Differential Regulation of the Mesoaccumbens Circuit by Serotonin 5-Hydroxytryptamine (5-HT)_2Aand 5-HT_2CReceptors

Abstract

Serotonin [5-hydroxytryptamine (5-HT)] 5-HT(2A) and 5-HT(2C) receptors (5-HT(2A)Rs and 5-HT(2C)Rs), which innervate the dopamine mesoaccumbens pathway, may play an important role in the behavioral effects of cocaine. To test this hypothesis, the present study measured cocaine-evoked locomotor activity after bilateral microinjection of selective 5-HT(2A)R and 5-HT(2C)R antagonists into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) shell. Locomotor activity was measured after intracranial microinjection of saline (0.2 microl/side), the selective 5-HT(2A)R antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (M100907) (0.1 or 0.3 microg. 0.2 microl(-1). side(-1)), or the selective 5-HT(2C)R antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfon-amido)phenyl-5-oxopentyl)]-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (0.05-0.5 microg. 0.2 microl(-1). side(-1)) followed by an injection of saline (1 ml/kg, i.p.) or cocaine (10 mg/kg, i.p.). Microinjection of M100907 (0.1-0.3 microg/side) into the VTA or RS 102221 (0.15-0.5 microg/side) into the NAc shell attenuated cocaine-induced hyperactivity in a dose-related manner. However, hyperactivity evoked by cocaine was not altered by microinjection of RS 102221 into the VTA or M100907 into the NAc shell. No changes in basal activity were observed after microinjection of M100907 or RS 102221 into either brain region. These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA and by activation of 5-HT(2C)Rs in the NAc shell. The selective regulation of the mesoaccumbens circuit by 5-HT(2A)Rs and 5-HT(2C)Rs implicates these 5-HT receptors as important in the behavioral outcomes of systemic cocaine administration.

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

“…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).…”

“…A stable baseline, defined as three consecutive samples, in which DA contents varied by less than 10%, was generally obtained 135 min after the beginning of the perfusion (stabilization period). Cocaine was diluted in 0.9% NaCl, and administered intraperitoneally at 10 mg/kg in a volume of 2 ml/kg (Filip and Cunningham, 2002;Fletcher et al, 2004;McMahon et al, 2001). The 5-HT 2C R agonist Ro 60-0175 was dissolved in 0.9% NaCl, and administered either into the VTA (1 and 5 mg/0.2 ml, microinjections) or into the NAc (0.1 and 1 mM, reverse dialysis) 15 min before the systemic administration of cocaine.…”

“…Recent intracranial microinjection studies aimed to identify the site(s) of action for the modulatory control of 5-HT 2C R within the mesoaccumbens pathway have shown that cocaine-induced DA behavior undergoes distinctly regional regulation by 5-HT 2C Rs located in the VTA and in the medio-ventral subdivision (shell) of the NAc (Filip and Cunningham, 2002;Fletcher et al, 2004;McMahon et al, 2001). 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). Thus, in contrast to the overall inhibitory influence of systematically administered 5-HT 2C R compounds on DA-dependent behaviors (Callahan and Cunningham, 1995;Filip et al, 2004;Fletcher et al, 2002;Frankel and Cunningham, 2004;Grottick et al, 2000), these results suggest that NAc 5-HT 2C Rs exert an excitatory control on accumbal DA function (Bowers et al, 2000;Dremencov et al, 2005;Yan, 2000).…”

“…Experiments were performed using in vivo microdialysis in halothane-anesthetized rats, an experimental procedure allowing simultaneous implantation of a dialysis cannula in the NAc and an injection cannula in the ipsilateral VTA (Ikemoto et al, 1997;McMahon et al, 2001). A selective 5-HT 2C R agonist (Ro 60-0175) and antagonist (SB 242084) were applied locally into the VTA or the NAc before the intraperitoneal administration of cocaine.…”