Effect of genetic and pharmacological blockade of GABA receptors on the 5-HT2C receptor function during stress.

Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptor-mediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the α3 subunit of GABA-A receptors. It can be inferred that non-α3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C -induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice.

Controversies on the role of 5-HT(2C) receptors in the mechanisms of action of antidepressant drugs.

Evidence from the various sources indicates alterations in 5-HT2C receptor functions in anxiety, depression and suicide, and other stress-related disorders treated with antidepressant drugs. Although the notion of a 5-HT2C receptor desensitization following antidepressant treatments is rather well anchored in the literature, this concept is mainly based on in vitro assays and/or behavioral assays (hypolocomotion, hyperthermia) that have poor relevance to anxio-depressive disorders. Our objective herein is to provide a comprehensive overview of the studies that have assessed the effects of antidepressant drugs on 5-HT2C receptors. Relevant molecular (second messengers, editing), neurochemical (receptor binding and mRNA levels), physiological (5-HT2C receptor-induced hyperthermia and hormone release), behavioral (5-HT2C receptor-induced changes in feeding, anxiety, defense and motor activity) data are summarized and discussed. Setting the record straight about drug-induced changes in 5-HT2C receptor function in specific brain regions should help to determine which pharmacotherapeutic strategy is best for affective and anxiety disorders.

Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences.

The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2(sert-cre) mice showed a major (-95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2(sert-cre) mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT(1A) autoreceptor coupling to G protein, as assessed with agonist-stimulated [(35)S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2(sert-cre) mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2(sert-cre) mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2(sert-cre) mouse brain. These findings are coherent with the notion that 5-HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors.

5-HT2C receptor activation prevents stress-induced enhancement of brain 5-HT turnover and extracellular levels in the mouse brain: modulation by chronic paroxetine treatment.

Stress is known to activate the central 5-hydroxytryptamine (5-HT) system, and this is probably part of a coping response involving several 5-HT receptors. Although 5-HT(2C) receptors are well known to be implicated in anxiety, their participation in stress-induced changes had not been investigated in parallel at both behavioral and neurochemical levels. We show here that the preferential 5-HT(2C) receptor agonist, m-chlorophenylpiperazine, as well as restraint stress increased anxiety in the mouse social interaction test. The selective 5-HT(2C) receptor antagonist, SB 242,084, prevented both of these anxiogenic effects. Restraint stress increased 5-HT turnover in various brain areas, and this effect was prevented by the 5-HT(2B/2C) receptor agonist RO 60-0175 (1 mg/kg), but not the preferential 5-HT(2A) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 mg/kg), and in contrast potentiated by SB 242,084 (1 mg/kg), which also blocked the effect of RO 60-0175. Using microdialysis, RO 60-0175 was shown to inhibit cortical 5-HT overflow in stressed mice when 5-HT reuptake was blocked locally. Chronic paroxetine prevented both the anxiogenic effect of m-chlorophenylpiperazine and the inhibitory effect of RO 60-0175 on locomotion and stress-induced increase in 5-HT turnover. The anxiolytic action of chronic paroxetine might be associated with an enhancement of 5-HT neurotransmission caused by a decreased 5-HT(2C) receptor-mediated inhibition of stress-induced increase in 5-HT release.