Histamine H-3 receptor-mediated inhibition of depolarization-induced, dopamine D-1 receptor-dependent release of [H-3]-gamma-aminobutyric acid from rat striatal slices

1 A study was made of the regulation of [H-3]-gamma -aminobutyric acid ([H- 3]-GABA) release from slices of rat striatum by endogenous dopamine and exo genous histamine and a histamine H-3-agonist. Depolarization-induced releas e of [H-3]-GABA was Ca2+-dependent and was increased in the presence of the dopamine D-2 receptor family antagonist, sulpiride (10 muM) The sulpiride- potentiated release of [H-3]-GABA was strongly inhibited by the dopamine D- 1 receptor family antagonist, SCH 23390 (1 muM). Neither antagonist altered basal release. 2 The 15 mM K+-induced release of [H-3]-GABA in the presence of sulpiride w as inhibited by 100 muM histamine (mean inhibition 78 +/- 3%) and by the hi stamine H-3 receptor-selective agonist, immepip, 1 muM (mean inhibition 81 +/- 5%). The IC50 values for histamine and immepip were 1.3 +/- 0.2 muM and 16 +/- 2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H-3 receptor antagonist, thioperamide, 1 muM. 3 The inhibition of 15 mM K+-induced [3H]-GABA release by immepip was rever sed by the H3 receptor antagonist, clobenpropit, K-d 0.11 +/- 0.04 nM. Clob enpropit alone had no effect on basal or stimulated release of [H-3]-GABA. 4 Elevated K+ caused little release of [H-3]-GABA from striatal slices from reserpinized rats, unless the D-1 partial agonist, R(+)-SKF 38393, 1 muM, was also present. The stimulated release in the presence of SKF 38393 was r educed by 1 muM immepip to the level obtained in the absence of SKF 38393. 5 These observations demonstrate that histamine H-3 receptor activation str ongly inhibits the dopamine D-1 receptor-dependent release of [H-3]-GABA fr om rat striatum; primarily through an interaction at the terminals of GABA neurones.