Neurotoxicity of chlorpromazine and modulation by amantadine as a function of mouse strain.
The separate and combined effects of successive administration of amantadine, 100 mg/kg, i.p., and chlorpromazine, 0.2 mg/kg, i.p., on motor activity and whole brain levels of certain biogenic amines and major metabolites were studied in four strains of mice. These were the albino ICR, the inbred BALB/C, C57BL/6 and the hybrid CDF-I mice. Amantadine produced a strain-dependent behavioral stimulation subsequent the fourth dose. This was apparent in ICR and C57BL/6 mouse strains and was followed by a behavioral depression phase occurring during the night in C57BL/6 mice which was antagonized by chlorpromazine. Administration of chlorpromazine alone affected only CDF-1 mouse mobility. Chlorpromazine reduced only ICR mouse brain dopamine without concomitant changes in major acid metabolites. Repeated administration of amantadine prior to chlorpromazine negated this effect. Chlorpromazine enhancement of BALB/C brain serotonin and 5-hydroxyindoleacetic acid was antagonised by pretreatment with amantadine. This antagonism was also evident in BALB/C mouse brain dihydroxyphenylacetic acid. The results suggest genotypic-dependent behavioral and cerebral effects by the drugs studied. The antagonism between amantadine and chlorpromazine on brain amines may explain the therapeutic efficacy of amantadine in modulating chlorpromazine-induced extrapyramidal disorders.
Messiha
F S
FS
Department of Pharmacology, University of North Dakota School of Medicine, Grand Forks 58203.
D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000235:genetics; D002746:Chlorpromazine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000547:Amantadine; D002746:Chlorpromazine