Behavioral Pharmacology of Serotonin Inverse Agoinsts

描述(申请人提供)：对与5-HT2C(5-HT2C)受体有亲和力的药物进行严格的药理学分析，对于将这些药物定性为致幻剂、抗精神病药物和抗抑郁药至关重要。在体外，5-HT2C受体表现出结构性活性，因此能够在没有激动剂的情况下启动信号转导。一种药物改变基本构成活性的能力，这一特性被称为内在效力，在不同的5-HT2C配体中是不同的；基础活性被完全激动剂增加，反向激动剂(分别为正效应和负效应)降低，而如果受体被中性拮抗剂占据(零效)，则基本活性不变。在这项提案中，将研究正负内在效应在决定5-HT2C激动剂、反向激动剂和中性拮抗剂相互作用的行为和药理学结果中的作用。将使用两种行为方法来研究小鼠的这些关系。在第一个过程中，5-HT2C药物的刺激效应作为产生CTA的线索，即辨别条件性厌味(CTA)。在第二个过程中，操作药物辨别，5-HT2C药物的刺激效应作用于发出信号，表明两个选择中的哪一个将导致强化。将训练小鼠在两种程序中辨别具有代表性的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的化合物(即5-HT2A或5-HT2B)和不同药理活性(即激动剂和反向激动剂)将在训练组之间产生不同的取代模式。其他实验将检验5-HT2C中性拮抗剂和反向激动剂阻断5-HT2C药物的歧视性刺激效应的能力中负内在效应所起的作用。最后，将研究疗效在中性拮抗剂和反向激动剂慢性治疗对5-HT2C药物辨别性刺激效应的影响中的作用。假设慢性使用反向激动剂将导致激动剂、中性拮抗剂和反向激动剂的剂量-反应曲线比使用中性拮抗剂的慢性治疗产生更大的变化。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一种新的药理学和/或行为概况，同时测试根据体外数据产生的假说。

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.