Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat.

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.

Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram.

Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors.