Elsevier

Neuropharmacology

Volume 119, June 2017, Pages 91-99
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2017.04.001Get rights and content

Highlights

  • The 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.

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 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-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.

Introduction

The central serotonin2B receptor (5-HT2BR) is now well-established as a modulator of dopamine (DA) neuron function in the mammalian brain (Auclair et al., 2010, Devroye et al., 2015, Doly et al., 2008, Doly et al., 2009). Interestingly, recent findings have pointed out this receptor as a new pharmacological target for treating schizophrenia (Devroye et al., 2016). Indeed, 5-HT2BR blockade reverses the cognitive deficit induced by phencyclidine (PCP) in the novel object recognition test and suppresses PCP-induced hyperlocomotion, two behavioral models classically used to predict the ability of antipsychotic drugs (APDs) to alleviate cognitive and positive symptoms of schizophrenia, respectively (Newman-Tancredi and Kleven, 2011, Porsolt et al., 2010). In keeping with the classical hypothesis that the cognitive and positive symptoms of schizophrenia result from a DA hypoactivity in the medial prefrontal cortex (mPFC) and a DA hyperactivity in the nucleus accumbens (NAc), respectively (Creese et al., 1976, Newman-Tancredi and Kleven, 2011, Svensson, 2000), the efficacy of 5-HT2BR antagonists in these behavioral trials has been related to their ability to increase DA outflow in the mPFC and decrease it in the NAc (Auclair et al., 2010, Devroye et al., 2016).

However, the mechanisms underlying the 5-HT2BR modulation of DA outflow remain unknown to date. The possibility of a local control has already been discarded by recent findings showing that intra-mPFC or intra-NAc perfusion of 5-HT2BR antagonists does not alter DA outflow in these brain regions (Devroye et al., 2016). On the other hand, the fact that 5-HT2BR blockade increases mPFC 5-HT outflow (Devroye et al., 2016) raises the possibility that 5-HT2BR antagonist-induced changes of DA outflow could involve polysynaptic cortico-subcortical circuits driven by the stimulation of 5-HT1ARs located in the mPFC. Indeed, agonists of the 5-HT1AR, a key pharmacological target in the therapeutic benefit of atypical APDs (Meltzer and Massey, 2011, Newman-Tancredi and Kleven, 2011), are known to increase mPFC DA outflow and decrease it in the NAc (Assié et al., 2005, Díaz-Mataix et al., 2005, Ichikawa and Meltzer, 2000, Ichikawa et al., 2001), likely via the stimulation of mPFC 5-HT1ARs (Lladó-Pelfort et al., 2012).

Thus, the present study, using in vivo intracerebral microdialysis and extracellular unitary recordings in rats, was aimed at assessing the role of mPFC 5-HT1ARs in the opposite effects of 5-HT2BR antagonists on NAc and mPFC DA outflow, by using two selective 5-HT2BR and 5-HT1AR antagonists, RS 127445 and WAY 100635, respectively (Bonhaus et al., 1999, Müller et al., 2007). First, we assessed the influence of the systemic and intra-mPFC administration of WAY 100635 on RS 127445-induced changes of DA outflow in the mPFC and the NAc. Thereafter, as 5-HT2BRs are expressed in the dorsal raphe nucleus (DRN) (Bonaventure et al., 2002), which contains 5-HT neurons projecting to the mPFC (Azmitia and Segal, 1978), we investigated the effect of the systemic administration of RS 127445 on DRN 5-HT neuron firing rate, as well as the effect of its systemic and intra-DRN administration on mPFC 5-HT outflow. Finally, the interaction between WAY 100635 and RS 127445 on mPFC and NAc DA outflow was studied following their administration into the mPFC and the DRN, respectively.

Section snippets

Animals

Male Sprague-Dawley rats (IFFA CREDO, Lyon, France) weighing 280–350 g were used. Animals, housed in individual plastic cages were kept at constant room temperature (21 ± 2 °C) and relative humidity (60%) with a 12 h light/dark cycle (dark from 20:00 h), and had free access to water and food. For electrophysiological experiments, rats were housed two per cage and kept under standard laboratory conditions as above. Animals were acclimated to the housing conditions for at least one week prior to

Effect of WAY 100635 on RS 127445-induced effects on mPFC and NAc DA outflow

Fig. 1 illustrates the effect of WAY 100635 on RS 127445-induced effects on DA outflow in the mPFC (Fig. 1A) and the NAc (Fig. 1B).

In the mPFC (Fig. 1A), statistical analysis revealed a significant and time-dependent effect of pretreatment × treatment interaction (FWAY × RS (1,15) = 4.6, p < 0.05; FWAY × RS × time (10,150) = 3.54, p < 0.001). Post-hoc analysis revealed that, as reported previously (Auclair et al., 2010, Devroye et al., 2016), RS 127445 produced an overall significant increase

Discussion

The present study demonstrates that mPFC 5-HT1ARs participate in the 5-HT2BR-mediated control of the mesocortical and mesoaccumbal DA pathway activity, and provides the first evidence of the functional role of a specific 5-HT2BR population in the rat brain. In particular, the ability of 5-HT2BR antagonists to increase and decrease DA outflow in the mPFC and the NAc, respectively, appears to be mediated by an increase of DRN 5-HT activity which subsequently translates into the activation of mPFC

Acknowledgements

This work was supported by grants from the Institut National de la Recherche et de la Santé (INSERM), Bordeaux University, the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM and grant SAF2015-68346-P (MINECO-FEDER). C. Devroye was a fellowship recipient from the International Ph.D. program in Neuropharmacology, University of Catania Medical School, Catania, Italy, during the course of this study. The authors wish to thank Cédric Dupuy for

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