiny neurons as a common and causal consequence of at least a significant subset of rewarding drug injections. A fact that would seem to go against the hypothesis that decreases in medium spiny neuron activation is rewarding, however, is the fact that rats will work for direct electrical stimulation of nucleus accumbens ŽPrado-Alcala and Wise, 1984.. Such stimulation is presumed, at first glance, to activate medium spiny neurons. However, the assumption that direct electrical stimulation activates cell bodies near the electrode tip is called into question by what is known of brain stimulation reward in the region of the dopaminergic cell bodies of the ventral tegmental area and substantia nigra. Inasmuch as Ži. dopaminergic antagonists block brain stimulation reward; and Žii. reward sites in this region have the same lateral, dorsal, and ventral ŽCorbett and Wise, 1980; Wise, 1981. boundaries as the region of dopaminergic cell bodies, it was first assumed ŽRouttenberg and Malsbury, 1969. that stimulation in this region was rewarding because it activated the dopaminergic cell bodies directly. However, the population of first-stage neurons in the ventral tegmental area has refractory periods that are, for the most part, considerably faster than those of dopaminergic neurons ŽYeomans, 1979.. Moreover, there are similar refractory periods and connectivity between VTA reward sites and lateral hypothalamic reward sites ŽShizgal et al., 1980., and the majority of 17 fibers common to lateral hypothalamic and ventral tegmental reward sites have conduction velocities too fast for dopaminergic fibers ŽBielajew and Shizgal, 1982; Murray and Shizgal, 1994. and project toward rather than away from the dopaminergic cell bodies ŽBielajew and Shizgal, 1986.. Finally, the medial forebrain bundle reward fibers are activated by levels of stimulation approximately three orders of magnitude lower than what is needed to antidromically activate dopaminergic fibers ŽYeomans et al., 1988. Žit is difficult to determine the activation threshold of dopaminergic cell bodies from stimulation in the field of the recording electrode.. Thus, in the case of the VTA, at least, rewarding stimulation preferentially activates fibers of passage at levels that do not activate local cells. This may also be true of rewarding NAS stimulation. At least some additional habit-forming drugs activate dopaminergic projections to nucleus accumbens and are likely to decrease the output of medium spiny neurons as a consequence. For example, nicotine increases dopamine release in nucleus accumbens ŽImperato et al., 1986.. Nicotinic receptors have been localized to dopaminergic cell bodies ŽClarke and Pert, 1985. and local nicotine injections increase dopaminergic cell firing ŽClarke et al., 1985.. Nicotine infused directly into NAS also enhances local dopamine release, presumably by a presynaptic action on the dopaminergic terminals of this region ŽWestfall et al., 1988.. Alcohol and cannabis also increase extracellular dopamine concentrations in NAS ŽDi Chiara and Imperato, 1985; Ng Cheong Ton et al., 1988.; alcohol does so by increasing dopaminergic cell firing ŽGessa et al., 1985.. 4. Endogenous reward circuitry: current candidates At the present time, the only firmly identified elements in brain reward circuitry are the mesolimbic dopamine system, its efferent targets in nucleus accumbens, and its local GABAergic afferents. As mentioned above, the reward-relevant actions of amphetamine and cocaine are in the dopaminergic synapses of NAS and perhaps mPFC. The lowestthreshold site for rewarding opiate effects involves mand d-opioid actions on GABAergic neurons in the VTA; a secondary site of opiate rewarding actions involves m- and d-opioid actions on medium spiny output neurons of NAS. Thus GABAergic afferents to the mesolimbic dopamine neurons Žprimary substrate of opiate reward., the mesolimbic dopamine neurons themselves Žprimary substrate of psychomotor stimulant reward., and GABAergic efferents to the mesolimbic dopamine neurons Ža secondary site of opiate reward. form the core of currently characterized drug reward circuitry. 