Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system

The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis.Single injection of risperidone (0.5 mg/kg, i.p.) or aripiprazole (1 mg/kg, i.p.), which have binding affinities to 5-HT1A, 2A, 2B and 2C receptors decreased food intake in C57BL/6 N mice with concomitant increase of hypothalamic histamine release. However, a selective D2-antagonist, haloperidol (0.5 mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H1 receptor-deficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT2A-antagonists, volinanserin (0.5, 1 mg/kg, i.p.) and ketanserin (5, 10 mg/kg, i.p.), significantly increased histamine release and 5-HT2B/2C -antagonist, SB206553 (2.5, 5 mg/kg, i.p.), slightly increased it. On the contrary, 5-HT1A -selective antagonist, WAY100635 (1, 2 mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT2 receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT2 receptors resulting in anorexia via the H1 receptor.

► Relatively high dose of risperidone or aripiprazole decreased food intake in mice.
► These drugs increased the hypothalamic histamine release.
► These drugs did not reduced food intake in histamine H1 receptor-KO mice.
► Hypothalamic histamine release was increased even in H1 receptor-KO mice.
► Selective 5-HT antagonists increased histamine release.