JNJ-10181457

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H₃ receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H₃ receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H₁ receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H₁ receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H₂ receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H₄ receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H₃ receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H₃ receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H₃ receptors, which then bind to the post-synaptic histamine receptor H₁ (but not H₂ or H₄). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.