OPIOID-CHOLINERGIC INTERACTIONS IN THE HIPPOCAMPUS

拟议的工作旨在确定阿片类药物之间的相互作用 肽和乙酰胆碱。 虽然 证据表明，这两个系统在记忆中发挥着重要作用， 海马体中的癫痫发作活动，几乎没有关于 两个系统之间的相互作用。 的影响 主要的海马阿片肽--脑啡肽和强啡肽A-- 与此相关的生化和行为反应 将研究毒蕈碱胆碱能系统。 的 实验旨在区分直接阿片类药物 影响和那些通过胆碱能介导的 系统 原型mu（DAGO），delta（（D-Pen 2，5）脑啡肽） 和kappa（强啡肽A）激动剂将检查其 在不同水平上影响毒蕈碱系统的能力。 生化指标包括第二信使系统，密度 毒蕈碱受体和乙酰胆碱的亚型分布 release. 要检查的第二信使系统是 磷脂酰肌醇周转和腺苷酸环化酶和GT3 活性，将利用体外切片测量， 膜制备。 急性和慢性的影响 海马内注射阿片肽对毒蕈碱 受体将通过放射自显影术使用（3 H）- 二苯羟乙酸奎宁环酯作为非选择性配体及其抑制作用 哌仑西平和加拉明作为选择性M1和M2毒蕈碱 拮抗剂，分别。 乙酰胆碱释放通过以下方式评估： 预加载的灌注切片的钾刺激 （3 H）-胆碱。 急性和慢性阿片类药物治疗的影响 在代表性存储器上（即，记忆依赖于线索， 在选择时存在）通过大鼠的表现来测量 在T型迷宫中进行配对交替任务。 慢性病的影响 阿片类药物对哌仑西平所致记忆障碍的治疗 和癫痫发作引起的gallamine将提供信息， 毒蕈碱受体介导的亚型特异性行为。 海马体是一种与记忆有关的结构 和癫痫发作的症状。 阿片样物质和毒蕈碱系统之间的相互作用 海马体可能在人类中起作用， 与药物滥用有关的行为问题。

The proposed work seeks to define the interaction between opioid peptides and acetylcholine in the hippocampus. Although there is evidence that both systems play important roles in memory and seizure activity in the hippocampus, there is little information on the interactions between the two systems. The effect of the major hippocampal opioid peptides--enkephalins and dynorphin A-- on biochemical and behavioral responses associated with the muscarinic cholinergic system will be investigated. The experiments are designed to distinguish between direct opioid effects and those that are mediated through the cholinergic system. Prototypical mu (DAGO), delta ((D-Pen 2,5) enkephalin) and kappa (dynorphin A) agonists will be examined for their abilities to affect the muscarinic system at different levels. Biochemical measures include second messenger systems, density and subtype distribution of muscarinic receptors and acetylcholine release. The second messenger systems to be examined are phosphtidylinositol turnover and adenylate cyclase and GTPase activities, which will be measured utilizing in vitro slice and membrane preparations. The effects of acute and chronic intrahippocampal injections of the opioid peptides on muscarinic receptors will be examined by autoradiography using (3H)- quinuclidinyl benzilate as a non-selective ligand and its inhibition by pirenzepine and gallamine as selective M1 and M2 muscarinic antagonists, respectively. Acetylcholine release is assessed by potassium-stimulated of superfused slices, which are preloaded with (3H)-choline. Effects of acute and chronic opioid treatment on representational memory (i.e., memory dependent on cues not present at the time of choice) is measured by performance of rats on a paired alternation task in a T-maze. The effects of chronic opioid treatment on memory impairments induced by pirenzepine and seizures induced by gallamine will provide information on muscarinic receptor-mediated behaviors that are subtype specific. The hippocampus is a structure known to be involved in memory and seizures in both humans and experimental animals. Interactions between opioid and muscarinic systems in the hippocampus may be operative in humans and contribute to behavioral problems associated with drug abuse.