Role of the central serotonin2B receptor in the regulation of ascending dopaminergic pathways: relevance for the treatment of schizophrenia and drug addiction

Four years ago, at the beginning of my thesis in Neuropharmacology, the functional role of the central serotonin2B receptor (5-HT2BR) remained poorly investigated. Indeed, in light of the relatively recent discovery of its presence in the mammalian brain, as compared to other 5-HT receptors, only few studies had explored its impact within the central nervous system. Interestingly, it had been shown that 5-HT2BRs, while having no effect at the level of the nigrostriatal dopaminergic (DA) pathway, afford a tonic excitatory control on the activity of the mesoaccumbal DA tract. This differential influence on subcortical DA brain regions had led to the proposal that 5-HT2BR antagonists may be a useful tool for improved treatment of DA-related disorders requiring an independent modulation of the activity of ascending DA pathways, such as schizophrenia. However, the effect of 5-HT2BR blockade at the level of the mesocortical DA pathway, which plays a pivotal role in the therapeutic benefit of atypical antipsychotic drugs (APDs), had never been studied. In addition, analysis of the literature revealed that 5-HT2BR blockade suppresses amphetamine and 3,4-methylenedioxymethamphetamine-induced neurochemical and behavioral responses, suggesting that this receptor may also be a relevant pharmacological target for treating drug addiction. Nevertheless, its possible implication in the effects induced by cocaine, one of the most worldwide abused drugs, remained unknown. Thus, the aim of the present thesis was to study the regulatory control exerted by the 5-HT2BR on both basal and cocaine-induced stimulation of DA activity, in order to evaluate its therapeutic relevance for improved treatment of schizophrenia and drug abuse and dependence. To this purpose, we assessed the effects of potent and selective 5-HT2BR antagonists (RS 127445 and LY 266097) on DA activity, by using biochemical, electrophysiological and behavioral approaches in rats. In a first group of experiments, we found that 5-HT2BRs exert a tonic inhibitory control on DA outflow in the medial prefrontal cortex (mPFC). This finding, by showing that 5-HT2BRs afford differential controls over the three ascending DA pathways, indicates that 5-HT2BR antagonists display an ideal pattern of effects to restore normal DA function in schizophrenia. Accordingly, 5-HT2BR antagonists were efficient in several behavioral models aimed at predicting APD efficacy, and had no effect in a behavioral task reflecting APD propensity to induce motor side effects. In a second group of experiments performed to determine the mechanisms underlying the differential control exerted by 5-HT2BRs on DA activity, we demonstrated that 5-HT2BR antagonist-induced opposite effects on DA ouflow in the mPFC and the nucleus accumbens (NAc) involve a functional interplay with 5-HT1ARs expressed in the mPFC. Finally, we found that 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion. This effect, which occurs independently from changes of DA outflow in the NAc and the striatum, where DA activity is tightly related to cocaine-induced behavioral responses, likely involves a post-synaptic interaction in subcortical DA brain regions. To conclude, the work accomplished over the past four years provides substantial information with regards to the functional role of 5-HT2BRs in the regulation of the activity of ascending DA pathways. In addition, while improving the understanding of the interaction between DA and 5-HT systems, the present findings altogether highlight the therapeutic potential of 5-HT2BR antagonists for treating schizophrenia and cocaine addiction.