Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9-39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA reduced cocaine seeking. Finally, extinction following cocaine self-administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects.

中文翻译：

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腹侧被盖区中的胰高血糖素样肽-1受体激活减弱了大鼠中的可卡因搜寻。

需要新的分子靶标来开发用于治疗可卡因成瘾的新药物。在这里，我们研究了胰高血糖素样肽1（GLP-1）受体在恢复可卡因寻找行为（一种复发的动物模型）中的作用。我们显示，在不影响随意食物摄入，进餐方式或体重的剂量下，外周给予GLP-1受体激动剂exendin-4剂量可减少大鼠中的可卡因搜寻。我们还证明了系统性exendin-4穿透了大脑，在这里它可能与腹侧被盖区（VTA）的神经元和星形胶质细胞上的受体结合。在VTA内输注GLP-1受体拮抗剂exendin-（9-39）预处理的大鼠中，全身exendin-4对可卡因恢复的作用减弱。提示全身exendin-4对可卡因的抑制作用部分归因于VTA中GLP-1受体的激活。与这些作用一致，将exendin-4直接输注到VTA中可减少可卡因的寻找。最后，可卡因自我给药后的灭绝与尾脑干中前胰高血糖素前体mRNA表达的降低有关。因此，我们的研究证明了GLP-1受体在恢复可卡因寻找行为方面的新作用，并确定了与行为有关的剂量的GLP-1受体激动剂，该剂量有选择地减少了可卡因的寻找并且未产生不利影响。可卡因自我给药后的灭绝与尾脑干中前胰高血糖素前体mRNA的表达降低有关。因此，我们的研究证明了GLP-1受体在恢复可卡因寻找行为方面的新作用，并确定了与行为有关的剂量的GLP-1受体激动剂，该剂量有选择地减少了可卡因的寻找并且未产生不利影响。可卡因自我给药后的灭绝与尾脑干中前胰高血糖素前体mRNA的表达降低有关。因此，我们的研究证明了GLP-1受体在恢复可卡因寻找行为方面的新作用，并确定了与行为有关的剂量的GLP-1受体激动剂，该剂量有选择地减少了可卡因的寻找并且未产生不利影响。