IMPAIRED LOCOMOTOR-ACTIVITY AND EXPLORATORY-BEHAVIOR IN MICE LACKING HISTAMINE H-1 RECEPTORS

From pharmacological studies using histamine antagonists and agonists, it has been demonstrated that histamine modulates many physiological functions of the hypothalamus, such as arousal state, locomotor activi ty, feeding, and drinking, Three kinds of receptors (H-1, H-2, and H-3 ) mediate these actions, To define the contribution of the histamine H -1 receptors (H1R) to behavior, mutant mice lacking the H1R were gener ated by homologous recombination, In brains of homozygous mutant mice, no specific binding of [(3)]pyrilamine was seen. [H-3]Doxepin has two saturable binding sites with higher and lower affinities in brains of wild-type mice, but H1R-deficient mice showed only the weak labeling of [H-3]doxepin that corresponds to lower-affinity binding sites, Muta nt mice develop normally, but absence of H1R significantly increased t he ratio of ambulation during the light period to the total ambulation for 24 hr in an accustomed environment, In addition, mutant mice sign ificantly reduced exploratory behavior of ambulation and rearings in a nem environment, These results indicate that through H1R, histamine i s involved in circadian rhythm of locomotor activity and exploratory b ehavior as a neurotransmitter.