A large-scale c-Fos brain mapping study on extinction of cocaine-primed reinstatement.

Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming. Here, we applied a large-scale c-Fos brain mapping approach following extinction of cocaine priming in male rats to identify brain regions implicated in processing the conditioned interoceptive stimuli of cocaine priming. We found that cocaine-primed reinstatement is associated with increased c-Fos expression in key brain regions (e.g., dorsal and ventral striatum, several prefrontal areas and insular cortex), while its extinction mostly disengages them. Moreover, while reinstatement behavior was correlated with insular and accumbal activation, extinction of cocaine priming implicated parts of the ventral pallidum, the mediodorsal thalamus and the median raphe. These brain patterns of activation and inhibition suggest that after repeated priming, interoceptive signals lose their conditioned discriminative properties and that action-outcome associations systems are mobilized in search for new contingencies, a brain state that may predispose to rapid relapse.

Large-scale brain correlates of sweet versus cocaine reward in rats.

Cocaine induces many supranormal changes in neuronal activity in the brain, notably in learning- and reward-related regions, in comparison with nondrug rewards-a difference that is thought to contribute to its relatively high addictive potential. However, when facing a choice between cocaine and a nondrug reward (e.g., water sweetened with saccharin), most rats do not choose cocaine, as one would expect from the extent and magnitude of its global activation of the brain, but instead choose the nondrug option. We recently showed that cocaine, though larger in magnitude, is also an inherently more delayed reward than sweet water, thereby explaining why it has less value during choice and why rats opt for the more immediate nondrug option. Here, we used a large-scale Fos brain mapping approach to measure brain responses to each option in saccharin-preferring rats, with the hope to identify brain regions whose activity may explain the preference for the nondrug option. In total, Fos expression was measured in 142 brain levels corresponding to 52 brain subregions and composing 5 brain macrosystems. Overall, our findings confirm in rats with a preference for saccharin that cocaine induces more global brain activation than the preferred nondrug option does. Only very few brain regions were uniquely activated by saccharin. They included regions involved in taste processing (i.e., anterior gustatory cortex) and also regions involved in processing reward delay and intertemporal choice (i.e., some components of the septohippocampal system and its connections with the lateral habenula).

Relapse to cocaine use persists following extinction of drug-primed craving.

Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming in rats - a phenomenon dubbed extinction of cocaine priming because it is thought to involve extinction of the conditioned interoceptive cues of the drug. Here we measured the effect of this extinction strategy on subsequent relapse-like behavior in rats (i.e., return to the pre-extinction pattern of cocaine self-administration once the drug is made again available after extinction). We found that extensive extinction of the conditioned priming effects of cocaine had no major impact on relapse-like behavior. This lack of effect occurred despite evidence for post-extinction loss of neuronal responses to cocaine priming in brain regions causally involved in cocaine reinstatement (i.e., the dorsomedial prefrontal cortex and the core of the nucleus accumbens). These findings suggest that the conditioned priming effects of cocaine can be dissociated from and are thus not essential for relapse-like behavior, and that extinction of these effects is unlikely to represent a viable approach to relapse prevention. Overall, these findings are in general agreement with previous neurobiological dissociation studies and with research on extinction of exteroceptive drug cues.

L-DOPA elicits non-vesicular releases of serotonin and dopamine in hemiparkinsonian rats in vivo.

