Rigorous pharmacological analysis of drugs with affinity for serotonin 2C (5-HT2C) receptors is critical to the characterization of these drugs as hallucinogens, antipsychotics, and antidepressants. In vitro, 5-HT2C receptors exhibit constitutive activity and thereby are capable of initiating signal transduction in the absence of agonists. The ability of a drug to alter the basal constitutive activity, a property referred to as intrinsic efficacy, varies among 5-HT2C ligands; basal activity is increased by full agonists, decreased by inverse agonists (positive and negative efficacy, respectively) and is unaltered if the receptor is occupied by a neutral antagonist (zero efficacy). The role of positive and negative intrinsic efficacy in determining the behavioral and pharmacological outcomes with 5-HT2C agonists, inverse agonists, and neutral antagonists interact will be investigated in this proposal. Two behavioral approaches will be used to study these relationships in mice. In the first procedure, discriminated conditioned taste aversion (CTA), the stimulus effects of 5-HT2C drugs serve as cues for producing CTA. In the second procedure, operant drug discrimination, the stimulus effects of 5 -HT2C drugs act to signal which of two choices will result in reinforcement. Mice will be trained to discriminate a representative 5-HT2C agonist, neutral antagonist, and an inverse agonist in both procedures. Compounds with different receptor selectivities (i.e., 5-HT2A or 5-HT2B) and different pharmacological activity (i.e., agonists versus inverse agonists) will produce different patterns of substitution among the training groups. Additional experiments will examine the role negative intrinsic efficacy plays in the capacity of 5-HT2C neutral antagonist and inverse agonists to block the discriminative stimulus effects of 5-HT2C drugs. Finally, the role of efficacy in the effects of chronic treatment with neutral antagonists and inverse agonists on the discriminative stimulus effects of 5-HT2C drugs will be investigated. It is hypothesized that chronic treatment with inverse agonists will produce greater alteration in dose-response curves of agonists, neutral antagonists, and inverse agonists than chronic treatment with neutral antagonists. Taken together, these experiments will provide a novel pharmacological and/or behavioral profile for 5-HT2C inverse agonists and neutral antagonists while testing hypotheses generated from in vitro data.
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