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Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB 1 -SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ 9 -tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 significantly reduced cannabis' positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.ClinicalTrials.gov identifiers: NCT03325595 , NCT03443895 and NCT03717272 ., (© 2023. The Author(s).)

The central serotonin 2B receptor (5-HT 2B R) modulates 5-HT and dopamine (DA) neuronal function in the mammalian brain and has been suggested as a potential target for the treatment of neuropsychiatric disorders involving derangements of these monoamine systems, such as schizophrenia, cocaine abuse and dependence and major depressive disorder. Studies in rats and mice yielded contrasting results on the control of 5-HT/DA networks by 5-HT 2B Rs, thereby leading to opposite views on the therapeutic potential of 5-HT 2B R agents for treating the above disorders. These discrepancies may result from anatomo-functional differences related to a different cellular location of 5-HT 2B Rs in rat and mouse brain. Using immunohistochemistry, we assessed this hypothesis by examining the expression of 5-HT 2B Rs in 5-HT and GABAergic neurons of rats and mice within different subregions of the dorsal raphe nucleus (DRN), currently considered as the main site of action of 5-HT 2B agents. Likewise, using in vivo microdialysis, we examined their functional relevance in the control of DRN 5-HT outflow, a surrogate index of 5-HT neuronal activity. In the DRN of both species, 5-HT 2B Rs are expressed in 5-HT cells expressing tryptophan hydroxylase 2 (TPH 2 ), in GABAergic cells expressing glutamic acid decarboxylase 67 (GAD67), and in cells expressing both markers (GAD67 & TPH 2 ; i.e., GABA-expressing 5-HT neurons). The proportion of 5-HT 2B R-positive cells expressing only TPH 2 was significantly larger in mouse than in rat DRN, whereas the opposite holds true for the expression in cells expressing GAD67 & TPH 2 . No major species differences were found in the dorsal and ventral subregions. In contrast, the lateral subregion exhibited large differences, with a predominant expression of 5-HT 2B Rs in TPH 2 -positive cells in mice (67.2 vs 19.9 % in rats), associated with a lower expression in GAD67 & TPH 2 cells (7.9 % in mice vs 41.5 % in rats). Intra-DRN (0.1 μM) administration of the preferential 5-HT 2B R agonist BW 723C86 decreased and increased DRN 5-HT outflow in rats and mice respectively, both effects being prevented by the intra-DRN perfusion of the selective 5-HT 2B R antagonist RS 127445 (0.1 μM). Altogether, these results show the existence of anatomical differences in the cellular expression of 5-HT 2B Rs in the rat and mouse DRN, which translate into an opposite control of 5-HT outflow. Also, they highlight the relevance of the subset of GAD67-positive 5-HT neurons as a key factor responsible for the functional differences between rats and mice in terms of 5-HT neuronal activity modulation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Serotonin 2B receptor (5-HT 2B R) antagonists inhibit cocaine-induced hyperlocomotion independently of changes of accumbal dopamine (DA) release. Given the tight relationship between accumbal DA activity and locomotion, and the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA neurotransmission and DA-dependent behaviors, it has been suggested that the suppressive effect of 5-HT 2B R antagonists on cocaine-induced hyperlocomotion may result from an activation of mPFC DA outflow which would subsequently inhibit accumbal DA neurotransmission. Here, we tested this hypothesis by means of the two selective 5-HT 2B R antagonists, RS 127445 and LY 266097, using a combination of neurochemical, behavioral and cellular approaches in male rats. The intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097 (0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 3β phosphorylation, a postsynaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT 2B Rs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABA A R antagonist bicuculline (100 μM) prevented the effect of the systemic or local (1 μM, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 μg/0.2 μl) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK3β phosphorylation. These results show that DRN 5-HT 2B R blockade suppresses cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in the mPFC and the subsequent inhibition of accumbal DA neurotransmission., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The central serotonin 2B receptor (5-HT 2B R) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT 2B R antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 μM) administration of the selective 5-HT 2B R antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABA A antagonist bicuculline (100 μM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 μM) administration of the selective 5-HT 1A R antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 μM) was potentiated by the intra-DRN administration (0.5 μM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT 2B R mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT 2B Rs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The serotonin 2B receptor (5-HT 2B R), which was first cloned and characterized in the rat stomach fundus, is the most recent addition to the 5-HT 2 R family. While