18 R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 While nicotinic blockade does not alter baseline brain stimulation reward it does block the ability of nicotine to potentiate brain stimulation reward ŽWise et al., 1997.. The reward-relevant target of nicotine appears to be the nicotinic receptor expressed by the mesolimbic dopamine cells and the cholinergic projections from LDTg and PPTg appear to be the endogenous cholinergic link in reward circuitry. Localization of reward-relevant nicotinic receptors to the dopaminergic neurons is suggested by four lines of evidence. First, nicotine is known to activate these neurons ŽClarke et al., 1985. and to cause dopamine release in nucleus accumbens ŽImperato et al., 1986.. Second, nicotine self-administration is attenuated by nicotinic antagonists localized to the ventral tegmental area ŽCorrigall et al., 1994.. Third, the nicotinic agonist cytisine is rewarding when microinjected into the VTA ŽMuseo and Wise, 1994.. Fourth, the rewarding ŽCorrigall et al., 1992. and reward-potentiating ŽWise et al., 1997. effects of nicotine, as well as the effects of nicotine on dopamine-mediated locomotion ŽClarke et al., 1988.. are blocked for a curiously long period by the atypical nicotinic antagonist chlorisondamine. Chlorisondamine is an insurmountable nicotinic antagonist that acts for a few days Žpresumably the life of the receptors it binds. in peripheral autonomic ganglia but that blocks nicotine’s actions on central dopaminergic neurons for a much longer period Žseveral weeks.. This drug is taken up by dopaminergic nerve terminals ŽEl-Bizri et al., 1995. and transported retrogradely to dopaminergic cell bodies ŽEl-Bizri et al., 1995. where it blocks dopamine-dependent nicotinic actions for months ŽClarke, 1984.. Chlorisondamine is a nicotinic channel blocker, and it would appear that once the drug is sequestered and concentrated in dopaminergic cell bodies it is inserted into new nicotinic receptors as they are expressed or as they are inserted into the dopaminergic cell membrane. Whereas the drug is not sequestered by peripheral autonomic neurons and blocks only those ganglionic nicotinic receptors that are expressed on the membrane at the time of pharmacological treatment, the centrally sequestered chlorisondamine is concentrated and stored where it can apparently block many generations of nicotinic receptors in dopaminergic neurons. Thus chlorisondamine exerts a longterm and insurmountable blockade of nicotinic actions on monoaminergic neurons just as it exerts a long-term and insurmountable blockade on the rewarding ŽCorrigall et al., 1992. and reward-potentiating ŽWise et al., 1997. actions of nicotine. While chlorisondamine is taken up by serotonergic and noradrenergic neurons as well ŽEl-Bizri et al., 1995., the fact that nicotine reward is blocked by selective dopamine antagonists and selective dopaminergic le- sions ŽCorrigall et al., 1992., taken with the fact that noradrenergic and serotonergic lesions or blockade fail to alter other forms of drug reward ŽYokel and Wise, 1975; de Wit and Wise, 1977; Roberts et al., 1977; Lacosta and Roberts, 1993., suggests that it is the nicotinic receptors on dopaminergic cell bodies Žand perhaps dopaminergic nerve terminals. that are critical for nicotinic reward. Thus the mesolimbic dopamine system appears to express the chemical trigger zones for not only amphetamine and cocaine reward but for nicotine reward as well. There is much less basis for speculation regarding the chemical trigger zones at which other drugs of abuse initiate their rewarding actions in the brain. Cannabinoid receptors are strongly concentrated in the zona reticulata of the substantia nigra ŽHerkenham et al., 1991. and the proximity to the dopaminergic cell bodies and the fact that cannabis increases dopamine release in NAS ŽNg Cheong Ton et al., 1988. again suggest an interaction involving GABAergic inputs to dopaminergic cell bodies. Ethanol, too, increases dopamine release in NAS ŽImperato et al., 1986., and does so by increasing dopaminergic cell firing ŽGessa et al., 1985.. The circuitry through which it does so is not known. Phencyclidine has rewarding actions in both NAS and mPFC ŽCarlezon and Wise, 1996., and the endogenous transmitter implicated in these effects is glutamate. The mechanism of rewarding action in NAS seems likely to involve blockade of NMDA-type glutamate receptors on medium spiny neurons, but the mechanism in mPFC is unidentified. Interestingly, there are glutamatergic projections from mPFC to both NAS and VTA ŽSesack and Pickel, 1992., but the effects of mPFC phencyclidine on these projections are not known. Not all habit-forming drugs elevate nucleus accumbens dopamine concentration or depend on dopamine for their rewarding actions. The rewarding effects of NAS microinjections of phencyclidine and other NMDA antagonists are dopamine-independent ŽCarlezon and Wise, 1996.. Benzodiazepines and barbiturates tend to decrease dopamine release, at least at high doses ŽWood, 1982; Finlay et al., 1992.. In the case of phencyclidine, however, it appears that the rewarding actions involve the GABAergic synaptic targets of the mesolimbic dopamine projection to NAS. Opiate effects on those targets also appear to be rewarding ŽOlds, 1982., and inasmuch as benzodiazepines and barbiturates are known to affect GABA receptor function it is quite possible that these drugs also act in GABAergic circuitry that is efferent to the mesolimbic dopamine system. 