NEUROPSYCHOPHARMACOLOGY OF CYCLIC AMP PDE INHIBITORS

描述（改编自申请人的摘要）：广泛，长期 本提案的目的是阐明PDE4在行为中的作用， 调节和介导PDE4抑制剂的AD效应。 首先，将进行实验以确定哪些PDE4亚型 PDE4A、PDE4B、PDE4D参与AD样行为的介导。 影响，以及其他中枢神经系统的影响。 这将通过 比较新开发的PDE4亚型选择性抑制剂的作用 在两个行为任务中，大鼠的行为保持在DRL 72秒 时间表和两个杠杆rolipram药物歧视程序，与他们的 抑制重组大鼠PDE 4A、PDE 4B、PDE 4C和PDE 4D。 相关 实验将检查反义核酸的行为效应， 靶向PDE4A变体（PDE4A1和PDE4A5）的寡脱氧核苷酸（ODN） 这被假设为参与介导AD样行为 方面的影响. 第二，将进行实验以确定 行为效应主要通过抑制剂与 PDE4上的低或高亲和力咯利普兰结合位点。 这将是 通过比较PDE 4抑制剂的行为效应与 他们与这些网站互动的亲和力。 第三，实验将 以确定哪些PDE4亚型与所选的 受体刺激的腺苷酸环化酶。 这将是完成 通过测定PDE4亚型选择性抑制剂的作用，以及 靶向PDE4A变体的反义ODNs，在水解 腺苷-3'，5'-环一磷酸（环AMP）由刺激 β-1和β-2肾上腺素能或D1多巴胺能受体刺激的腺苷酸 大鼠脑切片中的环化酶 第四，实验将检查的方式， 突触前神经支配和cAMP调节神经元中的PDE 4。 这 将通过确定抑制突触发生的影响来实现， 用靶向突触蛋白II的反义ODN诱导，或改变环 AMP，由腺苷酸环化酶抑制剂或不可水解的环AMP诱导 类似物，在原代神经元培养物中PDE4变体的发展， 大鼠大脑皮层 所提出的实验的结果将显示PDE4的哪些亚型是 AD的主要介质和PDE的其他行为效应4 抑制剂;此外，低和 将建立高亲和力的咯利普兰结合位点。 最后，PDE4 与特定信号转导系统相关的变体， 突触前神经支配和环磷酸腺苷调节这些的方式 将阐明关联。 对功能的更好理解 PDE4在大脑中的作用和药理学将开始阐明其在大脑中的作用。 抑郁症的病理生理学，并提供合理的依据， 药物治疗.

DESCRIPTION (Adapted from applicant's abstract): The broad, long-term objective of this proposal is to elucidate the role of PDE4 in behavioral regulation and in the mediation of the AD effects of PDE4 inhibitors. First, experiments will be carried our to determine which PDE4 subtypes (PDE4A, PDE4B, PDE4D) are involved in the mediation of AD-like behavioral effects, as well as other CNS effects. This will be accomplished by comparing the effects of newly developed PDE4 subtype-selective inhibitors in rats in two behavioral tasks, behavior maintained under a DRL 72-sec schedule and a two-lever rolipram drug discrimination procedure, with their inhibition of recombinant rat PDE4A, PDE4B, PDE4C, and PDE4D. Related experiments will examine the behavioral effects of antisense oligodeoxynucleotides (ODNs) targeted to PDE4A variants (PDE4A1 and PDE4A5) which are hypothesized to be involved in the mediation of AD-like behavioral effects. Second, experiments will be carried out to determine if the behavioral effects are mediated predominantly by inhibitor interaction with the low- or high-affinity rolipram binding sites on PDE4. This will be accomplished by comparing the behavioral effects of PDE4 inhibitors with their affinities for interacting with these sites. Third, experiments will be carried out to determine which PDE4 subtypes are associated with selected receptor-stimulated adenyl cyclase in the brain. This will be accomplished by determining the effects of PDE4 subtype-selective inhibitors, as well as antisense ODNs targeted to PDE4A variants, on the hydrolysis of adenosine-3',5'-cyclic monophosphate (cyclic AMP) formed by stimulation of beta-1 and beta-2 adrenergic or D1 dopaminergic receptor-stimulated adenylyl cyclase in rat brain slices. Fourth, experiments will examine the manner by which presynaptic innervation and cyclic AMP regulate PDE4 in neurons. This will be accomplished by determining the effects of inhibited synaptogenesis, induced with antisense ODNs targeted to synapsin II, or changes in cyclic AMP, induced by an adenylyl cyclase inhibitor or by nonhydrozable cyclic AMP analogs, on the development of PDE4 variants in primary neuronal cultures of rat cerebral cortex. The results of the proposed experiments will show which subtypes of PDE4 are the predominant mediators of the AD and other behavioral effects of PDE4 inhibitors; in addition the relative importance of the low- and high-affinity rolipram binding sites will be established. Finally, the PDE4 variants associated with particular signal transduction systems and the manner by which presynaptic innervation and cyclic AMP regulate these associations will be elucidated. The improved understanding of the function and pharmacology of PDE4 in the brain will begin to clarify its role in the pathophysiology of depression and provide a rational basis for improved pharmacotherapy.