Neuropsychopharmacology of Cyclic AMP PDE Inhibitors

描述(申请人提供)：4型环磷酸二酯酶(PDE4)的抑制剂，如罗利普兰，在临床前模型中既能产生抗抑郁药样作用，又能增强记忆力。与此一致的是，研究表明，这类药物具有临床抗抑郁效果，包括逆转抑郁症发生的认知缺陷。最终，有可能将PDE4抑制剂的抗抑郁和认知作用与它们的其他药理作用分开。要做到这一点，需要更好地了解脑中表达的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分子的两种亲和力状态(称为高亲和力和低亲和力罗利普兰结合位点)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PDE4抑制剂在行为上产生抗抑郁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。其具体目的是：1)确定反复使用抗抑郁药物对大鼠和小鼠脑区PDE4亚型表达和高、低亲和力罗利普兰结合位点的影响；2)确定PDE4抑制剂的抗抑郁药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亚型参与了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亚型参与了PDE4抑制剂的记忆增强作用；5)确定高亲和力和低亲和力的罗利普兰结合位点对PDE4抑制剂的行为和神经化学效应的贡献。 拟议实验的完成将确定单个PDE4亚型以及高和低亲和力的罗利普兰结合位点在PDE4抑制剂的抗抑郁样和增强记忆作用中的重要性。此外，去甲肾上腺素能和5-羟色胺能系统在调节PDE4抑制剂的神经精神药理效应中的作用也将被阐明。总体而言，这些信息将有助于确定抑郁症药物治疗的新药理靶点。

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.