Histamine responses of large neostriatal interneurons in histamine H1 and H2 receptor knock-out mice

Histamine (HA) is an important neuro-modulator, contributing to a variety of physiological responses in the mammalian central nervous system (CNS). However there is little information about the cell/signaling mechanism underlying its role. In the present study, we characterized HA responses in single large neostriatal neurons acutely dissociated from wild type (WT) and HA receptor knock-out (KO) mice, with a particular emphasis on identifying the role of HA receptor subtypes. HA (10 μM) and a selective H2 receptor agonist dimaprit (1 μM) both evoked an inward current in H1-KO mice, and HA and a selective H1 receptor agonist HTMT (10 μM) both evoked an inward current in H2-KO mice. In the H1 and H2 double (H1/2) KO mice, there was no response to either the application of HA or the selective H1, H2 receptor agonists. Hence we have confirmed that the targeted genes were indeed absent in these KO mice and that both receptor subtypes contribute to HA's excitatory actions. Furthermore the HA-induced inward currents were mediated by a decrease in current through K+ channels. In addition, we observed the effects of methamphetamine (METH) on the locomotor activity of WT and HA receptor KO mice, and found that METH-induced behavioral sensitization is evident in H1/2-KO mice, but not in H1- or H2-KO mice. These observations suggest that suppressive roles of HA on methamphetamine-induced behavioral sensitization would be mediated through both H1 and H2 receptors in the CNS including neostriatum.