Histamine H-3 receptor activation selectively inhibits dopamine D-1 receptor-dependent [H-3]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata

The release of [H-3]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K+ from 6 to 15 mM in the presence of 10 mu M sulpiride was inhibited by 73 +/- 3% by 1 mu M SCH 23390, consistent with a large component of release dependent upon D-1 receptor activation. The histamine H-3 receptor-selective agonist immepip (1 mu M) and the non-selective agonist histamine (100 mu M) inhibited [H-3]GABA release by 78 +/- 2 and 80 +/- 2%, respectively. The inhibition by both agonists was reversed by the H-3 receptor antagonist thioperamide(1 mu M). However, in the presence of 1 mu M SCH 23390 depolarization-induced release of [H-3]GABA was not significantly decreased by 1 mu M immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [H-3]GABA, but in the presence of 1 mu M SKF 38393, which produced a 7 +/- 1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip(1 mu M) also inhibited the depolarization-induced release of [3H]dopamine from substantia nigra pars reticulata slices, by 38 +/- 3%. The evidence is consistent with the proposition that activation of histamine H-3 receptors leads to the selective inhibition of the component of depolarization-induced [H-3]GABA release in substantia nigra pars reticulata slices which is dependent upon D-1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [H-3]dopamine release. (C) 1997 IBRO. Published by Elsevier Science Ltd.