Targeting GABA and Opioid Systems for a Pharmacotherapy for Methamphetamine Abuse

描述（由申请人提供）：甲基苯丙胺（MA）滥用和依赖是重大的公共卫生问题。从1998年到2007年，美国因MA使用而入院治疗的人数以惊人的速度增长。行为治疗减少了MA的使用。然而，许多参加行为治疗计划的患者无法达到明显的戒断期，这表明迫切需要其他策略，如药物治疗。g -氨基丁酸（GABA）和阿片系统调节多巴胺。GABAA受体调节剂（如恶西泮[OXP]）和阿片类拮抗剂（如纳曲酮[NTX]）可减弱安非他明的滥用相关作用。GABAA受体调节剂或阿片拮抗剂对安非他明滥用相关效应的衰减虽然具有统计学意义，但幅度不大。需要新的策略来提高这些药物的疗效。同时靶向GABA和阿片系统是一种创新策略，因为结合NTX和OXP可以更大程度地衰减MA的滥用相关效应。一项严格的受试者内实验将在不寻求治疗的ma滥用参与者中进行。NTX（0和50毫克/天）和OXP（0和40毫克/天）单独或联合将与MA（0、10、20和30毫克）一起进行测试。四种NTX-OXP维修条件将按随机顺序进行测试。同样，在每个NTX-OXP条件下，将按随机顺序检测MA剂量。鼻内MA剂量的强化效应将在每种NTX-OXP条件下维持4天后使用敏感渐进比率程序确定。减弱药物强化作用的能力是

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However, many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g., oxazepam [OXP]) and opioid antagonists (e.g., naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists, while statistically significant, is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking, MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day), alone and in combination, will be tested with MA (0, 10, 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly, within each NTX-OXP condition, the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination, NTX and OXP, for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability, which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.