Strategies for Enhancing Extinction of Drug-Seeking Behavior

描述（由申请人提供）：一种治疗药物滥用障碍的新兴临床方法涉及一种认知行为疗法，成瘾者通过提示暴露或消失训练来学习减少对药物配对刺激的反应性。然而，在长期滥用药物的人群中，“消失训练”不太可能作为一种单独的治疗方法一直有效，因为在“消失训练”期间招募的关键记忆系统会因长期使用药物而受损。迫切需要了解消退学习的机制，并建立可行的策略，以提高消退疗法对药物滥用障碍的疗效。提出的研究计划的关键要素建立在通过对甘氨酸（NMDA谷氨酸受体复合体的强制性共递质）的药理学调节治疗条理性恐惧、焦虑和其他认知障碍方面的最新进展之上。拟在大鼠和非人类灵长类动物中进行的研究的具体目的是：1)阐明灭绝学习的神经生物学基础；2)评估选定的甘氨酸位点部分激动剂和甘氨酸转运蛋白-1 （GlyT1）抑制剂作为候选药物治疗，以提高消除训练的效果；3)确定甘氨酸位点调节消退学习的神经生物学底物。拟议的研究将使用静脉注射可卡因自我给药程序，因为药物递送和行为之间的偶然性可能对理解人类持续滥用药物至关重要。测量Fos蛋白表达（神经元激活的标志）和用大霉素（新生蛋白合成的抑制剂）评估将在大鼠中用于研究可卡因自我给药训练后消失学习的神经生物学基础。此外，在大鼠和非人类灵长类动物中进行的拟议研究将专门研究部分甘氨酸激动剂d -环丝氨酸和选择性甘氨酸t1抑制剂加速灭绝学习并随后降低可卡因线索反应性和可卡因自我给药重新获得的能力。动物研究涉及学习和记忆的药理学调节是很好的服务于综合比较策略使用适当选择的实验动物。这种方法尤其适用于涉及认知增强药物的研究，在这些研究中，非人类灵长类动物可以作为药物治疗开发的关键翻译界面。

DESCRIPTION (provided by applicant): An emerging clinical approach to treat substance abuse disorders involves a form of cognitive-behavioral therapy whereby addicts learn to reduce their reactivity to drug-paired stimuli through cue-exposure or extinction training. It is, however, unlikely that extinction training would be consistently effective as a stand- alone treatment in populations that have abused drugs long-term because the key memory systems that are recruited during extinction training are impaired by long-term drug use. There is a critical need to understand mechanisms underlying extinction learning and to establish viable strategies to increase the efficacy of extinction therapies for substance abuse disorders. Key elements of the proposed research plan build on recent advances made in the treatment of conditioned fear and anxiety and other cognitive disorders by pharmacological modulation of glycine, an obligatory co-transmitter at the NMDA glutamate receptor complex. The specific aims of the proposed research in rats and non-human primates are to: 1) elucidate the neurobiological substrates of extinction learning; 2) evaluate selected glycine site partial agonists and glycine transporter-1 (GlyT1) inhibitors as candidate pharmacotherapies to increase the efficacy of extinction training; and 3) determine neurobiological substrates of glycine site modulation of extinction learning. The intravenous cocaine self-administration procedure will be used in the proposed studies because the contingency between drug delivery and behavior is likely paramount for understanding the persistent abuse of drugs in people. Measurement of Fos protein expression (a marker for neuronal activation) and evaluation with anisomycin (an inhibitor of de novo protein synthesis) will be used in rats to investigate the neurobiological substrates of extinction learning following cocaine self-administration training. In addition, the proposed research in rats and non-human primates will specifically investigate the effects of the partial glycine agonist D-cycloserine and selective GlyT1 inhibitors for their ability to accelerate extinction learning and to subsequently reduce cocaine cue reactivity and re-acquisition of cocaine self-administration. Animal research involving pharmacological modulation of learning and memory is well-served by an integrated comparative strategy using appropriately selected laboratory animals. This approach is especially relevant for research involving cognitive enhancing drugs, where non-human primates can serve as a key translational interface for the development of pharmacotherapies.