Biochemical and electrophysiological evidence for an agonist action of CM 57493 at pre- and postsynaptic 5-hydroxytryptamine1A receptors in brain.
The potential interaction of CM 57493 [4-(3-trifluoromethyl-phenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyri din e] with central 5-hydroxytryptamine (5-HT) receptors was assessed using biochemical and electrophysiological tests in the rat and in the cat. In vitro binding assays with rat brain membranes revealed that CM 57493 bound to 5-HT1A sites in a concentration range (pIC50 = 7.1) at least two orders of magnitude lower than that required for its interaction with 5-HT1B/5-HT1D, 5-HT2, 5-HT3 and 5-HTPre sites. The affinity of CM 57493 for 5-HT1A sites labeled by [3H]-8-OH-DPAT in hippocampal membranes was enhanced by Mn++ and reduced by GTP, as expected for an agonist. Like 8-OH-DPAT, CM 57493 inhibited forskolin-activated adenylate cyclase activity in hippocampal homogenates. The inhibitory effects of these two compounds were not additive and were prevented by 5-HT1A antagonists such as spiperone and dl-propranolol. In vivo treatment with CM 57493 decreased the levels of 5-hydroxyindole acetic acid in various brain areas, as observed with other 5-HT1A agonists such as 8-OH-DPAT and ipsapirone. Electrophysiological recording within the dorsal raphe nucleus in chloral hydrate anesthetized rats showed that CM 57493 administration induced a dose-dependent reduction of the spontaneous firing of serotoninergic neurons. In vitro, CM 57493 (5-20 microM) also reduced neuronal firing in the nucleus raphe dorsalis within brainstem slice, and this effect could be prevented by dl-propranolol. Finally, in cats pretreated with reserpine, CM 57493 induced a decrease in ponto-geniculo-occipital activity, which could be antagonized by methiothepin.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrien
J
J
Institut National de la Santé et de la Recherche Médicale U. 288, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Lanfumey
L
L
Gozlan
H
H
Fattaccini
C M
CM
Hamon
M
M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000032:analysis; D066298:In Vitro Techniques; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D011725:Pyridines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D012701:Serotonin; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C045604:CM 57493; D000262:Adenylyl Cyclases; D004298:Dopamine