Influence of the 5‐HT2C receptor antagonist SB242,084 on behaviour produced by the 5‐HT2 agonist Ro60‐0175 and the indirect 5‐HT agonist dexfenfluramine

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Abstract
Ro60‐0175 has been described as a selective agonist at the 5‐HT2C receptor, yet it has only 10‐ fold higher affinity at the 5‐HT2C compared to the 5‐HT2A subtype, and equivalent affinity for the 5‐HT2B receptor. The selective 5‐HT2C 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‐HT2A receptor antagonist MDL100,907 (0.5 mg kg−1 i.p.), but not the 5‐HT2B 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‐HT2C 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