Dopamine autoreceptors and the effects of drugs on locomotion and dopamine synthesis

Abstract

Criteria for distinguishing dopamine autoreceptor agonism from other mechanisms of inhibiting locomotion were examined, together with the relationship between inhibition of locomotion and dopamine synthesis. ED50 potencies to inhibit locomotion of mice were established for drugs from a number of categories. Spiperone 0.02 mg kg−1 significantly (P<0.05) reversed inhibition of locomotion by known dopamine agonists but not that by the other types of drug. Idazoxan antagonized inhibition of locomotion due to α2‐agonists but not dopamine agonists. RU 24926 (N‐propyl‐N,N‐di[2‐(3‐hydroxyphenyl)ethyl]amine) was antagonized by both spiperone and idazoxan. Only for dopamine agonists was there good correlation (r = 0.97) between potencies to inhibit locomotion in mice and 1‐dihydroxyphenylalanine (1‐DOPA) accumulation in the nucleus accumbens of rats treated with γ‐butyrolactone and 3‐hydroxybenzylhydrazine. The specific dopamine D1‐agonist, SK&F 38393 (2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐3‐benzazepine), was inactive in both tests at doses up to 10 mg kg−1. The mixed dopamine agonist/antagonist, (—)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine, commonly known as (—)‐3‐PPP, acted as a dopamine agonist in both tests but inhibited locomotion more potently than 1‐DOPA accumulation. The inhibitory effects of dopamine agonists on locomotion were not prevented by α‐methyl‐p‐tyrosine pretreatment. The data suggest that spiperone‐reversible inhibition of locomotion in mice is a good criterion for dopamine autoreceptor agonists. The receptors involved are affected by low doses of both dopamine agonists and antagonists and seem similar to those involved in the autoreceptor mediated inhibition of dopamine synthesis. However, inhibition of locomotion is not due simply to suppression of dopamine release brought about as a secondary consequence of effects on synthesis; a separate mechanism for inhibiting dopamine release is probably involved. 1985 British Pharmacological Society