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。 虽然酒精 使用是由于，部分，它的强化作用，这种双重成瘾可能 反映了其他因素，正如最近的研究所表明的那样。 乙醇块 NMDA-谷氨酸激活离子通道，一个涉及许多神经系统 可塑性现象，包括与慢性药物 exposure. 吗啡镇痛耐受和依赖的研究进展 对精神兴奋剂的运动敏感性被减弱， 地佐环平，一种非竞争性NMDA拮抗剂。 考虑到乙醇可能模拟 地佐环平也可能减弱长期用药的可塑性效应。 事实上，我们的初步数据证实，乙醇，像地佐环平， 减轻吗啡依赖。 拟议的研究将扩大这一范围， 发现包括几个行为可塑性现象与 慢性吗啡暴露，包括：1）依赖，通过 纳洛酮诱发的戒断厌恶; 2）运动敏化; 3)对吗啡位置调节作用的耐受性 exposure. 地佐环平和乙醇对吗啡的减毒作用 依赖性可能通过其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 无论是地佐环平还是乙醇减弱吗啡 依赖性可以通过NMDA治疗来阻断。 最后，地佐环平， 也许是乙醇，可能会增强吗啡的行为效应。 我确 发现地佐环平增强吗啡降低 大脑刺激奖励的阈值。 因此，最后一组研究将 进一步研究地佐环平和乙醇是否能增强运动 敏感性、辨别性刺激和位置条件作用 吗啡 所有的研究都将通过评估 吗啡剂量反应函数 这些临床前研究可能提供 信息表明，这两种药物的药理学相互作用 药物增加了其滥用的可能性， 了解和治疗海洛因和酒精的双重成瘾。

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.