Influence of the 5‐HT 2C receptor antagonist SB242,084 on behaviour produced by the 5‐HT 2 agonist Ro60‐0175 and the indirect 5‐HT agonist dexfenfluramine

• Published in: British journal of pharmacology Vol. 133; no. 4; pp. 459 - 466
• Main Authors: Higgins, G A, Ouagazzal, A M, Grottick, A J
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704082

Ro60‐0175 has been described as a selective agonist at the 5‐HT 2C receptor, yet it has only 10‐ fold higher affinity at the 5‐HT 2C compared to the 5‐HT 2A subtype, and equivalent affinity for the 5‐HT 2B receptor. The selective 5‐HT 2C receptor antagonist SB242,084 (0.5 mg kg −1 i.p.), blocked the hypoactivity and penile grooming induced by Ro60‐0175 (1 mg kg −1 s.c.). The combination of SB242,084 (0.5 mg kg −1 i.p.) and Ro60‐0175 (3 – 10 mg kg −1 ) produced a completely different pattern of behaviours including wet‐dog shakes, hyperactivity and back muscle contractions. These latter effects were blocked by the selective 5‐HT 2A receptor antagonist MDL100,907 (0.5 mg kg −1 i.p.), but not the 5‐HT 2B receptor antagonist SB215,505 (3 mg kg −1 p.o.). The indirect 5‐HT releaser/reuptake inhibitor dexfenfluramine (1 – 10 mg kg −1 i.p.) produced a mild increase in locomotor activity, penile grooming, and occasional back muscle contractions and wet‐dog shakes. Pre‐treatment with SB242,084 (0.5 mg kg −1 ), blocked the incidence of penile grooming, and markedly potentiated both the dexfenfluramine‐induced hyperactivity, the incidence of back muscle contractions, and to a lesser extent wet‐dog shakes. Some toxicity was also evident in animals treated with dexfenfluramine (10 mg kg −1 )/SB242,084 (0.5 mg kg −1 ), but not in any other treatment groups. The hyperactivity and toxicity produced by the dexfenfluramine (10 mg kg −1 )/SB242,084 (0.5 mg kg −1 ) combination was replicated in a further study, and hyperthermia was also recorded. Both hyperthermia and toxicity were blocked by MDL100,907 (0.5 mg kg −1 ) but not SB215,505 (3 mg kg −1 ). An attenuation of the hyperlocomotor response was also observed following MDL100,907. These findings suggest that 5‐HT 2C receptor activation can inhibit the expression of behaviours mediated through other 5‐HT receptor subtypes. British Journal of Pharmacology (2001) 133 , 459–466; doi: 10.1038/sj.bjp.0704082