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，吸毒者通过线索暴露或消除训练来学习减少他们对药物配对刺激的反应。然而，在长期滥用药物的人群中，消退训练不太可能作为一种独立的治疗方法持续有效，因为在消退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潜在机制，并建立可行的策略，以提高药物滥用障碍的消退疗法的疗效。拟议研究计划的关键要素建立在通过对甘氨酸的药物调节来治疗条件性恐惧、焦虑和其他认知障碍方面的最新进展。甘氨酸是NMDA谷氨酸受体复合体中的一种强制性共同递质。拟在大鼠和非人灵长类动物上进行的研究的具体目的是：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体1(GlyT1)抑制剂作为候选药物以提高消退训练的有效性；以及3)确定甘氨酸位点调节消退学习的神经生物学底物。在拟议的研究中将使用静脉注射可卡因的自我给药程序，因为药物传递和行为之间的偶然性可能对于理解人们持续滥用药物至关重要。通过测量Fos蛋白的表达(神经元激活的标志)，并用大鼠的新蛋白质合成抑制剂山奈素进行评估，以探讨可卡因自我给药训练后消退学习的神经生物学基础。此外，这项拟在大鼠和非人类灵长类动物身上进行的研究将专门调查部分甘氨酸激动剂D-环丝氨酸和选择性GlyT1抑制剂对加速灭绝学习和随后减少可卡因线索反应性和可卡因自我给药重新获得的能力的影响。使用适当选择的实验动物的综合比较策略很好地支持了涉及学习和记忆的药理学调节的动物研究。这种方法与涉及认知增强药物的研究特别相关，在这些研究中，非人类灵长类动物可以作为药物疗法开发的关键翻译接口。

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.