Neuropsychopharmacology of Cyclic AMP PDE Inhibitors

描述（由申请人提供）：4型环AMP磷酸二酯酶（PDE 4）抑制剂，如咯利普兰，在临床前模型中产生抗抑郁样和记忆增强作用。与此相一致的是，已经表明这类药物具有临床抗抑郁功效，包括逆转抑郁症中发生的认知缺陷。最终，可以将PDE 4抑制剂的抗抑郁和认知作用与其其他药理学作用分离。要做到这一点，需要更好地了解脑中表达的PDE 4亚型（PDE 4A，PDE 4 B和PDE 4D）在介导PDE 4抑制剂的行为效应中的作用。此外，必须阐明PDE 4抑制剂与PDE 4分子的两种亲和力状态（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。 拟议的实验将解决PDE 4抑制剂对行为产生抗抑郁和记忆增强作用的神经药理学机制。此外，他们还将评估PDE 4在介导已证实的抗抑郁药物的行为效应中的作用。具体目标是：1）确定用抗抑郁药物重复治疗对大鼠和小鼠脑区域中PDE 4亚型表达和高亲和力和低亲和力咯利普兰结合位点的影响; 2）确定PDE 4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去甲肾上腺素能功能; 3）确定哪些PDE 4亚型参与介导抗抑郁药的行为效应和PDE 4抑制剂的抗抑郁样行为效应; 4）确定哪些PDE 4亚型参与介导PDE 4抑制剂的记忆增强作用;和5）确定高亲和力和低亲和力咯利普兰结合位点对PDE 4抑制剂的行为和神经化学作用的贡献。 完成拟议的实验将建立个人的PDE 4亚型和高-和低-亲和力rolipram结合位点的抗抑郁样和记忆增强作用的PDE 4抑制剂的调解的重要性。此外，将阐明去甲肾上腺素能和肾上腺素能系统在介导PDE 4抑制剂的神经精神药理学作用中的作用。总体而言，这些信息将有助于确定新的药理学目标的药物治疗抑郁症。

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.