First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased Nup>蟿up>-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines.
Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by 伪-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that Hub>3ub>R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in Hub>1ub>R gene knockout mice but not in histamine Hub>2ub> receptor (Hub>2ub>R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an Hub>1ub>R antagonist, and dominantly by zolantidine, an Hub>2ub>R antagonist. These results suggest that Hub>3ub>R blockade induces histamine release, activates Hub>2ub>R and elicits exploratory locomotor activity and anxiety-like behaviours.