Alterations of serotonin neurotransmission and inhibition of mouse-killing behavior: III Effects of minaprine, CM 30366 and SR 95191

Abstract

Three closely related aminopyridazine derivatives: minaprine [3-(2-morpholino-ethylamino)-4-methyl-6-phenyl pyridazine, dihydrochloride], CM 30366 [3-(2-morpholino-ethylamino)-4-methyl-6-(4-hydroxyphenyl) pyridazine, hydrobromide] and SR 95191 [3-(2-morpholino-ethylamino)-4-cyano-6-phenyl pyridazine] were examined for their inhibitory effects on mouse-killing behavior (MKB). Three groups of killer rats were used: spontaneous killer rats (K rats) and nonkillers which became killers following para-chlorophenylalanine (PCPA) treatment or electrolytical destruction of the dorsal and median raphe nuclei. When given intraperitoneally (IP), the three drugs inhibited MKB of K rats without sedation. When given orally, miniprine showed no antimuricidal effect in K rats. After chronic IP administration of minaprine, MKB inhibition in K rats decreased after 25 days of treatment, probably because serotonin receptors became subsensitive. Minaprine and SR 95191, a derivative of minaprine, are inhibitors of type A monoamine oxidase (MAO), whereas CM 30366, a metabolite of minaprine, has no effect on MAO activity. SR 95191 displayed a similar MKB inhibition in the three groups of killer rats, and in this respect, it behaved like other type A MAO inhibitors. Minaprine and CM 30366 were less efficient in their antimuricidal effect in PCPA-treated and raphe-lesioned killer rats as compared with spontaneous killer rats. Moreover, the time courses of MKB inhibition by miniaprine did not correlate. The effect of miniaphrine on mKB seemed not related in a simple way to an alteration of serotonin level through MAO A inhibition, and rise the question of an alternative mechanism of antimuricidal action, until now unknown.