Adeline Cathala

Pregnenolone Can Protect the Brain from Cannabis Intoxication

Counteracting Cannabis What is the role of steroid hormones in vulnerability to addiction? Working with rodents, Vallée et al. (p. 94) found that all major drugs of abuse (morphine, cocaine, alcohol, nicotine) increase neurosteroid levels, with the active ingredient in cannabis (THC) inducing a particularly large increase. THC and other drugs increased levels of pregnenolone, long thought to be an inactive precursor of downstream active steroids. Pregnenolone antagonized most of the known behavioral and somatic effects of THC. The universal precursor of steroid hormones acts as a negative allosteric modulator of cannabinoid receptors. 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), ∆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.

In vivo evidence that constitutive activity of serotonin2C receptors in the medial prefrontal cortex participates in the control of dopamine release in the rat nucleus accumbens: differential effects of inverse agonist versus antagonist

Control of the mesoaccumbens dopamine (DA) pathway by central serotonin2C receptors (5‐HT2CRs) involves different 5‐HT2CR 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‐HT2CRs in the control of basal and activated accumbal DA outflow, to identify the modalities of their recruitment and the role of 5‐HT2CR constitutive activity. Intra‐mPFC injection of the 5‐HT2CR inverse agonist SB 206553 (0.5 μg/0.2 μL), 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‐HT2CR antagonist SB 242084 (0.5 μg/0.2 μL), 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‐HT2CR 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‐HT2CR antagonist and inverse agonist behave differently in vivo, demonstrate that mPFC 5‐HT2CRs facilitate activated accumbal DA outflow and that 5‐HT2CR constitutive activity participates in this interaction.

Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens.

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.

The central serotonin2B receptor: a new pharmacological target to modulate the mesoaccumbens dopaminergic pathway activity

J. Neurochem. (2010) 114, 1323–1332.

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

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.

Coupled intracerebral microdialysis and electrophysiology for the assessment of dopamine neuron function in vivo.

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.

Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine

In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5‐HT2CR) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5‐HT2CR agonists on cocaine‐induced responses have suggested that 5‐HT2CRs 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‐HT2CR 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‐D2R 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‐HT2CR antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5‐HT2CRs 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.

Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

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.

Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin2B receptor blockade: Involvement of medial prefrontal cortex serotonin1A receptors

ABSTRACT Recent studies have shown that serotonin2B receptor (5‐HT2BR) 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‐HT1ARs 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‐HT1AR (WAY 100635) and 5‐HT2BR (RS 127445) antagonists. WAY 100635, administered either subcutaneously (0.16 mg/kg, s.c) or locally into the mPFC (0.1 &mgr;M), 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 &mgr;g/0.2 &mgr;l). 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‐HT1ARs and DRN 5‐HT2BRs 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. HIGHLIGHTSThe effects of 5‐HT2BR blockade on DA outflow result from mPFC 5‐HT1AR stimulation.Blockade of 5‐HT2BRs increases DRN 5‐HT neuronal firing rate.Systemic and DRN 5‐HT2BR blockade increases mPFC 5‐HT outflow.Blockade of DRN 5‐HT2BRs increases mPFC DA outflow and decreases it in the NAc.DA changes induced by DRN 5‐HT2BR blockade are prevented by mPFC 5‐HT1AR blockade.

The central serotonin2B receptor as a new pharmacological target for the treatment of dopamine-related neuropsychiatric disorders: Rationale and current status of research

ABSTRACT The serotonin2B receptor (5‐HT2BR), which was first cloned and characterized in the rat stomach fundus, is the most recent addition to the 5‐HT2R 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‐HT2BR 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‐HT2BR 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‐HT2BR, as well as of the 5‐HT2BR 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‐HT2BR antagonists for improved treatment of schizophrenia and drug addiction will be discussed.