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，成瘾者通过线索暴露或消退训练来学习减少对药物配对刺激的反应。然而，在长期滥用药物的人群中，灭绝训练作为一种独立的治疗方法不太可能持续有效，因为在灭绝训练期间招募的关键记忆系统因长期药物使用而受损。有一个关键的需要，以了解潜在的灭绝学习的机制，并建立可行的策略，以提高药物滥用障碍的灭绝疗法的疗效。拟议的研究计划的关键要素建立在最近取得的进展，在治疗条件性恐惧和焦虑和其他认知障碍的药理学调制甘氨酸，在NMDA谷氨酸受体复合物的强制性共递质。在大鼠和非人灵长类动物中进行拟议研究的具体目的是：1）阐明消退学习的神经生物学底物; 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（GlyT 1）抑制剂作为候选药物疗法，以提高消退训练的有效性; 3）确定甘氨酸位点调节消退学习的神经生物学底物。在拟定的研究中将使用静脉内可卡因自我给药程序，因为药物给药和行为之间的偶然性对于理解人们持续滥用药物可能至关重要。将在大鼠中测量Fos蛋白表达（神经元活化的标志物）并使用茴香霉素（从头蛋白合成的抑制剂）进行评价，以研究可卡因自我给药训练后消退学习的神经生物学底物。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GlyT 1抑制剂加速消退学习的能力，以及随后降低可卡因线索反应性和重新获得可卡因自我给药的能力。使用适当选择的实验室动物，通过综合比较策略，很好地服务于涉及学习和记忆药理学调节的动物研究。这种方法对于涉及认知增强药物的研究特别相关，其中非人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.