Behavioral Pharmacology of Serotonin Inverse Agoinsts

描述（由申请人提供）：对具有5-羟色胺2C （5-HT2C）受体亲和力的药物进行严格的药理学分析对于这些药物作为致幻剂、抗精神病药和抗抑郁药的表征至关重要。在体外，5-HT2C受体表现出组成活性，因此能够在没有激动剂的情况下启动信号转导。药物改变基础组成活性的能力，一种被称为内在功效的性质，在5-HT2C配体中是不同的；完全激动剂增加基础活性，反向激动剂降低基础活性（分别为正效和负效），如果受体被中性拮抗剂占据（零效），基础活性不变。本提案将研究5-HT2C激动剂、逆激动剂和中性拮抗剂相互作用时，阳性和阴性内在功效在决定行为和药理学结果中的作用。两种行为方法将用于研究小鼠的这些关系。在第一个过程中，辨别条件味觉厌恶（CTA）， 5-HT2C药物的刺激作用作为CTA产生的线索。在第二个过程中，操作性药物辨别，5 -HT2C药物的刺激作用表明两种选择中哪一种会导致强化。小鼠将被训练在两个程序中区分具有代表性的5-HT2C激动剂、中性拮抗剂和反向激动剂。具有不同受体选择性（即5-HT2A或5-HT2B）和不同药理活性（即激动剂与反激动剂）的化合物将在训练组中产生不同的替代模式。其他实验将检验负内在功效在5-HT2C中性拮抗剂和逆激动剂阻断5-HT2C药物的区别性刺激作用中的作用。最后，我们将探讨中性拮抗剂和逆激动剂慢性治疗对5-HT2C药物区别性刺激作用的疗效作用。据推测，与慢性治疗中性拮抗剂相比，慢性治疗中使用反向激动剂会产生更大的激动剂、中性拮抗剂和反向激动剂的剂量-反应曲线变化。综上所述，这些实验将为5-HT2C反向激动剂和中性拮抗剂提供新的药理学和/或行为特征，同时测试从体外数据产生的假设。

DESCRIPTION (provided by applicant): 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.