Bals-Kubik R, Ableitner A, Herz A, Shippenberg T S
Department of Neuropharmacology, Max-Planck Institute for Psychiatry, Martinsried, Germany.
J Pharmacol Exp Ther. 1993 Jan;264(1):489-95.
An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation of kappa receptors in the VTA and its limbic-cortical terminal regions.
采用无偏倚条件性位置偏爱范式来研究介导μ和κ阿片样物质激动剂的强化和厌恶作用的神经解剖学底物。将选择性μ激动剂DAMGO单侧微量注射到中脑边缘和中脑皮质多巴胺（DA）系统的起源部位——腹侧被盖区（VTA），会导致对药物相关位置产生剂量依赖性偏爱。然而，将DAMGO颅内注射到VTA DA神经元的终末投射部位——伏隔核和内侧前额叶皮质，以及外侧下丘脑，均无效果。相比之下，将κ激动剂U50,488H和强啡肽衍生物E - 2078微量注射到VTA会产生位置厌恶。将U50,488H和E - 2078微量注射到伏隔核、内侧前额叶皮质和外侧下丘脑后也观察到位置厌恶。然而，将μ和κ激动剂微量注射到中脑纹状体DA系统的起源部位——黑质，或其主要终末场——尾状核 - 壳核，均无效果。放射自显影研究表明，这些物质保留在注射部位周围的受限区域内，证实观察到的效应是在该区域介导的。因此，这些数据表明VTA中的A10神经元在调节μ和κ阿片样物质诱导的动机状态中起重要作用。奖赏效应与VTA中μ受体的激活有关，而厌恶效应与VTA及其边缘 - 皮质终末区域中κ受体的激活有关。
