The interactions in the rat striatum between H3 receptors (H3Rs) and D2 receptors (D2Rs) were investigated with the [35S]GTPγ[S] binding assay. The H3R agonist (R)α-methylhistamine increased [35S]GTPγ[S] binding to striatal membranes with an EC50 = 14 ± 5 nM and a maximal effect of +19 ± 1%. This effect was inhibited by the H3R antagonist ciproxifan with a Ki = 1.0 ± 0.3 nM. The D2R agonist quinpirole increased [35S]GTPγ[S] binding to the same membranes with an EC50 = 1.5 ± 0.5 μM and a maximal effect of +28 ± 2%. Its effect was blocked by haloperidol with a Ki = 0.3 ± 0.1 nM. The maximal effects of the H3R and D2R agonists were additive (+46 ± 3%). However, D2R ligands did not modify the effects of H3R ligands and vice versa. Ciproxifan behaved as an H3R 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 H3Rs and D2Rs 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 H3Rs and D2Rs suggest that they cooperate to generate some schizophrenic symptoms. Such a postsynaptic mechanism may underlie the antipsychotic-like effects of H3R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics.