1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.