Neuropsychopharmacology of Cyclic AMP PDE Inhibitors

环 AMP PDE 抑制剂的神经精神药理学

• 批准号: 7036839
• 负责人: JAMES M O'DONNELL
• 金额: $ 35.76万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036839
• 关键词: adenylate cyclase; adrenergic receptor; antidepressants; antisense nucleic acid; behavior test; cyclic AMP; dopamine receptor; dosage; enzyme activity; ethology; laboratory mouse; laboratory rat; memory; neuropharmacology; pharmacokinetics; phosphodiesterase inhibitors; psychopharmacology; second messengers; synaptogenesis; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Inhibitors of Type 4 cyclic AMP phosphodiesterase (PDE4), such as rolipram, produce both antidepressant-like and memory-enhancing effects in preclinical models. Consistent with this, it has been shown that drugs from this class possess clinical antidepressant efficacy, including reversal of cognitive deficits that occur in depression. Ultimately, it may prove possible to dissociate the antidepressant and cognitive effects of PDE4 inhibitors from their other pharmacological effects. To do so will require a better understanding of the roles of the PDE4 subtypes expressed in brain (PDE4A, PDE4B, and PDE4D) in mediating the behavioral effects of PDE4 inhibitors. In addition, the manner in which PDE4 inhibitors interact with two affinity states of the PDE4 molecule (termed the high-affinity and low-affinity rolipram binding sites) to produce their effects on behavior must be elucidated. The proposed experiments will address the neuropharmacological mechanisms by which PDE4 inhibitors produce antidepressant-like and memory-enhancing effects on behavior. In addition they will assess the role of PDE4 in mediating the behavioral effects of proven antidepressant drugs. The specific aims are to: 1) Determine the effects of repeated treatment with antidepressant drugs on the expression of PDE4 subtypes and on high- and low-affinity rolipram binding sites in brain regions of rats and mice; 2) Determine whether the antidepressant-like effects of PDE4 inhibitors depend on intact noradrenergic and serotonergic function; 3) Determine which PDE4 subtypes are involved in mediating the behavioral effects of antidepressants and the antidepressant-like behavioral effects of PDE4 inhibitors; 4) Determine which PDE4 subtypes are involved in mediating the memory-enhancing effects of PDE4 inhibitors; and 5) Determine the contribution of the high- and low-affinity rolipram binding sites to the behavioral and neurochemical effects of PDE4 inhibitors. Completion of the proposed experiments will establish the importance of the individual PDE4 subtypes and the high- and low-affinity rolipram binding sites in the mediation of antidepressant-like and memoryenhancing effects of PDE4 inhibitors. In addition, the role of noradrenergic and serotonergic systems in the mediation of the neuropsychopharmacological effects of PDE4 inhibitors will be elucidated. Overall, such information will aid in the identification of novel pharmacological targets for the pharmacotherapy of depression.

描述（由申请人提供）：4 型环 AMP 磷酸二酯酶 (PDE4) 抑制剂，例如咯利普兰，在临床前模型中产生抗抑郁样作用和记忆增强作用。与此相一致的是，此类药物已被证明具有临床抗抑郁功效，包括逆转抑郁症中出现的认知缺陷。最终，可能会证明将 PDE4 抑制剂的抗抑郁和认知作用与其其他药理作用分开。为此，需要更好地了解大脑中表达的 PDE4 亚型（PDE4A、PDE4B 和 PDE4D）在介导 PDE4 抑制剂的行为效应中的作用。此外，必须阐明 PDE4 抑制剂与 PDE4 分子的两种亲和状态（称为高亲和力和低亲和力咯利普兰结合位点）相互作用以产生其对行为的影响的方式。 拟议的实验将探讨 PDE4 抑制剂对行为产生抗抑郁样作用和增强记忆作用的神经药理学机制。此外，他们还将评估 PDE4 在调节已证实的抗抑郁药物的行为效应中的作用。具体目的是：1）确定抗抑郁药物重复治疗对大鼠和小鼠脑区PDE4亚型表达以及咯利普兰高亲和力和低亲和力结合位点的影响； 2）确定PDE4抑制剂的抗抑郁样作用是否依赖于完整的去甲肾上腺素能和5-羟色胺能功能； 3）确定哪些PDE4亚型参与介导抗抑郁药的行为效应和PDE4抑制剂的抗抑郁样行为效应； 4）确定哪些PDE4亚型参与介导PDE4抑制剂的记忆增强作用； 5) 确定高亲和力和低亲和力咯利普兰结合位点对 PDE4 抑制剂的行为和神经化学作用的贡献。 完成所提出的实验将确定各个 PDE4 亚型以及高亲和力和低亲和力咯利普兰结合位点在介导 PDE4 抑制剂的抗抑郁样和记忆增强作用中的重要性。此外，还将阐明去甲肾上腺素能和血清素能系统在介导 PDE4 抑制剂的神经精神药理学作用中的作用。总的来说，这些信息将有助于确定抑郁症药物治疗的新药理学靶点。