Bonci A, Williams J T
Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.
J Neurosci. 1997 Jan 15;17(2):796-803. doi: 10.1523/JNEUROSCI.17-02-00796.1997.
Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAA synapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAA IPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.
位于腹侧被盖区（VTA）中间神经元上的阿片受体抑制γ-氨基丁酸A型（GABA(A)）介导的向多巴胺投射神经元的突触传递。VTA中多巴胺能细胞由此产生的去抑制作用被认为在药物滥用中起关键作用；然而，关于慢性吗啡治疗后这种GABA(A)突触如何受到影响却知之甚少。在接受吗啡治疗6 - 7天的动物的脑片中研究了吗啡急性戒断期间GABA释放的调节。制备包含VTA的脑片并维持在无吗啡溶液中，从多巴胺能细胞记录GABA(A)抑制性突触后电流（IPSCs）。在吗啡处理的豚鼠脑片中测量的诱发IPSCs的幅度和自发微小IPSCs的频率大于安慰剂处理的对照组。此外，用福司可林激活腺苷酸环化酶以及用Sp-cAMPS激活cAMP依赖性蛋白激酶，在吗啡处理动物的脑片中引起IPSCs更大的增加。相反，激酶抑制剂星形孢菌素和Rp-CPT-cAMPS在药物处理后使GABA IPSCs降低的程度更大。结果表明，在慢性吗啡治疗戒断期间GABA释放的概率增加，并且这种效应是由cAMP依赖性级联反应的上调引起的。急性戒断期间阿片敏感突触递质释放增加可能是长期吗啡治疗产生的一种适应性机制。
