Abstract

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)