Modulation of dopamine release by striatal 5‐HT2C receptors

Abstract

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…Interestingly, these effects were TTX-resistant, and therefore the 5-HT2C receptors responsible for these effects are located on the responsive SNpr neurons (Rick et al, 1995). In addition, we have shown recently that perfusion of the striatum with the 5-HT2C receptor inverse agonist SB 206553 increased striatal DA in a concentration-dependent manner (Alex et al, 2005), supporting a role for striatal 5-HT2C receptors in this regulation. Furthermore, systemic administration of the 5-HT2C agonist mCPP decreased striatal DA and this was blocked by intrastriatal infusions of SB 206553.…”

“…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).…”

“…Systemic administration of the 5-HT2C receptor agonist Ro 60-0175 also causes a decrease in DA efflux in the PFC (Millan et al, 1998a;Gobert et al, 2000) while inverse agonists (Gobert et al, 2000) and antagonists (Millan et al, 1998a;Gobert et al, 2000;Pozzi et al, 2002) increase DA efflux in the PFC. As for the localization of the relevant receptors, studies suggest that 5-HT2C receptors localized in the PFC do not modulate DA release in this region, either tonically (Pozzi et al, 2002;Alex et al, 2005) or phasically (Pozzi et al, 2002;Alex et al, 2005;Pehek et al, 2006). 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).…”

“…Although systemic administration of 5-HT2C receptor agonists, including the selective agonist Ro 60-0175, does not significantly decrease basal firing of these neurons , such treatment decreases DA efflux in the striatum (Gobert et al, 2000;De Deurwaerdere et al, 2004;Alex et al, 2005). Likewise, systemic administration of antagonists (SB 242084) and inverse agonists (SB 206553) at 5-HT2C receptors increases DA efflux in this region Porras et al, 2002b;De Deurwaerdere et al, 2004).…”

“…As for the localization of the relevant receptors, studies suggest that 5-HT2C receptors localized in the PFC do not modulate DA release in this region, either tonically (Pozzi et al, 2002;Alex et al, 2005) or phasically (Pozzi et al, 2002;Alex et al, 2005;Pehek et al, 2006). 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).…”