Self D W, McClenahan A W, Beitner-Johnson D, Terwilliger R Z, Nestler E J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Synapse. 1995 Dec;21(4):312-8. doi: 10.1002/syn.890210405.
Previous studies have shown that chronic, forced exposure to opiates produces specific biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc). The functional consequences of these adaptations have been hypothesized to contribute to certain motivational aspects of drug addiction. In this study, the possibility that similar adaptations could occur in response to intermittent heroin self-administration was tested by comparing homogenates of VTA and NAc from rats self-administering heroin, rats receiving yoked injections of heroin, and rats receiving yoked injections of saline (controls). Tyrosine hydroxylase (TH) immunoreactivity was increased (31-38%) in the VTA and decreased (11%) in the NAc of heroin-exposed rats relative to controls. Heroin exposure also increased cAMP-dependent protein kinase (PKA) activity in both particulate (19-27%) and soluble (17-20%) fractions of the NAc, and decreased (16-17%) the level of Gi alpha immunoreactivity in this brain region. In contrast, no significant biochemical changes were found in the substantia nigra or caudate-putamen, indicating a selective effect on the mesolimbic dopamine system. Overall, adaptations in the VTA and NAc of heroin-exposed rats were similar to, but generally smaller in magnitude than, adaptations produced by chronic morphine administration. However, in contrast to morphine-treated animals, heroin-exposed animals failed to display overt signs of opiate physical dependence, suggesting that adaptations in motivational systems may occur more readily than adaptations in brain regions associated with physical dependence.
先前的研究表明，长期、强迫性接触阿片类药物会在腹侧被盖区（VTA）和伏隔核（NAc）产生特定的生化适应性变化。这些适应性变化的功能后果被认为与药物成瘾的某些动机方面有关。在本研究中，通过比较自行注射海洛因的大鼠、接受配对注射海洛因的大鼠以及接受配对注射生理盐水的大鼠（对照组）的VTA和NAc匀浆，测试了对间歇性海洛因自行给药产生类似适应性变化的可能性。与对照组相比，暴露于海洛因的大鼠VTA中酪氨酸羟化酶（TH）免疫反应性增加（31 - 38%），NAc中则降低（11%）。海洛因暴露还使NAc的颗粒部分（19 - 27%）和可溶性部分（17 - 20%）的环磷酸腺苷依赖性蛋白激酶（PKA）活性增加，并使该脑区的Giα免疫反应性水平降低（16 - 17%）。相比之下，黑质或尾状核 - 壳核未发现明显的生化变化，表明对中脑边缘多巴胺系统有选择性作用。总体而言，暴露于海洛因的大鼠VTA和NAc中的适应性变化与慢性给予吗啡产生的适应性变化相似，但程度通常较小。然而，与吗啡处理的动物不同，暴露于海洛因的动物未表现出明显的阿片类药物身体依赖性迹象，这表明动机系统中的适应性变化可能比与身体依赖性相关的脑区中的适应性变化更容易发生。
