DETERMINANTS OF DRUG EFFECTS ON DRUG MAINTAINED BEHAVIOR

描述（改编自申请人摘要）：药物滥用是对社会的严重威胁，需要寻求有效的治疗方法。由于没有确定药物滥用的单一有效治疗方法，目前的策略寻求将行为和药物治疗结合起来。成功的药物疗法包括基于激动剂的维持疗法：美沙酮（用于海洛因滥用）和尼古丁贴片（用于烟草滥用）。尽管对这些药物的药理作用有了深刻的了解，但其治疗效果的基础仍不清楚。此外，还没有发现对可卡因滥用的有效治疗方法。来自动物模型的行为数据可能会改进开发这些药物的方法。能够减少自我给药而不影响其他行为的药物可能是潜在的候选药物。我们最近在选择性多巴胺（DA）再摄取抑制剂GBR 12909治疗可卡因维持反应方面取得了一系列有希望的发现。急性给药消除了可卡因维持的反应，而对食物维持的反应没有影响。反复给药可以维持这种效果，单次注射长效癸酸酯制剂可以在近30天内降低可卡因维持的反应，而对食物维持的反应几乎没有影响。虽然GBR 12909及其癸酸酯的行为学效应很有前景，但其生理效应仍有待进一步研究。例如，可卡因对心血管有影响，应该探索这些药物与这种影响相互作用的可能性。最后，激动剂治疗的效果可能取决于具体的药理学作用和行为因素。我们的合作者继续修改GBR系列以改善其药理学，我们也建议测试其他药物作为潜在的佐剂来改善GBR类似物的效果。该资助的具体目的是：1)进一步评估GBR 12909单独和与其他药物联合使用的超长效制剂的效果；2)评估新型GBR 12909类似物的行为效应，目的是确定改进的癸酸盐候选药物；3)评估GBR 12909类似物和GBR 12909癸酸盐单独使用以及与可卡因联合使用对心血管功能的影响。这些研究旨在将基于激动剂的方法扩展到开发治疗可卡因滥用的潜在药物，并进一步了解可卡因自我给药的行为药理学。

DESCRIPTION (Adapted From The Applicant's Abstract): Substance abuse is a serious threat to society for which effective therapies are sought. Since no single effective treatment for substance abuse has been identified, current strategies seek to combine behavioral and pharmacological therapies. Successful pharmaceutical therapies include the agonist-based maintenance therapies: methadone (for heroin abuse) and nicotine patches (for tobacco abuse). Despite a profound understanding of the pharmacological actions of these drugs, the basis for their therapeutic effects remain unclear. In addition, no effective treatment has been found for cocaine abuse. Behavioral data from animal models may improve methods for developing these medications. Drugs that can decrease drug self-administration without having effects on other behaviors may be potential candidates. We recently developed a promising series of findings on the treatment of cocaine-maintained responding with the selective dopamine (DA) reuptake inhibitor GBR 12909. Acute administration abolished cocaine-maintained responding, while having no effect on food-maintained responding. Repeated administration sustained this effect, and a single injection of a long-acting decanoate formulation decreased cocaine-maintained responding for almost thirty days, while having little or no effect on food-maintained responding. While the behavioral effects of GBR 12909 and its decanoate appear very promising, their physiological effects may warrant further study. For example, cocaine has cardiovascular effects, and the potential of these drugs for interaction with this effect should be explored. Lastly, the effects of agonist-based treatments are likely to depend upon both specific pharmacological actions and behavioral factors. Our collaborators continue to modify the GBR series to improve its pharmacology and we also propose testing additional drugs as potential adjuvants to improve the effects of GBR analogs. The specific aims of this grant are to 1) further evaluate the effects of an ultra long-acting formulation of GBR 12909 alone and in combination with other drugs, 2) assess the behavioral effects of novel GBR 12909 analogs, with the aim of identifying improved decanoate candidates, and 3) assess the effects of GBR 12909 analogs and GBR 12909 decanoate alone, and in combination with cocaine, on cardiovascular functioning. These studies are designed to extend the agonist-based approach to the development of potential medications for the treatment of cocaine abuse and further our understanding of the behavioral pharmacology of the self-administration of cocaine.