Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats.
In this study, we used a complementary in vivo electrophysiological and (in individual rats) neurochemical approach to characterize the actions of chemically diverse serotonin (5-HT)1A receptor ligands at central 5-HT1A autoreceptors as compared to dopamine (DA) D2 autoreceptors and presynaptic alpha-2 adrenergic receptors (ARs). The novel, high efficacy, 5-HT1A agonists, WY 48,723 (an arylpiperazine), (+)-flesinoxan (a benzodioxane) and S 14671 and S 14506 (methoxynaphtylpiperazines) mimicked the aminotetralin, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), in inhibiting the firing of dorsal raphe nucleus (DRN) neurons. Similarly, the firing rate of DRN neurons was reduced by the "partial" agonists, MDL 73005EF, BMY 7378, NAN-190, tandospirone and the novel pyrimidinylpiperazine, zalospirone. Furthermore, S 14489, S 15535 and S 15931, novel benzodioxopiperazines, which behave as antagonists at postsynaptic 5-HT1A receptors, inhibited completely DRN firing, whereas the methoxyphenylpiperazine, WAY 100,135, and the aryloxoarylamine, (-)-tertatolol, were ineffective. Indeed, in analogy to spiperone, both WAY 100,135 and (-)-tertatolol behaved as apparently competitive antagonists in that, in their presence, the dose-response curves for inhibition of DRN firing by S 14671, S 14506 or 8-OH-DPAT were shifted in parallel to the right with no loss of maximal effect. In distinction to WAY 100,135 and (-)-tertatolol, a further novel, putative "antagonist," SDZ 216-525 (a benzoisothiazolpiperazine) weakly inhibited the electrical activity of the DRN. With the exception of (-)-tertatolol, which behaved as a weak agonist, a very similar pattern of inhibition of 5-HT turnover was seen in the striatum (innervated by the DRN), the hippocampus and the hypothalamus (DRN and median raphe nucleus) and the spinal cord (nucleus raphe magnus), with the striatum displaying the greatest sensitivity. Drug potency for inhibition of firing and turnover was highly correlated (r = 0.80-0.82) and these actions were significantly correlated to affinity at (hippocampal) 5-HT1A receptors (r = 0.62-0.73). As concerns DA D2 autoreceptors, the agonist action of apomorphine in reducing DA turnover were mimicked only by 8-OH-DPAT, whereas the majority of the other 5-HT1A ligands, in analogy to raclopride, enhanced DA turnover. The facilitation of DA turnover appeared to reflect direct blockade of DA D2 autoreceptors because potency was correlated powerfully to affinity at these D2 sites (r = 0.89).(ABSTRACT TRUNCATED AT 400 WORDS)
Gobert
A
A
Department of Psychopharmacology, Institut de Recherches Servier, Croissy-sur-Seine, France.
Lejeune
F
F
Rivet
J M
JM
Audinot
V
V
Newman-Tancredi
A
A
Millan
M J
MJ
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D018341:Receptors, Adrenergic, alpha-2; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D004298:Dopamine