Histamine H 3 and dopamine D 2 receptor-mediated [ 35S]GTPγ[S] binding in rat striatum: Evidence for additive effects but lack of interactions

Abstract

The interactions in the rat striatum between H 3 receptors (H 3Rs) and D 2 receptors (D 2Rs) were investigated with the [ 35S]GTPγ[S] binding assay. The H 3R agonist ( R)α-methylhistamine increased [ 35S]GTPγ[S] binding to striatal membranes with an EC 50 = 14 ± 5 nM and a maximal effect of +19 ± 1%. This effect was inhibited by the H 3R antagonist ciproxifan with a K i = 1.0 ± 0.3 nM. The D 2R agonist quinpirole increased [ 35S]GTPγ[S] binding to the same membranes with an EC 50 = 1.5 ± 0.5 μM and a maximal effect of +28 ± 2%. Its effect was blocked by haloperidol with a K i = 0.3 ± 0.1 nM. The maximal effects of the H 3R and D 2R agonists were additive (+46 ± 3%). However, D 2R ligands did not modify the effects of H 3R ligands and vice versa. Ciproxifan behaved as an H 3R inverse agonist and decreased [ 35S]GTPγ[S] binding. Haloperidol had no effect and did not change the inverse agonist effect of ciproxifan. Administrations for 10 days of ciproxifan (1.5 mg/kg/day) or haloperidol (0.5 mg/kg/day) did not change the effects of quinpirole and ( R)α-methylhistamine, respectively. These data suggest that striatal H 3Rs and D 2Rs do not interact through their coupling to G-proteins. However, a hyperactivity of histaminergic and dopaminergic neurons being observed in schizophrenia, the additive activations of H 3Rs and D 2Rs suggest that they cooperate to generate some schizophrenic symptoms. Such a postsynaptic mechanism may underlie the antipsychotic-like effects of H 3R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics.