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.
Gobert
A
A
Psychopharmacology Department, Institut de Recherches Servier, Croissy-sur-Seine, France.
Rivet
J M
JM
Lejeune
F
F
Newman-Tancredi
A
A
Adhumeau-Auclair
A
A
Nicolas
J P
JP
Cistarelli
L
L
Melon
C
C
Millan
M J
MJ
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D004837:Epinephrine / Q000378:metabolism / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology / Q000502:physiology; D008297:Male; D009474:Neurons / Q000502:physiology; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000378:metabolism
D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012701:Serotonin; D004298:Dopamine; D004837:Epinephrine