Serotonin_1BReceptors in the Ventral Tegmental Area Modulate Cocaine-Induced Increases in Nucleus Accumbens Dopamine Levels

Abstract

Previous work has demonstrated that peripheral serotonin 1B (5-HT 1B ) receptor agonist administration facilitates the behavioral and neurochemical effects of cocaine. This study used dual probe microdialysis to investigate whether activation of serotonin 1B (5-HT 1B ) receptors in the ventral tegmental area (VTA) alters the ability of peripherally administered cocaine to elevate dopamine (DA) levels in the ipsilateral nucleus accumbens (NAcc) of drug-naive Wistar rats. Intra-VTA administration of the selective 5-HT 1B agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b]pyridin-5-one dihydrochloride (CP 93,129) by reverse dialysis produced a dose-dependent (30 and 100 M) potentiation of cocaine-induced (10 mg/kg i.p.) increases in NAcc DA efflux and concurrent cocaine-induced decreases in VTA GABA efflux. There was no effect of either local CP 93,129 or peripheral cocaine on VTA glutamate efflux. Intra-VTA administration of the 5-HT 1A/7 receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT; 100 M) did not alter cocaine-induced alterations in NAcc DA or VTA GABA, suggesting that the effects of CP 93,129 were not mediated through 5-HT 1A receptors. Moreover, the effects of intra-VTA CP 93,129 (100 M) on both cocaine-induced increases in NAcc DA levels and cocaine-induced decreases in VTA GABA levels were reversed by coadministration of the selective 5-HT 1B receptor antagonist 3-[3-(dimethylamine)propyl]-4-hydroxy-N-[4-(4-pyridinyl] phenyl] benzamide dihydrochloride (GR 55562; 300 M). In the absence of cocaine, intra-VTA CP 93,139 produced an increase in NAcc DA and decrease in VTA GABA levels. However, intra-VTA GR 55562 alone had no effect on any of our neurochemical measures. These findings indicate that activation of VTA 5-HT 1B receptors potentiates cocaine-induced increases in NAcc DA levels by enhancing the ability of cocaine to decrease VTA GABA efflux.The reinforcing effects of cocaine are mediated, in large part, by the mesolimbic dopamine (DA) pathway that originates in the ventral tegmental area (VTA) and terminates in several forebrain structures, including the nucleus accumbens (NAcc; Koob et al., 1994;Wise 1996). Several lines of evidence indicate that 5-hydroxytryptamine (serotonin) (5-HT) systems heavily modulate mesolimbic DA activity. Indeed, the VTA receives a dense serotonergic innervation, and serotonergic manipulations in the VTA modulate the behavioral and neurochemical effects produced by cocaine (for review, see Walsh and Cunningham, 1997).A growing body of evidence indicates that 5-HT 1B receptors play an important role in modulating the behavioral, neurochemical, and cellular effects of cocaine Cunningham, 1995, 1997;Parsons et al., 1998Parsons et al., , 1999Rocha et al., 1998;Castanon et al., 2000;Przegalinski et al., 2001). Although the neural mechanisms involved in these processes have not been elucidated, several recent studies implicate the VTA as an important locus for the modulatory influence of 5-HT 1B receptors on cocaine-induced behavior...

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…In addition, overexpression of 5-HT1B receptors on terminals of NA projection neurons to the VTA resulted in enhanced cocaine-induced hyperlocomotion and a left-ward shift in the dose-response curve for cocaine-conditioned place preference indicating an enhancement of the rewarding effects of cocaine (Neumaier et al, 2002). Likewise, studies have shown that systemic or intra-VTA 5-HT1B receptor agonism (CP 93129 and RU 24969 respectively) potentiates the cocaine-induced increase in DA in the NA and decrease in GABA in the VTA (Parsons et al, 1999;O'Dell and Parsons, 2004). Figure 1 illustrates the circuitry suggested by this body of data.…”

“…Administration of the 5-HT1B receptor agonist CP 93129 into the VTA has been shown to increase DA levels in the NA (Yan and Yan, 2001a;O'Dell and Parsons, 2004;Yan et al, 2004) and concurrently decrease GABA in the VTA (O'Dell and Parsons, 2004;Yan et al, 2004). Systemic 5-HT1B agonism also decreases VTA GABA (Parsons et al, 1999).…”

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

“…On the other hand, genetic studies suggest that 5-HT is involved in the rewarding effects of cocaine (Uhl et al, 2002). Nevertheless, when dealing with specific 5-HT receptors, most studies demonstrate a facilitatory role of 5-HT 1B receptors on the biochemical, discriminative stimulus, motor, and rewarding effects of cocaine (Callahan and Cunningham, 1997;Lucas et al, 1997;Parsons et al, 1998;Castanon et al, 2000;Filip et al, 2001;Neumaier et al, 2002;Przegalinski et al, 2002;O'Dell and Parsons, 2004). The dampening effects of serotoninergic drugs on the behavioral effects of cocaine or other psychostimulants are most probably related to a predominant stimulation of receptors other than 5-HT 1B , such as 5-HT 2C (Fletcher et al, 2002(Fletcher et al, , 2006.…”

“…In the striatum, they are probably localized in GABAergic terminals, but they are also localized in glutamatergic terminals and their stimulation inhibits striatal glutamatergic neurotransmission (Morikawa et al, 2000). In the VTA, 5-HT 1B receptors seem to be localized primarily in the terminals of GABAergic neurons projecting from the NAc and they modulate GABA release (Morikawa et al, 2000;O'Dell and Parsons, 2004). Activation of 5-HT 1B receptors in the VTA, with the consequent disinhibition of dopaminergic cells that project to the NAc, potentiates cocaineinduced increases in NAc DA (O'Dell and Parsons, 2004).…”

“…In the VTA, 5-HT 1B receptors seem to be localized primarily in the terminals of GABAergic neurons projecting from the NAc and they modulate GABA release (Morikawa et al, 2000;O'Dell and Parsons, 2004). Activation of 5-HT 1B receptors in the VTA, with the consequent disinhibition of dopaminergic cells that project to the NAc, potentiates cocaineinduced increases in NAc DA (O'Dell and Parsons, 2004). However, this mechanism does not seem to be involved in the present results, at least in the potentiating effect of methamphetamine on methylphenidate-induced locomotor activation, as DA release in the NAc induced by methylphenidate was not modified by pretreatment with methamphetamine.…”