The effects of the selective histamine H₃ receptor agonist (R)-α-methylhistamine and antagonist thioperamide on stimulant-induced locomotor activity in the mouse were examined. Amphetamine (1 mg·kg⁻¹ s.c.), apomorphine (2 mg·kg⁻¹ s.c.) or cocaine (5 mg·kg ⁻¹ s.c.) increased locomotor activity. Neither thioperamide (10 mg·kg ⁻¹ i.p.) nor (R)-α-methylhistamine (20 mg·kg⁻¹ i.p.) affected spontaneous locomotor activity in their own right. (R)-α-Methylhistamine (0.3, 3 or 20 mg·kg⁻¹ i.p.) also had no effect on amphetamine (1 mg·kg ⁻¹ s.c.)-induced locomotor activity. In contrast, thioperamide (0.2–10 mg·kg ⁻¹ i.p. or 0.3–20 μg i.c.v.) inhibited, in a dose-dependent manner, the hyperactivity response induced by amphetamine (1 mg·kg ⁻¹ s.c.). (R)-α-Methylhistamine (20 mg·kg ⁻¹ i.p.) completely reversed the inhibitory response to thioperamide (2 mg·kg⁻¹ i.p.). Thioperamide (2 or 10 mg·kg ⁻¹ i.p.) also inhibited apomorphine (2 mg·kg ⁻¹ s.c.)- and, to a lesser extent, cocaine (5 mg·kg⁻¹ s.c.)-induced hyperactivity. We therefore conclude that antagonism of the central histamine H₃ receptor inhibits, to a varying degree, the effects of locomotor stimulants.