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

A study was made of the regulation of [ 3 H]‐γ‐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 μ M ). The sulpiride‐potentiated release of [ 3 H]‐GABA was strongly inhibited by the dopamine D 1 receptor family antagonist, SCH 23390 (1 μ M ). Neither antagonist altered basal release. The 15 m M K + ‐induced release of [ 3 H]‐GABA in the presence of sulpiride was inhibited by 100 μ M histamine (mean inhibition 78±3%) and by the histamine H 3 receptor‐selective agonist, immepip, 1 μ M (mean inhibition 81±5%). The IC 50 values for histamine and immepip were 1.3±0.2 μ M and 16±2 n M , respectively. The inhibitory effects of histamine and immepip were reversed by the H 3 receptor antagonist, thioperamide, 1 μ M . The inhibition of 15 m M K + ‐induced [ 3 H]‐GABA release by immepip was reversed by the H 3 receptor antagonist, clobenpropit, K d 0.11±0.04 n M . Clobenpropit alone had no effect on basal or stimulated release of [ 3 H]‐GABA. 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 μ M , was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 μ M immepip to the level obtained in the absence of SKF 38393. 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. British Journal of Pharmacology (2001) 133 , 165–171; doi: 10.1038/sj.bjp.0704053