NEUROCHEMICAL PHARMACOLOGY OF PHENCYCLIDINE

苯环利定的神经化学药理学

• 批准号: 3207111
• 负责人: KENNETH Maurice JOHNSON
• 金额: $ 22.91万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-30 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207111
• 关键词: NMDA receptors; PCP receptor; albino rat; amine oxidoreductase; aminoacid inhibitor; biological signal transduction; cerebral cortex; corpus striatum; cyclic AMP; dopamine; drug abuse; drug addiction antagonist; drug metabolism; experimental brain lesion; frontal lobe /cortex; gamma aminobutyrate; glutamate receptor; hippocampus; lenticular nucleus; neurochemistry; neuropharmacology; neurotransmitter metabolism; neurotransmitter receptor; phencyclidine; psychopharmacology; psychotomimetic drug; radiotracer; second messengers; somatostatin

Phencyclidine (PCP) is a drug of abuse with multiple sites of action. Current thinking is that the most relevant of these is blockade of the NMDA receptor ionophore complex and blockade of dopamine and norepinephrine uptake. The proposed study will focus on the function of the; NMDA receptor and how it interacts with other excitatory amino acid receptors as well as with dopaminergic and noradrenergic receptors in signal transduction mechanisms at the intracellular level. These experiments will attempt to determine how PCP alters the glutamatergic and catecholaminergic regulation of these second messengers and how this change alters transmitter release from the predominant neurons in brain slices from three brain regions. There are five specific aims: 1. The basic regulation of GABA and glutamate release by dopaminergic and glutamatergic agonists in slices of the striatum-globus pallidus and frontal cortex and by noradrenergic and glutamatergic agonists in hippocampal slices will be determined. In addition, in the striatum only, where nitric oxide synthase (NOS) and somatostatin are colocalized, the regulation of somatostatin release by glutamate, GABA and DA will be determined. Finally the effect of PCP on glutamatergic and catecholaminergic regulation of transmitter release will be determined. 2. The regulation of NOS activity in these areas by glutamate and catecholamines will be determined. 3. The potential role of nitric oxide (NO) in the effects of glutamate and excitatory amino acid agonists on transmitter release will be determined. In addition, the mechanisms by which NO generators such as hydroxylamine and sodium nitroprusside alter transmitter release will be studied. 4. The regulation of IP3 and cAMP formation by glutamate and catecholamines will be studied, with particular attention being paid to the effect that inhibition of catecholamine reuptake and blockade of the NMDA receptor by PCP has on this regulation. Changes in cAMP and IP3 levels will also be correlated with NOS activity. 5. The changes in these second messengers resulting from activation of glutamatergic and catecholaminergic receptors will be correlated with their effect on transmitter release. Finally, the extent to which PCP alteration of transmitter release is dependent on alterations in second messengers will be determined. Because of the role of NMDA receptor in cocaine and amphetamine sensitization, methamphetamine and HIV neurotoxicity, morphine tolerance and dependence, learning, neural plasticity, and stroke-induced brain damage, this study could have implications beyond understanding the neurochemical mechanisms of action of PCP.

Phencyclidine（PCP）是一种具有多种作用部位的滥用药物。 当前的想法是，其中最相关的是封锁 NMDA受体离子化合物复合物和多巴胺的阻断和封锁 去甲肾上腺素的吸收。 拟议的研究将侧重于 这; NMDA受体及其如何与其他兴奋性氨基酸相互作用 受体以及多巴胺能和去甲肾上腺素能受体 信号转导机制在细胞内水平。 这些 实验将尝试确定PCP如何改变谷氨酸能 以及这些第二使者的儿茶酚胺能调节以及如何调节 改变从大脑中主要神经元释放发射机的变化 三个大脑区域的切片。 有五个具体目标：1。 通过多巴胺能和谷氨酸释放的GABA和谷氨酸的基本调节 在纹状体 - 果胶片的切片中的谷氨酸能激动剂和 额叶皮层以及甲肾上腺素能和谷氨酸能激动剂的作者 将确定海马切片。 另外，在纹状体中 仅在一氧化氮合酶（NOS）和生长抑素共定位的情况下， 谷氨酸，GABA和DA对生长抑素释放的调节将是 决定。 最后，PCP对谷氨酸能和 将确定发射机释放的儿茶酚胺能调节。 2。通过谷氨酸和 将确定儿茶酚胺。 3。一氧化氮的潜在作用 （否）在谷氨酸和兴奋性氨基酸激动剂对 将确定发射机释放。 另外，该机制通过 没有发电机，例如羟胺和硝普钠替代 将研究发射器释放。 4。IP3和CAMP的规定 将研究谷氨酸和儿茶酚胺的形成，并研究 特别注意抑制的影响 Catecholamine的再摄取和PCP对NMDA受体的封锁已在 这个法规。 营地和IP3级别的变化也将相关 具有NOS活性。 5。这些第二个使者的变化 谷氨酸能和儿茶酚胺能受体的激活将是 与它们对发射器释放的影响相关。 最后，程度 发射机释放的PCP更改取决于 将确定第二任信使的更改。 因为角色 可卡因和苯丙胺致敏的NMDA受体的 甲基苯丙胺和HIV神经毒性，吗啡耐受性和依赖性， 学习，神经可塑性和中风引起的脑损伤，这项研究 可能有含义，而不是理解神经化学机制 PCP的作用。