Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: implications for understanding the neurobiology of addiction.

Serotonin (5-HT) action via the 5-HT(2C) receptor (5-HT(2C)R) provides an important modulatory influence over neurons of the prefrontal cortex (PFC), which is critically involved in disorders of executive function including substance use disorders. In the present study, we investigated the distribution of the 5-HT(2C)R in the rat prelimbic prefrontal cortex (PrL), a subregion of the medial prefrontal cortex (mPFC), using a polyclonal antibody raised against the 5-HT(2C)R. The expression of 5-HT(2C)R immunoreactivity (IR) was highest in the deep layers (layers V/VI) of the mPFC. The 5-HT(2C)R-IR was typically most intense at the periphery of cell bodies and the initial segment of cell processes. Approximately 50% of the 5-HT(2C)R-IR detected was found in glutamate decarboxylase, isoform 67 (GAD 67)-positive neurons. Of the subtypes of GABA interneurons identified by expression of several calcium-binding proteins, a significantly higher percentage of neurons expressing IR for parvalbumin also expressed 5-HT(2C)R-IR than did the percentage of neurons expressing calbindin-IR or calretinin-IR that also expressed 5-HT(2C)R-IR. Since parvalbumin is located in basket and chandelier GABA interneurons which project to cell body and initial axon segments of pyramidal cells, respectively, these results raise the possibility that the 5-HT(2C)R in the mPFC acts via the parvalbumin-positive GABAergic interneurons to regulate the output of pyramidal cells in the rat mPFC.

Distribution of serotonin 5-HT2C receptors in the ventral tegmental area.

Serotonin 2C receptors (5-HT2CR) appear to exert tonic inhibitory influence over dopamine (DA) neurotransmission in the ventral tegmental area (VTA), the origin of the mesolimbic DA system, thought to be important in psychiatric disorders including addiction and schizophrenia. Current literature suggests that the inhibitory influence of 5-HT2CR on DA neurotransmission occurs via indirect activation of GABA inhibitory neurons, rather than via a direct action of 5-HT2CR on DA neurons. The present experiments were performed to establish the distribution of 5-HT2CR protein on DA and GABA neurons in the VTA of male rats via double-label immunofluorescence techniques. The 5-HT2CR protein was found to be co-localized with the GABA synthetic enzyme glutamic acid decarboxylase (GAD), confirming the presence of the 5-HT2CR on GABA neurons within the VTA. The 5-HT2CR immunoreactivity was also present in cells that contained immunoreactivity for tyrosine hydroxylase (TH), the DA synthetic enzyme, validating the localization of 5-HT2CR to DA neurons in the VTA. While the degree of 5-HT2CR+GAD co-localization was similar across the rostro-caudal levels of VTA subnuclei, 5-HT2CR+TH co-localization was highest in the middle relative to rostral and caudal levels of the VTA, particularly in the paranigral, parabrachial, and interfascicular subnuclei. The present results suggest that the inhibitory influence of the 5-HT2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT2CR control of the output of both GABA and DA neurons within this region.

Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens.

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.