NEUROBEHAVIORAL STUDIES OF DUAL DRUG ADDICTION

描述：(申请人摘要) 在海洛因成瘾者中，酗酒是一个严重的问题。在喝酒的时候 使用的部分原因是它的强化作用，这种双重上瘾可能 反映其他因素，正如最近的研究所表明的那样。乙醇块 NMDA-谷氨酸激活的离子通道，一个涉及许多神经的系统 可塑性现象，包括与慢性药物相关的反应 曝光。吗啡镇痛耐受和依赖的研究进展 而运动对精神刺激剂的敏感度则通过以下方式减弱 地佐西平，一种非竞争性的NMDA拮抗剂。鉴于乙醇可能会模仿 地佐西平也可能减弱慢性药物使用的可塑性影响。 事实上，我们的初步数据证实，乙醇和地佐西平一样， 减轻吗啡依赖。拟议的研究将延长这一期限 发现包括与以下几种行为可塑性现象相关的 慢性吗啡暴露，包括：1)依赖，由 纳洛酮催促戒断厌恶：2)运动敏感化； 3)慢性吗啡对局部条件反射的耐受性 曝光。地佐西平和乙醇对吗啡的抑制作用 依赖可能通过它们的NMDA拮抗剂作用发生，这将是 在本文提出的另一项研究中进行了评估。具体来说，我们将确定 地佐西平或乙醇对吗啡的抑制作用 依赖可以通过NMDA治疗来阻止。最后是地佐西平，以及 也许乙醇可以增强吗啡的行为效应。事实上，我们 发现地佐西平可增强吗啡的降压作用 脑部刺激奖励阈值。因此，最后一套研究将 进一步研究地佐西平和乙醇是否能增强运动能力 的敏感化、区别性刺激和位置制约效应 吗啡。所有研究都将通过评估以下变化来解决这些问题 吗啡的剂量-反应功能。这些临床前研究可能会提供 有信息表明，这两种药物的药理作用 毒品增加了他们的滥用潜力，这可能会对 认识和治疗海洛因和酒精双重成瘾。

DESCRIPTION: (Applicant's Abstract) Among heroin addicts, alcohol abuse is a significant problem. While alcohol use is due, in part, to its reinforcing effects, this dual addiction may reflect additional factors, as suggested by recent research. Ethanol blocks the NMDA-glutamate activated ion channel, a system implicated in many neural plasticity phenomena, including responses associated with chronic drug exposure. The development of analgesic tolerance and dependence to morphine and locomotor sensitization to psychostimulants is attenuated by dizocilpine, an uncompetitive NMDA antagonist. Given that ethanol may mimic dizocilpine, it too, may attenuate plasticity effects of chronic drug use. Indeed, our preliminary data confirm that ethanol, like dizocilpine, attenuates morphine dependence. The proposed studies would extend that finding to include several behavioral plasticity phenomena associated with chronic morphine exposure, including: 1) dependence, as evaluated by naloxone-precipitated withdrawal aversion; 2) locomotor sensitization and; 3) tolerance to the place conditioning effects of morphine after chronic exposure. The ability of dizocilpine and ethanol to attenuate morphine dependence may occur via their NMDA antagonist effects, which will be assessed in another study proposed herein. Specifically, we will determine whether the ability of dizocilpine or ethanol to attenuate morphine dependence can be blocked by NMDA treatment. Finally, dizocilpine, and perhaps ethanol, may enhance the behavioral effects of morphine. Indeed, we find that dizocilpine enhances the ability of morphine to lower the threshold for brain stimulation reward. Thus, a final set of studies will investigate further whether dizocilpine and ethanol enhance the locomotor sensitizing, discriminative stimulus, and place conditioning effects of morphine. All studies will address these questions by assessing shifts in morphine dose-response functions. These preclinical studies may provide information indicating that the pharmacological interactions of these two drugs enhance their abuse potentials which may have implications for understanding and treating dual addiction to heroin and alcohol.