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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.

Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.