Serotonin2C receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: A combined dialysis and electrophysiological analysis in the rat

Abstract

The present study evaluated, via a combined electrophysiological and dialysis approach, the potential influence of serotonin (5-HT)(2C) as compared to 5-HT(2A) and 5-HT(2B) receptors on dopaminergic, adrenergic, and serotonergic transmission in frontal cortex (FCX). Whereas the selective 5-HT(2A) antagonist MDL100,907 failed to modify extracellular levels of dopamine (DA), noradrenaline (NA) or 5-HT simultaneously quantified in single dialysate samples of freely-moving rats, the 5-HT(2B)/5-HT(2C) antagonist SB206,553 dose-dependently increased levels of DA and NA without affecting those of 5-HT. This action was attributable to 5-HT(2C) receptor blockade inasmuch as the selective 5-HT(2C) antagonist SB242,084 likewise increased FCX levels of DA and NA, whereas the selective 5-HT(2B) antagonist SB204,741 was ineffective. Further, the preferential 5-HT(2C) receptor agonist Ro60-0175 dose-dependently depressed FCX levels of DA. The suppressive influence of 5-HT(2C) receptors on DA release was also expressed on mesolimbic and nigrostriatal dopaminergic pathways, in that levels of DA in nucleus accumbens and striatum were likewise reduced by Ro60-0175 and elevated, though less markedly, by SB206,553. In line with the above findings, Ro60-0175 dose-dependently decreased the firing rate of ventrotegmental dopaminergic and locus coeruleus (LC) adrenergic perikarya, whereas their activity was dose-dependently enhanced by SB206,553. Furthermore, SB206,553 transformed the firing pattern of ventrotegmental dopaminergic neurons into a burst mode. In contrast to SB206,553, MDL100,907 had little affect on the firing rate of dopaminergic or adrenergic neurons. In conclusion, as compared to 5-HT(2A) and 5-HT(2B) receptors, 5-HT(2C) receptors exert a tonic, suppressive influence on the activity of mesocortical - as well as mesolimbic and nigrostriatal - dopaminergic pathways, likely via indirect actions expressed at the level of their cell bodies. Frontocortical adrenergic, but not serotonergic, transmission is also tonically suppressed by 5-HT(2C) receptors.

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

“…In terms of neuroanatomical substrates, both the VTA and the nucleus accumbens appear to be important elements of the circuitry mediating this behavior since microinfusion of the group II metabotropic glutamate receptor agonist LY379268 into these areas reduced context-induced reinstatement of heroin seeking (Bossert et al, , 2006. Previous work with 5-HT 2C receptor agonists including Ro60-0175 indicates that 5-HT 2C receptor activation reduces the activity of the mesolimbic dopamine system (Di Matteo et al, 2000a, b;Gobert et al, 2000) probably via an action at the VTA (Fletcher et al, 2004). Thus, a logical candidate mechanism for the effects of Ro60-0175 on context-induced reinstatement is that this response results from dampened mesolimbic DA activity.…”

“…The moderately selective 5HT 2C receptor agonist Ro60-0175 (Martin et al, 1998) reduces the firing rate of mesolimbic DA neurons originating in the VTA, leading to a reduction in DA release in terminal regions of the nucleus accumbens and frontal cortex (Di Matteo et al, 2000a, b;Gobert et al, 2000). These effects are reversed by the selective 5-HT 2C receptor antagonist SB242084 (Di Matteo et al, 2000a;Gobert et al, 2000).…”

“…The moderately selective 5HT 2C receptor agonist Ro60-0175 (Martin et al, 1998) reduces the firing rate of mesolimbic DA neurons originating in the VTA, leading to a reduction in DA release in terminal regions of the nucleus accumbens and frontal cortex (Di Matteo et al, 2000a, b;Gobert et al, 2000). These effects are reversed by the selective 5-HT 2C receptor antagonist SB242084 (Di Matteo et al, 2000a;Gobert et al, 2000). Additionally, acute 5-HT 2C receptor block with SB242084 increases the burst-firing of dopaminergic neurons in the VTA leading to increased release of DA in the nucleus accumbens (Di Matteo et al, 1999;Gobert et al, 2000).…”

“…These effects are reversed by the selective 5-HT 2C receptor antagonist SB242084 (Di Matteo et al, 2000a;Gobert et al, 2000). Additionally, acute 5-HT 2C receptor block with SB242084 increases the burst-firing of dopaminergic neurons in the VTA leading to increased release of DA in the nucleus accumbens (Di Matteo et al, 1999;Gobert et al, 2000). Thus, it appears that 5-HT 2C receptors may exert a tonic inhibitory influence over the activity of ascending DA neurons.…”

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…Classically, the modulatory actions of the 5-HT 2C R locally in the VTA have been associated with its ability to inhibit the neuronal firing of DA-containing neurons through indirect mechanisms (Di Giovanni et al, 2001;Gobert et al, 2000;Navailles et al, 2004). Indeed, GABA neurons in the VTA co-express both the transcript (Eberle-Wang et al, 1997) and the protein for the 5-HT 2C R (Bubar and Cunningham, 2006).…”