Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design.
The actions of intracerebroventricularly-infused histamine and selective histamine H1, H2 and H3 receptor agonists on food and water intake and urine flow were studied in rats. It was found that 100-800 nmoles of histamine significantly suppressed feeding. The H1 agonist 2-(3- trifluoromethylphenyl)histamine (FMPH) decreased food intake, whereas the H2 agonist dimaprit was without effect. Histamine- and FMPH-induced suppressions of feeding were attenuated by blockade of H1 but not by H2 receptors. The results clearly demonstrate that activation of brain H1 receptors decreases food intake. In subsequent studies, we found that both metoprine and thioperamide, which increase histaminergic activity through different mechanisms, also reduced food intake. This finding indicates that the brain histaminergic system is associated with feeding behavior. The same is true with body water homeostasis. Histamine caused a long-lasting diuresis. Also dimaprit and metoprine increased urine flow and the blockade of H2 receptors abolished the diuretic responses to histamine and dimaprit. On the other hand, the H3 agonist (R)-alpha-methylhistamine elicited drinking and this effect could be prevented by thioperamide pretreatment. The results imply that activation of H3 receptors predominantly provokes drinking, whereas central H2 receptors mediate the diuretic effect of histamine.