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.