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 (H_1/2) 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 H_1/2-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.