Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens

Abstract

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin2C receptor (5-HT2CR) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT2CR located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT2CRs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT2CR agonist Ro 60-0175 at 5 µg/0.2 µl, but not 1 µg/0.2 µl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT2CR antagonist SB 242084 (0.5 µg/0.2 µl) or SB 243213 (0.5 and 1 µg/0.2 µl). These results show that mPFC 5-HT2CRs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT2CRs on accumbal DA output is dependent on the functional balance among different 5-HT2CR populations located within the mesocorticoaccumbens system, and that 5-HT2CRs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.

Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction

“…Particularly, a role for 5-HT 3 receptors in the regulation of accumbens dopamine has suggested that this may be a pharmacological target for treating aspects of substance abuse (Di Matteo et al, 2008; McBride et al, 2004; Weiss et al, 2001). In contrast to most 5-HT receptors, 5HT 2C receptors exert tonic inhibitory control over dopamine release in the nucleus accumbens, although enhancing effects that are indirectly mediated through actions in the medial prefrontal cortex have also been reported (Bubar and Cunningham, 2008; Leggio et al, 2009). Certain drugs of abuse, such as cocaine, increase 5-HT as well as dopamine in the nucleus accumbens (Andrews and Lucki, 2001; Parsons et al, 1995).…”

The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen

“…Neurochemically, 5-HT 2C receptors tonically inhibit dopamine release in the frontal cortex, while 5-HT 2A receptor stimulation increases dopamine release in the frontal cortex (Gobert and Millan 1999; Gobert et al 2000; Millan et al 1998). However, a recent report shows that injections of the 5-HT 2C agonist RO 60-0175 into the medial prefrontal cortex of rats enhance dopamine outflow in nucleus accumbens caused by cocaine administration (Leggio et al 2009). …”

Evidence for a role of a dopamine/5-HT6 receptor interaction in cocaine reinforcement

“…Among the various 5-HT receptor subtypes, several studies point to the potential involvement of 5-HT2 receptor family (Auclair et al, 2010;Leggio et al, 2009aLeggio et al, , 2009bNavailles et al, 2008). Moreover, 5-HT2A and the 5-HT2C receptors have been shown to modulate the behavioral effects of cocaine (Bubar and Cunningham, 2006;Fletcher et al, 2004;Grottick et al, 2000;Muller and Huston, 2006;Nic Dhonnchadha et al, 2009).…”