Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP accumulation in rat striatal slices

In striatal membranes bearing significant levels of histamine H-3 receptors (72 +/- 14 fmol/mg protein), the H-3 agonist immepip (1 muM) increased [S-35]GTPgammaS binding to 119 +/- 2% of basal, an effect prevented by the H-3 antagonist clobenpropit and by pre-treatment with pertussis toxin. In slices labelled with [H-3]adenine and in the presence of 1 mM isobutylmethylxantine (IBMX), the selective dopamine D-1-like (D-1/D-5) receptor agonist SKF-81297 stimulated cyclic [H-3]AMP ([H-3]cAMP) accumulation (maximal stimulation 205 +/- 24% of basal, EC50 113 +/- 12 nM), an effect fully blocked by the D-1/D-5 antagonist SCH-23390. The accumulation of [H-3]cAMP induced by 1 muM SKF-81297 was inhibited in aconcentration-dependent mannerby the selective H-3 receptor agonist immepip (maximal inhibition 60 +/- 5%, IC50 13 +/- 5 nM). The inhibitory action of 100 nM immepip was reversed in a concentration-dependent manner by the H-3 antagonist thioperamide (EC50 13 +/- 3 nM, K-i 1.4 +/- 10.3 nM). Forskolin-induced [H-3]cAMP accumulation (726 +/- 57% of basal) was also reduced by H-3 receptor activation, although to a lesser extent (19.1 +/- 3.2% inhibition), an action not affected by the absence of either IBMX or Ca2+ ions in the incubation medium. Neither the density of [H-3]SCH-23390 binding sites (D-1 receptors) nor the inhibition by SKF-81297 were affected by 1 muM immepip, ruling out a direct interaction between D-1 and H-3 receptors. These results indicate that through H-3 receptors coupled to Galphai/o proteins, histamine modulates cAMP formation in striatal neurones that possess D-1 receptors, most probably GABAergic striato-nigral neurones. (C) 2004 Published by Elsevier Ireland Ltd.