Schmidt Heath D, Mietlicki-Baase Elizabeth G, Ige Kelsey Y, Maurer John J, Reiner David J, Zimmer Derek J, Van Nest Duncan S, Guercio Leonardo A, Wimmer Mathieu E, Olivos Diana R, De Jonghe Bart C, Hayes Matthew R
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
Neuropsychopharmacology. 2016 Jun;41(7):1917-28. doi: 10.1038/npp.2015.362. Epub 2015 Dec 17.
Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food. As the neural circuits and neurobiological mechanisms underlying drug taking overlap to some degree with those regulating food intake, these findings suggest that activation of central GLP-1 receptors may also attenuate cocaine taking. Here, we show that intra-VTA administration of the GLP-1 receptor agonist exendin-4 (0.05 μg) significantly reduced cocaine, but not sucrose, self-administration in rats. We also demonstrate that cocaine taking is associated with elevated plasma corticosterone levels and that systemic infusion of cocaine activates GLP-1-expressing neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus that projects monosynaptically to the VTA. To determine the potential mechanisms by which cocaine activates NTS GLP-1-expressing neurons, we microinjected corticosterone (0.5 μg) directly into the hindbrain fourth ventricle. Intraventricular corticosterone attenuated cocaine self-administration and this effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin-(9-39) (10 μg) in the VTA. Finally, AAV-shRNA-mediated knockdown of VTA GLP-1 receptors was sufficient to augment cocaine self-administration. Taken together, these findings indicate that increased activation of NTS GLP-1-expressing neurons by corticosterone may represent a homeostatic response to cocaine taking, thereby reducing the reinforcing efficacy of cocaine. Therefore, central GLP-1 receptors may represent a novel target for cocaine addiction pharmacotherapies.
可卡因成瘾仍然是一个重大的公共卫生问题，目前尚无美国食品药品监督管理局（FDA）批准的有效治疗方法。因此，明确需要识别和开发用于治疗可卡因成瘾的新型药物疗法。最近的证据表明，腹侧被盖区（VTA）中胰高血糖素样肽-1（GLP-1）受体的激活会减少对高度可口食物的摄取。由于药物摄取背后的神经回路和神经生物学机制在一定程度上与调节食物摄取的机制重叠，这些发现表明中枢GLP-1受体的激活也可能减弱可卡因摄取。在此，我们表明在大鼠中向VTA内注射GLP-1受体激动剂艾塞那肽-4（0.05μg）可显著减少可卡因的自我给药，但不会减少蔗糖的自我给药。我们还证明，摄取可卡因与血浆皮质酮水平升高有关，并且全身性注射可卡因会激活孤束核（NTS）中表达GLP-1的神经元，孤束核是一个后脑核，它单突触投射到VTA。为了确定可卡因激活NTS中表达GLP-1的神经元的潜在机制，我们将皮质酮（0.5μg）直接微量注射到后脑第四脑室。脑室内注射皮质酮减弱了可卡因的自我给药，并且在用VTA中的GLP-1受体拮抗剂艾塞那肽-（9-39）（10μg）预处理的动物中这种作用被阻断。最后，腺相关病毒（AAV）短发夹RNA（shRNA）介导的VTA中GLP-1受体的敲低足以增强可卡因的自我给药。综上所述，这些发现表明皮质酮对NTS中表达GLP-1的神经元的激活增加可能代表了对摄取可卡因的一种稳态反应，从而降低了可卡因的强化效力。因此，中枢GLP-1受体可能代表了可卡因成瘾药物疗法的一个新靶点。
