Effects of serotonin 5-HT1/2 receptor agonists in a limited-access operant food intake paradigm in the rat

Hypophagic effects of serotonergic drugs have mostly been investigated in free-feeding paradigms and are generally ascribed to drug-induced acceleration of satiety, or to behavioral disruption. The present study investigated the hypophagic effects of various 5-HT1/2 receptor agonists in an operant paradigm. Because of its limited duration (10-min session) the procedure was considered to be relatively insensitive to satiety processes. The behavioral specificity of the hypophagic effect was assessed by additional testing of the compounds in a locomotor activity assay. Male Wistar rats, maintained at about 80% of their free-feeding weights, were trained to acquire stable operant responding in daily fixed ratio:10 food-reinforced sessions; after which they were tested once a week with a 5-HT receptor agonist. Each compound dose-dependently suppressed the number of earned pellets after i.p. administration: DOI (5-HT2A/2C receptor agonist; ED50: 0.36 mg/kg), TFMPP (5-HT1B/2C/2A; 0.37 mg/kg), m-CPP (5-HT2C/1B/2A; 0.54 mg/kg), ORG 37684 (5-HT2C/2A; 0.85 mg/kg), CP-94,253 (5-HT1B; 2.09 mg/kg), BW 723C86 (5-HT2B; 6.26 mg/kg) and ipsapirone (5-HT1A; 10.17 mg/kg). When tested at the dose equivalent to the ED50 value in the operant paradigm, only ORG 37684 and DOI weakly suppressed activity counts in a locomotor activity assay; suggesting that the inhibition of operant food intake obtained with the other compounds at these doses is not a direct consequence of unconditioned motor effects. It is suggested that the hypophagic effect induced by relatively low doses of CP-94,253, TFMPP and m-CPP, and by moderate doses of ipsapirone and BW 723C86, is partly due to a drug-induced suppression of appetite. Although the exact contribution of the diverse 5-HT1/2 receptor subtypes to appetite control remains to be studied in more detail, it is hypothesized that activation of 5-HT1B and/or 5-HT2C receptors attenuates appetite.