its involvement in the regulation of gastrointestinal, vascular, pulmonary and cardiac physiology has been widely investigated, its functional role within the central nervous system (CNS) has received much less attention. Nevertheless, when considering the data available in the literature with regards to the regulatory control exerted by the central 5-HT 2B R on dopamine (DA) and serotonin (5-HT) neuron activity, a very interesting picture emerges and highlights the key role of these receptors for future therapeutic strategies of DA-related neuropsychiatric disorders. Thus, the present review, by compiling molecular, biochemical, electrophysiological and behavioral findings from the literature of the past twenty years, aims at providing a sound analysis of the current knowledge supporting the interest of the central 5-HT 2B R for future therapeutic avenues. First, we recall the neuroanatomical and functional data supporting the therapeutic relevance of the 5-HT/DA interaction in the CNS. Thereafter, after a short overview of the central expression and molecular properties of the 5-HT 2B R, as well as of the 5-HT 2B R agonists and antagonists available in the market, we will focus on the functional role of this receptor in the control of 5-HT, DA and neuroglia activity in the rodent brain. Finally, the therapeutic potential of 5-HT 2B R antagonists for improved treatment of schizophrenia and drug addiction will be discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent studies have shown that serotonin 2B receptor (5-HT 2B R) antagonists exert opposite facilitatory and inhibitory effects on dopamine (DA) release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc), respectively, thereby leading to the proposal that these compounds could provide an interesting pharmacological tool for treating schizophrenia. Although the mechanisms underlying these effects remain unknown, several data in the literature suggest that 5-HT 1A Rs located into the mPFC could participate in this interaction. The present study, using in vivo microdialysis and electrophysiological recordings in rats, assessed this hypothesis by means of two selective 5-HT 1A R (WAY 100635) and 5-HT 2B R (RS 127445) antagonists. WAY 100635, administered either subcutaneously (0.16 mg/kg, s.c) or locally into the mPFC (0.1 μM), blocked the changes of mPFC and NAc DA release induced by the intraperitoneal administration of RS 127445 (0.16 mg/kg, i.p.). The administration of RS 127445 (0.16 mg/kg, i.p.) increased both dorsal raphe nucleus (DRN) 5-HT neuron firing rate and 5-HT outflow in the mPFC. Likewise, mPFC 5-HT outflow was increased following the intra-DRN injection of RS 127445 (0.032 μg/0.2 μl). Finally, intra-DRN injection of RS 127445 increased and decreased DA outflow in the mPFC and the NAc, respectively, these effects being reversed by the intra-mPFC perfusion of WAY 100635. These results demonstrate the existence of a functional interplay between mPFC 5-HT 1A Rs and DRN 5-HT 2B Rs in the control of the DA mesocorticolimbic system, and highlight the clinical interest of this interaction, as both receptors represent an important pharmacological target for the treatment of schizophrenia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Recent studies suggest that the central serotonin2B receptor (5-HT2BR) could be an interesting pharmacological target for treating neuropsychiatric disorders related to dopamine (DA) dysfunction, such as schizophrenia. Thus, the present study was aimed at characterizing the role of 5-HT2BRs in the control of ascending DA pathway activity. Using neurochemical, electrophysiological and behavioral approaches, we assessed the effects of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on in vivo DA outflow in DA-innervated regions, on mesencephalic DA neuronal firing, as well as in behavioral tests predictive of antipsychotic efficacy and tolerability, such as phencyclidine (PCP)-induced deficit in novel object recognition (NOR) test, PCP-induced hyperlocomotion and catalepsy. Both RS 127445 (0.16 mg/kg, i.p.) and LY 266097 (0.63 mg/kg, i.p.) increased DA outflow in the medial prefrontal cortex (mPFC). RS 127445, devoid of effect in the striatum, decreased DA outflow in the nucleus accumbens, and potentiated haloperidol (0.1 mg/kg, s.c.)-induced increase in mPFC DA outflow. Also, RS 127445 decreased the firing rate of DA neurons in the ventral tegmental area, but had no effect in the substantia nigra pars compacta. Finally, both RS 127445 and LY 266097 reversed PCP-induced deficit in NOR test, and reduced PCP-induced hyperlocomotion, without inducing catalepsy. These results demonstrate that 5-HT2BRs exert a differential control on DA pathway activity, and suggest that 5-HT2BR antagonists could represent a new class of drugs for improved treatment of schizophrenia, with an ideal profile of effects expected to alleviate cognitive and positive symptoms, without eliciting extrapyramidal symptoms., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting pharmacological target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new pharmacological target in drug addiction., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1 mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15 mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5 mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity., (© 2014 Society for the Study of Addiction.)

