Alterations of serotonin neurotransmission and inhibition of mouse-killing behavior: III. Effects of minaprine, CM 30366 and SR 95191.
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, minaprine 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 and MAO A inhibition by minaprine did not correlate. The effects of minaprine 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.
Isel
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F
Centre de Neurochimie du CNRS, Strasbourg, France.
Mandel
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P
D000284:Administration, Oral; D000374:Aggression; D000378:Agonistic Behavior / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000293:injuries; D051381:Rats; D011919:Rats, Inbred Strains; D012934:Social Isolation; D013997:Time Factors
D008996:Monoamine Oxidase Inhibitors; D011724:Pyridazines; C006149:minaprine; C050474:CM 30366; C051273:SR 95191; D010134:Fenclonine