5. Synaptic inputs to drug reward circuitry While not yet identified as links crucial to the R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22 rewarding effects of drugs of abuse, there are several inputs to the mesolimbic dopamine system that might modulate drug reward by modulating mesolimbic activation. One source of input is GABAergic feedback from NAS; NAS medium spiny neurons project not only to VTA but also to other GABAergic neurons linked to VTA and NAS ŽAlexander and Crutcher, 1990; Kalivas et al., 1993; Van Bockstaele and Pickel, 1995.. Opiates have rewarding actions in some of these GABAergic links that form a feedback loop from regions of dopaminergic terminals to regions of dopaminergic cell bodies. It is not clear how many of the GABAergic feedback pathways to the VTA are targets of rewarding actions of morphine. Another potentially important source of input to reward circuitry is glutamatergic afferents to dopaminergic neurons of the VTA. The VTA receives glutamatergic input from mPFC ŽSesack and Pickel, 1992., amygdala ŽWallace et al., 1992., and PPTg ŽLavoie and Parent, 1994; Charara et al., 1996. and NAS receives glutamatergic input from these limbic sources as well as from hippocampus. Electrical stimulation of regions within each of these structures is rewarding, and such stimulation may have trans-synaptic importance for the mesolimbic system. Cholinergic input from PPTg and LDTg has been mentioned ŽOakman et al., 1995.; this now seems to be an important link in the circuitry of brain stimulation reward and it may provide endogenous cholinergic activation of nicotinic receptors involved in nicotine reward. The VTA also receives serotonergic innervation. Manipulation of serotonergic neuronal activation appears to modulate reward function. Serotonergic lesions appear to make cocaine more rewarding ŽLoh and Roberts, 1990., suggesting that blockade of serotonin reuptake by cocaine may be a factor limiting the rewarding effects of cocaine. Drug-free Žbut not ‘primed’. rats show some degree of ambivalence to cocaine ŽEttenberg and Geist, 1991., and serotonin may contribute to that ambivalence. Infusion of 8OH-DPAT into the dorsal raphe, where it inhibits cell firing by acting as an agonist at serotonergic autoreceptors, potentiates the rewarding effects of MFB simulation ŽFletcher et al., 1995., and is rewarding in its own right ŽFletcher, 1993.. These reward-relevant effects of serotonergic inhibition may be mediated through the serotonergic projection to VTA; another possibility would involve the serotonergic projection to NAS. Finally, there are noradrenergic projections from locus coeruleus to both VTA and NAS ŽSaleem et al., 1996. and locus coeruleus has been implicated in aspects of opiate dependence ŽAghajanian, 1978.. While the noradrenergic nucleus locus coeruleus was 19 once proposed as a source of reward circuitry ŽStein, 1971., this view is no longer held ŽWise, 1978; Wise and Rompre, ´ 1989.. Nonetheless, it is interesting to note that clonidine, a noradrenergic agonist with great potency at the noradrenergic autoreceptor, can serve as a reward in its own right ŽDavis and Smith, 1977. and, at higher doses, can strongly degrade the rewarding effects of MFB brain stimulation ŽGallistel and Freyd, 1987.. Thus noradrenergic function appears to have some ability to modulate reward function. These several inputs to the mesolimbic dopamine system offer potential targets for medication development ŽFig. 1.. Drugs that act in these systems may prove more subtle in their ability to modulate the resting tone of the mesolimbic system and also its responsiveness to drugs of abuse. Drugs that act in these systems may thus be less likely than direct dopamine agonists or antagonists to have abuse liability of their own or to be rejected as dysphoric agents, causing problems of compliance with a medication regimen. References Aghajanian, G.K., 1978. 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