Hyperlocomotive and Discriminative Stimulus Effects of Cocaine Are Under the Control of Serotonin_2C(5-HT_2C) Receptors in Rat Prefrontal Cortex

Abstract

The serotonin 2C (5-hydroxytryptamine 2C ; 5-HT 2C ) receptor (5-HT 2C R) is found in abundance in dopamine (DA) mesocorticolimbic pathways and is one of the important target proteins that modulates the behavioral effects of cocaine. In the present study, the hypothesis was tested that the 5-HT 2C R in the prefrontal cortex (PFC) may control either spontaneous or cocaineevoked locomotor activity as well as the discriminative stimulus properties of cocaine. In male Sprague-Dawley rats implanted with bilateral cannulae aimed at the PFC, local microinjections of the preferential 5-HT 2C R agonist 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride (MK 212) (0.05-0.5 g/side) did not alter spontaneous activity, but dose-dependently decreased horizontal hyperactivity evoked by cocaine (10 mg/kg i.p.). Given alone, the selective 5-HT 2C R antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluorophenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazo-spiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (5 g/side) increased basal locomotor activity of rats expressed in the vertical plane. Microinjections of RS 102221 (5 g/side, but not 0.15-1.5 g/side) significantly enhanced the horizontal activity induced by cocaine (10 mg/kg). In rats trained to discriminate cocaine (10 mg/kg i.p.) from saline (i.p.) in a two-lever, water-reinforced fixed ratio 20 task, intra-PFC microinjections of MK 212 (0.05 and 0.5 g/side) did not substitute for cocaine, but attenuated the stimulus effects of cocaine. However, intra-PFC microinjections of RS 102221 (1.5 and 5 g/side) evoked 13 and 40% cocaine-lever responding when tested alone and enhanced the recognition of cocaine. These data indicate that the PFC is a brain site at which the 5-HT 2C R exerts an inhibitory control over the hyperactive and discriminative stimulus effects of cocaine known to be dependent upon activation of the DA mesoaccumbens circuit.Augmented dopamine (DA) neurotransmission and indirect activation of DA D 1 -and D 2 -like receptors have been established to play a central role in the in vivo effects of cocaine. A sizeable body of literature supports the importance of the mesoaccumbens DA pathway, which originates in DA cell bodies in the ventral tegmental area (VTA) and terminates in the nucleus accumbens (NAc) in mediating the behavioral effects of cocaine. In addition to the pronounced involvement of DA in its in vivo effects, cocaine also inhibits serotonin (5-hydroxytryptamine; 5-HT) reuptake and enhances 5-HT availability for interaction with potentially all sixteen 5-HT receptors found in the brain (Hoyer et al., 2002). One such receptor, the 5-HT 2C receptor (5-HT 2C R), is densely localized in brain DA circuits (Lopez-Gimenez et al., 2001), and neurochemical studies implicate a tonic inhibitory control of the 5-HT 2C R in brain DA pathways (De Deurwaerdere and Spampinato, 1999). In keeping with an inhibitory role for 5-HT 2C R, systemic pretreatment with 5-HT 2C

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…Further studies suggest that these effects are mediated, at least in part, by 5-HT2C receptors in the VTA (Fletcher et al, 2004). Additionally, there is evidence that constitutive or agonist-induced activity at 5-HT2C receptors in the PFC is capable of attenuating the hyperlocomotive and discriminative stimulus effects of cocaine (Filip and Cunningham, 2003). Taken together, these data suggest a role for the 5-HT2C receptor in the treatment of psychostimulant drug abuse/addiction.…”

“…We have recently shown that infusions of SB 206553 directly into the PFC did not alter basal, K + -stimulated, or stress-induced cortical DA release (Alex et al, 2005;Pehek et al, 2006). Cortical 5-HT2C receptors do modulate DAmediated behaviors for intracortical infusions of a 5-HT2C antagonist potentiated the hyperlocomotion induced by a systemic injection of cocaine (Filip and Cunningham, 2003). However, current evidence suggests that this effect is not mediated by alterations in extracellular DA in the PFC (Alex et al, 2005).…”

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…Other sites, such as the PFC, may be involved as well. Inactivation of this area attenuates reinstatement induced by contextual cues (Fuchs et al, 2005), and the locomotor stimulant, and discriminative stimulus properties of cocaine are reduced by activation of 5-HT 2C receptors in the PFC (Filip and Cunningham, 2003), suggesting a functional role for these cortical receptors.…”

“…Many of the behavioral effects of psychomotor stimulants such as cocaine involve increased activity of mesolimbic dopamine function (eg, Callahan et al, 1991;Kelly and Iversen, 1976;Pettit et al, 1984). A number of studies have now shown that 5-HT 2C receptor agonists attenuate cocainestimulated locomotor activity (Filip et al, 2004;Filip and Cunningham, 2003;Fletcher et al, 2004;Grottick et al, 2000). Ro60-0175 also reduced responding for intravenous infusions of cocaine under both fixed ratio (FR) and progressive ratio schedules of reinforcement (Grottick et al, 2000).…”

Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy

“…Within the substantia nigra/ventral tegmentum, 5-HT 2C receptors are expressed on inhibitory GABA-ergic interneurons (Eberle-Wang et al, 1997). 5-HT 2C receptor stimulation inhibits reward system-related behaviors including cocaine-induced hyperlocomotion (Filip and Cunningham, 2003;Grottick et al, 2000). 5-HT 2C receptor blockade increases both dopaminergic cell firing and DA release in nucleus accumbens and frontal cortex (Alex et al, 2005;Millan et al, 1998).…”