In Vivo Evidence that 5-HT2C Receptor Antagonist but not Agonist Modulates Cocaine-Induced Dopamine Outflow in the Rat Nucleus Accumbens and Striatum

Abstract

During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT 2C receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothaneanesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT 2C agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10-30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT 2C/2B antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT 2C antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT 2C/2B agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT 2C receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT 2C agonists, at variance with 5-HT 2C antagonists, exert a preferential control on the impulse-stimulated release of DA.

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…In agreement with previous reports (Andrews and Lucki, 2001;Bubar et al, 2003;Navailles et al, 2004;Pontieri et al, 1995), the systemic administration of cocaine elicited a significant increase in DA extracellular levels in the NAc. As suggested by Fletcher et al (2004), we found that cocaineinduced DA outflow was dose-dependently inhibited by the intra-VTA injection of the 5-HT 2C R agonist Ro 60-0175.…”

“…As reported previously (Andrews and Lucki, 2001;Navailles et al, 2004), the systemic administration of 10 mg/kg of cocaine elicited an overall significant increase in accumbal DA efflux, reaching approximately 450% of baseline (po0.001, Fisher's PLSD test). Indeed, the effect of cocaine peaked at 650% of baseline 30 min after its injection, and thereafter decreased progressively to about 350% of baseline at the end of the experiment.…”

“…Intra-VTA injection of the 5-HT 2C R agonist Ro 60-0175 (Fletcher et al, 2004), but not of the 5-HT 2C R antagonist RS 102221 (McMahon et al, 2001), reduced cocaine-induced hyperlocomotion and self-administration. In line with the idea that the VTA may represent a primary site of action for the inhibitory control of the mesoaccumbens DA pathway by 5-HT 2C Rs Grottick et al, 2000;Navailles et al, 2004), it was concluded that VTA 5-HT 2C R stimulation was sufficient to attenuate the locomotor and reinforcing effects of cocaine (Fletcher et al, 2004). On the other hand, intra-NAc shell injections of 5-HT 2C R agonists and antagonists have been shown to respectively increase and decrease the hyperlocomotive and discriminative stimulus effects of cocaine (Filip and Cunningham, 2002;McMahon et al, 2001).…”

“…Classically, the modulatory actions of the 5-HT 2C R locally in the VTA have been associated with its ability to inhibit the neuronal firing of DA-containing neurons through indirect mechanisms (Di Giovanni et al, 2001;Gobert et al, 2000;Navailles et al, 2004). Indeed, GABA neurons in the VTA co-express both the transcript (Eberle-Wang et al, 1997) and the protein for the 5-HT 2C R (Bubar and Cunningham, 2006).…”

“…During recent years, numerous studies have focused on the role of the serotonergic2C receptor (5-HT 2C R) in the modulation of this DA pathway and its potential to control cocaine dependence (Bubar and Cunningham, 2006;Di Matteo et al, 2002;Higgins and Fletcher, 2003). Indeed, 5-HT 2C Rs are densely localized in brain regions containing DA cell bodies (VTA) and terminals (NAc) (Bubar and Cunningham, 2006;Clemett et al, 2000;Pazos et al, 1985;Pompeiano et al, 1994), and are known to modulate DA-dependent behavioral and neurochemical effects induced by cocaine (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000;McCreary and Cunningham, 1999;Navailles et al, 2004). Specifically, the systemic administration of the 5-HT 2C R agonist Ro 60-0175, and the 5-HT 2C R antagonist SB 242084 has been shown to respectively inhibit and potentiate cocaineinduced behaviors including its hypermotive and rewarding effects (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000).…”