The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.

Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

Introduction: The central dopaminergic system is involved in the pathophysiology of several neuropsychiatric disorders. Intracerebral microdialysis and electrophysiology provide two powerful techniques to investigate dopamine (DA) function and the mechanism of action of psychotropic drugs in vivo., Methods: Here, we developed a protocol allowing the combined measurement of neurochemical and electrical activities of the nigrostriatal and mesoaccumbens DA pathways, by coupling in vivo microdialysis and electrophysiology in the same isoflurane-anesthetized animal. DA neuron firing rate and burst firing were measured in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), whereas extracellular levels of DA and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were monitored in the striatum and the nucleus accumbens (NAc). The validity of the protocol was assessed using various drugs known to modify DA neuron activity in vivo., Results: The peripheral administration of the DA-D2 agonist quinpirole decreased SNc DA neuron firing rate and burst firing, as well as DA and DOPAC outflow in the rat striatum. Opposite effects were observed after the peripheral administration of the DA-D2 antagonist haloperidol. In rats and mice, the peripheral administration of cocaine elicited a decrease in VTA DA neuron firing rate and burst firing, and an increase in accumbal DA outflow, paralleled by a reduction in DOPAC outflow., Discussion: The obtained results, confirming previous electrophysiological and microdialysis studies, demonstrate that this protocol provides a suitable method for the study of DA neuron function and the mechanism of action of psychotropic drugs in the living brain of both rats and mice., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The function of the serotonin(2B) receptor (5-HT(2B)R) in the mammalian brain is poorly characterized, especially with regard to its influence on dopamine (DA) neuron activity. Here, we assessed this issue by evaluating effects of 5-HT(2B)Rs ligands in the control of striatal and accumbal DA outflow, using in vivo microdialysis in halothane-anesthetized rats, and amphetamine-induced hyperlocomotion in vigil rats. The selective 5-HT(2B)R antagonist 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-B]indole (LY 266097; 0.16 mg/kg, i.p.) had no influence on basal accumbal and striatal DA outflow but reduced significantly accumbal DA outflow when injected at 0.63 mg/kg. A significant reduction of basal DA outflow in the nucleus accumbens was also observed after i.p. administration of 0.16 mg/kg 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, another selective 5-HT(2B)R antagonist. In contrast, the 5-HT(2B)R agonist alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (3 mg/kg, s.c.) had no influence on basal DA outflow in either brain region. The increase in striatal and accumbal DA outflow induced by the 5-HT(2C)R inverse agonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole (5 mg/kg, i.p.) was unaltered by LY 266097 (0.63 mg/kg) pre-treatment. Conversely, LY 266097 (0.63 mg/kg) significantly diminished the increase in DA outflow induced by haloperidol (0.01 mg/kg, s.c.) or amphetamine (0.5 mg/kg, i.p.) in the nucleus accumbens, but not in the striatum. Amphetamine-induced hyperlocomotion (1 mg/kg) was also attenuated by LY 266097 (0.63 mg/kg). These findings demonstrate that 5-HT(2B)Rs exert a facilitatory control on mesoaccumbens DA pathway activity, and suggest that they may constitute a new target for improved treatment of DA-related neuropsychiatric disorders.

Control of the mesoaccumbens dopamine (DA) pathway by central serotonin(2C) receptors (5-HT(2C)Rs) involves different 5-HT(2C)R populations located within multiple brain areas. Here, using in vivo microdialysis in halothane-anesthetized rats, we assessed the role of medial prefrontal cortex (mPFC) 5-HT(2C)Rs in the control of basal and activated accumbal DA outflow, to identify the modalities of their recruitment and the role of 5-HT(2C)R constitutive activity. Intra-mPFC injection of the 5-HT(2C)R inverse agonist SB 206553 (0.5 microg/0.2 microL), without effect by itself, decreased accumbal DA outflow induced by morphine (2.5-10 mg/kg, s.c.), haloperidol (0.01 mg/kg, s.c.) or GBR 12909 (2.5 mg/kg, i.p.). Conversely, intra-mPFC injection of the 5-HT(2C)R antagonist SB 242084 (0.5 microg/0.2 microL), without effect by itself, decreased the effect of 10 mg/kg morphine, the only drug enhancing basal 5-HT outflow in the mPFC. The inhibitory effect of SB 206553 on 2.5 mg/kg morphine-stimulated DA outflow was suppressed by the concomitant intra-mPFC injection of SB 242084. Finally, changes of basal DA outflow induced by the 5-HT(2C)R agonist Ro 60-0175 (3 mg/kg, i.p.) or SB 206553 (5 mg/kg, i.p.) were unaffected by intra-mPFC injection of SB 242084. These results, showing that 5-HT(2C)R antagonist and inverse agonist behave differently in vivo, demonstrate that mPFC 5-HT(2C)Rs facilitate activated accumbal DA outflow and that 5-HT(2C)R constitutive activity participates in this interaction.

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin(2C) receptor (5-HT(2C)R) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT(2C)R located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT(2C)Rs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT(2C)R antagonist SB 242084 (0.5 microg/0.2 microl) or SB 243213 (0.5 and 1 microg/0.2 microl). These results show that mPFC 5-HT(2C)Rs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent on the functional balance among different 5-HT(2C)R populations located within the mesocorticoaccumbens system, and that 5-HT(2C)Rs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.