Blockade of Serotonin 2C Receptors with SB-242084 Moderates Reduced Locomotor Activity and Rearing by Cannabinoid 1 Receptor Antagonist AM-251

The endocannabinoid and serotonin (5-HT) systems have key roles in the regulation of several physiological functions such as motor activity and food intake but also in the development of psychiatric disorders. Here we tested the hypothesis, whether blockade of serotonin 2C (5-HT2C) receptors prevents the reduced locomotor activity and other behavioral effects caused by a cannabinoid 1 (CB1) receptor antagonist. As a pretreatment, we administered SB-242084 (1 mg/kg, ip.), a 5-HT2C receptor antagonist or vehicle (VEH) followed by the treatment with AM-251 (5 or 10 mg/kg, ip.), a CB1 receptor antagonist or VEH. The effects of the two drugs alone or in co-administration were investigated in social interaction (SI) and elevated plus maze (EPM) tests in male Wistar rats. Our results show that AM-251 decreased the time spent with rearing in the SI test and decreased locomotor activity in EPM test. In contrast, SB-242084 produced increased locomotor activity in SI test and evoked anxiolytic-like effect in both SI and EPM tests. When applied the drugs in combination, these behavioral effects of AM-251 were moderated by SB-242084. Based on these findings, we conclude that certain unwanted behavioral effects of CB1 receptor antagonists could be prevented by pretreatment with 5-HT2C receptor antagonists.