GLUTAMATE AND THE SELF ADMINISTRATION OF AMPHETAMINES

描述：(改编自申请人的摘要) 本申请中提出的实验是继续 申请人进行的旨在确定神经基础的研究工作 药物诱导的行为敏感化和对本质的理解 以及其表达的意义。精神运动兴奋剂，如 安非他明以及鸦片类药物，这两种药物都是自我 由人和实验动物管理，产生运动 激活。反复接触这些药物会产生长期的 增强了它们引发运动的能力，从而使随后的 在几周到几个月后再次接触这种药物，会产生更大的 行为激活比最初看到的要多。更重要的是，普赖斯 暴露于安非他明注射的这种致敏方案也是 已知对动物的易感性有持久的增强作用 随后自行给药。 相当多的证据表明，中隔伏核的多巴胺神经元与 运动产生与精神运动支持的自我管理 兴奋剂。这种神经系统的敏感化也与 以上运动能力的长期增强，似乎与 增强了动物自我给药的能力。 其他发现表明兴奋性氨基的重要贡献。 酸性谷氨酸对运动神经元的诱导和表达 安非他明致敏。然而，人们对此知之甚少 这种神经递质在促进吸毒中的作用 通过暴露于致敏药物疗法而产生。通过研究 苯丙胺在大鼠体内的自我给药，拟议的实验将 试图通过回答三个问题来阐明这一贡献 问题： 问题1：归纳法。是否已知的操作可以阻止诱导 对苯丙胺的运动敏化，如预先敏化 注射具有离子亲和性和代谢性的拮抗剂 谷氨酸受体，也阻断自我给药的便利性 关于毒品的？ 问题2：表情。事先接触安非他明会增加 伏隔膜终末区胞外谷氨酸水平的研究 在随后的自我给药过程中的多巴胺神经元 并在它被消灭后恢复这种行为？ 问题3：表情。事先接触安非他明是否会增加 该位点谷氨酸受体亚型选择性配体结合能力的研究 从而影响药物的自我给药以及 它灭绝后的复活？

DESCRIPTION: (Adapted From The Applicant's Abstract) The experiments proposed in this application are part of a continuing research effort by the applicant aimed at determining the neural basis of drug-induced behavioral sensitization and at understanding the nature and significance of its expression. Psychomotor stimulants like the amphetamines as well as opiate drugs, both of which are self- administered by man and laboratory animals, produce locomotor activation. Repeated exposure to these drugs produces long-term enhancements in their ability to elicit locomotion so that subsequent re-exposure to the drug, weeks to months later, produces greater behavioral activation than seen initially. More importantly, prior exposure to such sensitizing regimens of amphetamine injections is also known to produce long lasting enhancements in animals' predisposition to subsequently self-administer the drug. Considerable evidence links mesoaccumbens dopamine neurons to the locomotion produced and the self-administration supported by psychomotor stimulants. Sensitization in this neuronal system also parallels the above long-term enhancements in locomotion and appears to be associated with enhancements in animals' predisposition to self-administer drug. Other findings indicate important contributions by the excitatory amino acid glutamate both to the INDUCTION and EXPRESSION of locomotor sensitization by amphetamines. Little is known, however, of the contribution of this neurotransmitter to the facilitation of drug taking produced by exposure to sensitizing drug regimens. By studying amphetamine self-administration in rats, the proposed experiments will attempt to elucidate this contribution by seeking to answer three questions: QUESTION 1: INDUCTION. Do manipulations known to block the induction of locomotor sensitization to amphetamine, such as preceding sensitizing injections with antagonists specific for ionotropic and metabotropic glutamate receptors, also block the facilitation of self-administration of the drug? QUESTION 2: EXPRESSION. Does prior exposure to amphetamine enhance extracellular levels of glutamate in the terminal field of mesoaccumbens dopamine neurons during the subsequent self-administration of the drug and reinstatement of this behavior after it has been extinguished? QUESTION 3: EXPRESSION. Does prior exposure to amphetamine enhance the ability of glutamate receptor subtype selective ligands in this site to subsequently influence the self-administration of the drug as well as its reinstatement after extinction?