Blockade of brain histamine metabolism alters methamphetamine-induced expression pattern of stereotypy in mice via histamine H 1 receptors

Abstract

The administration of methamphetamine (METH, 10 mg/kg, i.p.) to male ICR mice induced stereotyped behavior consisting of nail and/or wood chip biting (86.0%), continuous sniffing (12.0%), head bobbing (1.1%), and circling (1.0%) during the observation period of 1 h. Pretreatment of the mice with metoprine (2, 10, and 20 mg/kg, i.p.), a selective inhibitor of histamine N-methyltransferase (HMT), which metabolizes histamine in the brain, significantly increased and decreased METH-induced continuous sniffing (20.5, 51.3, and 80.3%) and nail and/or wood chip biting (77.4, 45.3, and 14.2%), respectively, in a dose-dependent manner. The hypothalamic contents of histamine and its metabolite N τ-methylhistamine were significantly increased and decreased by metoprine (10 mg/kg, i.p.), respectively. The metoprine action on METH-induced behavior was completely abolished by pyrilamine (10 and 20 mg/kg) and ketotifen (10 mg/kg), selective, centrally acting histamine H 1 receptor antagonists, but not by fexofenadine (20 mg/kg), zolantidine (10 mg/kg) and thioperamide (10 mg/kg), a peripherally acting histamine H 1 receptor antagonist and a selective, brain-penetrating antagonist for histamine H 2 and H 3 receptors, respectively. The metoprine action was mimicked by SKF 91488 (100 μg/animal, i.c.v.), another HMT inhibitor, and the action of SKF 91488 was also blocked by pyrilamine. The frequency of the expression of METH-induced total stereotypic patterns was unchanged after metoprine pretreatment. Mice pretreated with metoprine displayed no anxiety-like behavior in the elevated plus maze test. These results suggest that brain histamine, increased by agents such as metoprine and SKF 91488, binds to histamine H 1 receptors in the brain, resulting in the modulation of dopaminergic transmission associated with stereotyped behavioral patterns induced by METH.