The control of the secretory activity of serotonergic neurons has been pointed out to reduce motor and non-motor side effects of the antiparkinsonian drug L-DOPA. This strategy deserves further investigation because it is presently unclear whether L-DOPA promotes a non-vesicular release of dopamine and serotonin from serotonergic neurons. To get a full neurochemical picture compatible with the existence of such a mechanism, we combined multisite intracerebral microdialysis, post mortem tissue measurement and single unit extracellular recordings in the dorsal raphe nucleus from hemiparkinsonian rats. L-DOPA (3-100mg/kg, ip.) non-homogeneously decreased extracellular serotonin levels in the striatum, substantia nigra pars reticulata, hippocampus and prefrontal cortex and homogenously serotonin tissue content in the striatum, cortex and cerebellum. L-DOPA (12mg/kg) did not modify the firing rate or pattern of serotonergic-like neurons recorded in the dorsal raphe nucleus. When focusing on serotonin release in the prefrontal cortex and the hippocampus, we found that L-DOPA (12 or 100mg/kg) enhanced serotonin extracellular levels in both regions upon Ca(2+) removal. Concomitantly, L-DOPA-stimulated dopamine release partly persisted in the absence of Ca(2+) in a region-dependent manner. Local application of the serotonin reuptake inhibitor citalopram (1µM) blunted the responses to L-DOPA (3-12mg/kg), measured as extracellular dopamine levels, most prominently in the hippocampus. These data stress that L-DOPA, already at low to moderate doses, promotes non-vesicular releases of serotonin and dopamine in a region-dependent manner.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.

Noradrenergic terminals regulate L-DOPA-derived dopamine extracellular levels in a region-dependent manner in Parkinsonian rats.

AIMS: Serotonin (5-HT) neurons mediate the ectopic release of dopamine (DA) induced by L-DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of L-DOPA in extrastriatal regions compared with the striatum. METHODS: Using a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5-HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6-hydroxydopamine-lesioned rats. RESULTS: L-DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated L-DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated L-DOPA effect in the SNr and HIPP. 5-HT extracellular levels were enhanced only when L-DOPA was combined to NET blockers. CONCLUSION: Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.

Serotonin2C Receptors and the Motor Control of Oral Activity.

Data from many experiments has shown that serotonin2C (5-HT2C) receptor plays a role in the control of orofacial activity in rodents. Purposeless oral movements can be elicited either by agonists or inverse agonists implying a tight control exerted by the receptor upon oral activity. The effects of agonists has been related to an action of these drugs in the subthalamic nucleus and the striatum, the two input structures for cortical efferents to the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. The oral effects of agonists are dramatically enhanced in case of chronic blockade of central dopaminergic transmission induced by neuroleptics or massive destruction of dopamine neurons. The mechanisms involved in the hypersensitized oral responses to 5-HT2C agonists are not clear and deserve additional studies. Indeed, while the oral behavior triggered by 5-HT2C drugs would barely correspond to the dyskinesia observed in humans, the clinical data have consistently postulated that 5-HT2C receptors could be involved in these aberrant motor manifestations.

Catecholamine/Serotonin interactions: systems thinking for brain function and disease.

This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative.

A tobacco extract containing alkaloids induces distinct effects compared to pure nicotine on dopamine release in the rat.

It has been suggested that minor alkaloids in plants play a role in the biological and neuronal actions of nicotine. We hypothesized that these molecules modulate the effect of nicotine on the activity of central dopamine (DA) neurons, one of the main cellular targets in addiction to drugs. In this study the effect of a single intraperitoneal injection of either nicotine or an alkaloid extract of the tobacco plant (0.5 mg/kg) on the efflux of DA were investigated. DA was measured in vivo by intracerebral microdialysis in the nucleus accumbens and the striatum of freely-moving rats. Results show that nicotine enhanced accumbal and striatal DA extracellular levels (+47 and 20% above baseline, respectively). The extract also evoked a significant increase in DA extracellular levels in both regions (+33 and +38% above baseline). However, this effect was significantly higher compared to nicotine in the striatum only. In conclusion, the tobacco extract enhanced the neurochemical effect of nicotine alone in the striatum, a response that could underlie the higher propensity of developing addictive-like behavior using nicotine with tobacco alkaloids.

Serotonin2c receptor constitutive activity: in vivo direct and indirect evidence and functional significance.

