Ketotifen can antagonise changes in sensitivity of cerebral dopamine receptors: behavioural correlates in rodent and primate.

Rats preselected as "low responders" to the hyperactivity-inducing action of (-)N-n-propylnorapomorphine [(-)NPA] responded to an infusion of dopamine into the nucleus accumbens (25 micrograms/24 hr for 13 days) with hyperactivity during the infusion and long-term increased sensitivity to (-)NPA administered after the infusion. Both effects were antagonised by ketotifen (intraperitoneal infusion, 1 mg/kg/day), administered during the period of infusion of dopamine. Animals subject to infusion of dopamine also showed enhanced hyperactivity to L-DOPA (plus benserazide): this enhanced response was also antagonised by ketotifen, given acutely as a single dose (1 mg/kg i.p.). When haloperidol was given concurrently with the infusion of dopamine, spontaneous locomotor activity was markedly increased after the infusion for a period of at least 7 weeks: this long-term change was antagonised by ketotifen (1 mg/kg/24 hr), given during the period of treatment with dopamine/haloperidol or by a single acute injection of ketotifen (0.1-1.0 mg/kg i.p.) on an established response. Ketotifen, in doses up to 20 mg/kg (i.p.) did not reduce spontaneous locomotor activity, cause catalepsy or antagonise amphetamine-induced stereotypy in normal rats. In the marmoset, an enhanced sensitivity to the locomotor-stimulant effects of L-DOPA was induced 5 to 8 weeks after a treatment for 4 days with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which led to the development of akinesia and severe depletion of dopamine in the striatum. Treatment with a single dose of ketotifen (1 mg/kg i.p.) 60 min before L-DOPA antagonised the enhanced locomotor responsiveness to the L-DOPA/benserazide regimen.(ABSTRACT TRUNCATED AT 250 WORDS)