Serotonin2c (5-HT2c) receptors are widely expressed in the central nervous system where they play a pivotal role in the regulation of neuronal network excitability. Along with this fundamental physiological function, 5-HT2c receptors are thought to be implicated in the pathophysiology of several neuropsychiatric disorders and have become a major pharmacological target for the development of improved treatments of these disorders. In the past decade, many studies have focused on the constitutive activity of 5-HT2c receptors and the therapeutic potential of drugs acting as inverse agonists. Although the constitutive activity of the 5-HT2c receptor has been clearly described in vitro, the transposition of this concept to living animals is often difficult to ascertain. Nevertheless, cumulating evidence has demonstrated the functional relevance of such property in regulating physiological systems in vivo both at the level of the central and peripheral nervous systems. The present review provides an update of the growing number of studies that show, by means of pharmacological tools, the participation of the constitutive activity of 5-HT2c receptors in the control of various biochemical and behavioural functions in vivo and emphasizes the functional organization of this constitutive control together with the phasic and tonic (involving the spontaneous release of 5-HT) modalities of the 5-HT2c receptor in the brain.

Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex.

BACKGROUND: Recent neuroimaging studies have shown that people with cocaine addiction retain some degree of control over drug craving that correlates with neural activity in the lateral prefrontal cortex (PFC). Here, we report similar findings in a rat model of inhibitory control of cocaine seeking. METHODS: Rats actively responding for cocaine were trained to stop responding when presented with a discriminative stimulus that signaled lack of reinforcement. Rats were then tested for inhibitory control of cocaine seeking in novel behavioral contexts and in circumstances when cocaine seeking is particularly intense (e.g., following drug priming). The role of neuronal activity in different subregions of the PFC was assessed using local pharmacologic inactivation and c-Fos immunohistochemistry. RESULTS: Rats progressively acquired the ability to stop cocaine seeking, even during drug intoxication and after a long history of cocaine self-administration. Inhibitory control of cocaine seeking was flexible, sufficiently strong to block cocaine-primed reinstatement, and selectively depended on increased neuronal activity within the prelimbic PFC, which is considered the rodent functional homolog of the human lateral PFC. CONCLUSIONS: Parallel evidence in both animal models and humans indicate that recruitment of prefrontal inhibitory control of drug seeking is still functional after prolonged cocaine use. Preclinical investigation of the mechanisms underlying this capacity may contribute to designing new behavioral and/or pharmacologic strategies to promote its use for the prevention of relapse in addiction.

Serotonin2C ligands exhibiting full negative and positive intrinsic activity elicit purposeless oral movements in rats: distinct effects of agonists and inverse agonists in a rat model of Parkinson's disease.

This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT(2C)) receptor ligands differing in their intrinsic activity at 5-HT(2C) receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta-chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT(2C) agonists enhanced oral bouts in naive rats. The 5-HT(2C) inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide], but not the 5-HT(2C) antagonist SB243213 [1-10 mg/kg; 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT(2C) agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7-dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT(2C) agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia.

Diverse effects of 5-HT2C receptor blocking agents on c-Fos expression in the rat basal ganglia.

Serotonin(2C) receptors (5-HT(2)C) exert continuous control on the activity of specific populations of neurons in the basal ganglia. While antagonists block the effect of endogenous 5-HT at 5-HT(2C) receptors, the actions of inverse agonists may also involve interruption of activity at constitutively active populations of 5-HT(2C) receptors. We have evaluated the regional impact of these controls by studying, in rats, the expression of the product of the proto-oncogene c-Fos in rat basal ganglia after peripheral doses of the 5-HT(2C) antagonist SB 243213 (5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline) and the 5-HT(2B/2C) inverse agonists SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole.hydrochloride) and S32006 (N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide). The results show that 1 and 10mg/kg SB 243213 enhanced equally c-Fos expression in the subthalamic nucleus (STN) and dose-dependently in the striatum and nucleus accumbens core (NAcc). SB 206553 (1-10mg/kg), at 10mg/kg only, enhanced c-Fos expression in STN, striatum (except the dorsomedial part), NAcc, entopeduncular nucleus, substantia nigra pars reticulata (SNr) and compacta (SNc) and ventral tegmental area. S32006 induced a similar increase in c-Fos expression in the medial parts of the striatum and NAcc at doses of 1-10mg/kg while it dose-dependently enhanced c-Fos expression in medial parts of the STN and SNr. None of these drugs induced c-Fos expression in the globus pallidus. The distinct pattern of c-Fos expression elicited by the 5-HT(2C) antagonist and inverse agonists suggests the existence of cellular and functional heterogeneity in the response of the basal ganglia to drugs inhibiting 5-HT(2C) receptors.

Contribution of serotonergic transmission to the motor and cognitive effects of high-frequency stimulation of the subthalamic nucleus or levodopa in Parkinson's disease.

Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.

Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia.

L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs.

L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson's disease.

L-DOPA is the gold standard medication of Parkinson's disease, a neurological disorder consequent upon the degeneration of mesencephalic dopaminergic neurons. The therapeutic efficacy of L-DOPA has been related to its ability to restore dopamine (DA) extracellular levels in the Parkinsonian brain. The origin of the L-DOPA-induced rise in DA has been the object of numerous studies and controversies but the data collectively point to serotonergic (5-HT) neurons as being most significant in the release. Here, we review biochemical and behavioral evidence supporting serotonergic neurons as playing the main role in the actions of L-DOPA, considered from two points of view. The main aspect concerns the biochemical demonstration that 5-HT neurons are almost solely implicated in the release of DA induced by L-DOPA. The mechanism of action of L-DOPA inside 5-HT neurons will be thoroughly dissected on the basis of L-DOPA effects on extracellular versus tissue DA levels. The unique contribution of 5-HT neurons in mediating the release of newly synthesised DA from L-DOPA will be discussed in parallel with DA-dependent behaviors induced by L-DOPA. The other, and neglected, aspect concerns the possible deleterious impact of the presence of L-DOPA inside 5-HT neurons on 5-HT neuronal function. Overall, the fact that 5-HT neurons release the newly synthesised DA from L-DOPA in multiple brain regions beyond the striatum gives new insight into the large impact of L-DOPA in the Parkinsonian brain and strengthens therapeutic perspectives targeting the 5-HT system to reduce both motor and non-motor complications of L-DOPA medication.

Presynaptic control of serotonin on striatal dopamine function.

RATIONALE: The influences of the serotonergic system on dopamine (DA) neuron activity have received considerable attention during the last three decades due to the real opportunity to improve disorders related to central DA neuron dysfunctions such as Parkinson's disease, schizophrenia, or drug abuse with serotonergic drugs. Numerous biochemical and behavioral data indicate that serotonin (5-HT) affects dopaminergic terminal function in the striatum. OBJECTIVE: The authors propose a thorough examination of data showing controversial effects induced by striatal 5-HT on dopaminergic activity. RESULTS: Inhibitory and excitatory effects of exogenous 5-HT have been reported on DA release and synthesis, involving various striatal 5-HT receptors. 5-HT also promotes an efflux of DA through reversal of the direction of DA transport. By analogy with the mechanism of action described for amphetamine, the consequences of 5-HT entering DA terminals might explain both the excitatory and inhibitory effects of 5-HT on presynaptic DA terminal activity, but the physiological relevance of this mechanism is far from clear. The recent data suggest that the endogenous 5-HT system affects striatal DA release in a state-dependent manner associated with the conditional involvement of various 5-HT receptors such as 5-HT(2A), 5-HT(2C), 5-HT(3), and 5-HT(4) receptors. CONCLUSION: Methodological and pharmacological issues have prevented a comprehensive overview of the influence of 5-HT on striatal DA activity. The distribution of striatal 5-HT receptors and their restricted influence on DA neuron activity suggest that the endogenous 5-HT system exerts multiple and subtle influences on DA-mediated behaviors.