Schoffelmeer A N, De Vries T J, Vanderschuren L J, Tjon G H, Nestby P, Wardeh G, Mulder A H
Graduate School Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit, Department of Pharmacology, Free University, Medical Faculty, The Netherlands.
Synapse. 1997 Apr;25(4):381-8. doi: 10.1002/(SICI)1098-2396(199704)25:4<381::AID-SYN9>3.0.CO;2-6.
Glucocorticoid receptor (GR)-mediated facilitation of striatal dopaminergic (DA) neurotransmission has been proposed to play a role in behavioral sensitization induced by intermittent exposure to drugs of abuse or stressors. Searching for possible common neuronal substrates acted upon by drugs of abuse and corticosterone, we addressed the question as to whether such a facilitatory effect is apparent (i.e., persists) in primary cultures of rat striatum subsequent to intermittent (prenatal) morphine administration. As previously observed in striatal slices of morphine-treated rats, intermittent morphine exposure in vivo caused a long-lasting increase in DA D1 receptor-stimulated adenylyl cyclase activity, that appeared to persist in primary cultures of rat striatal gamma-aminobutyric acid (GABA) neurons. Subsequent in vitro exposure of these striatal neurons to corticosterone or dexamethasone, simultaneously activating GR and mineralocorticoid receptors (MR), about doubled this adaptive effect of previous in vivo morphine administration. The selective MR agonist aldosterone was ineffective in this respect. Prior in vivo morphine treatment also enhanced the stimulatory in vitro effect of corticotropin releasing hormone (CRH) on adenylyl cyclase in cultured GABA neurons. However, the enhanced CRH receptor functioning was not potentiated by in vitro corticosterone exposure. Activation of GR by corticosterone did not facilitate the increase in D1 receptor efficacy induced by sustained activation of muscarinic receptors in cultured striatal neurons. These data indicate that previous intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on enhanced striatal DA neurotransmission at the level of postsynaptic D1 receptors. Moreover, the induction of this neuroadaptation seems to display opioid receptor selectivity and its long-term expression may be confined to D1 receptors. Since exposure to drugs of abuse or stressors not only increase striatal DA release but also plasma corticosterone levels, we hypothesize that this adaptive phenomenon in DA-sensitive GABA neurons is involved in the expression of morphine-induced long-term behavioral sensitization to drugs of abuse and stressors.
糖皮质激素受体（GR）介导的纹状体多巴胺能（DA）神经传递促进作用被认为在间歇性接触滥用药物或应激源所诱导的行为敏化中起作用。为了寻找可能受滥用药物和皮质酮作用的共同神经元底物，我们探讨了在间歇性（产前）给予吗啡后，这种促进作用在大鼠纹状体原代培养物中是否明显（即持续存在）。正如先前在吗啡处理大鼠的纹状体切片中观察到的那样，体内间歇性吗啡暴露导致DA D1受体刺激的腺苷酸环化酶活性长期增加，这种增加似乎在大鼠纹状体γ-氨基丁酸（GABA）神经元的原代培养物中持续存在。随后将这些纹状体神经元在体外暴露于皮质酮或地塞米松，同时激活GR和盐皮质激素受体（MR），这使先前体内吗啡给药的这种适应性效应增加了约一倍。选择性MR激动剂醛固酮在这方面无效。先前的体内吗啡处理还增强了促肾上腺皮质激素释放激素（CRH）对培养的GABA神经元中腺苷酸环化酶的体外刺激作用。然而，体外皮质酮暴露并未增强CRH受体功能的增强。皮质酮对GR的激活并未促进培养的纹状体神经元中由毒蕈碱受体持续激活所诱导的D1受体效能增加。这些数据表明，先前的间歇性吗啡给药在突触后D1受体水平上诱导了皮质酮对增强的纹状体DA神经传递的持久协同作用。此外，这种神经适应性的诱导似乎表现出阿片受体选择性，其长期表达可能局限于D1受体。由于接触滥用药物或应激源不仅会增加纹状体DA释放，还会增加血浆皮质酮水平，我们推测DA敏感的GABA神经元中的这种适应性现象参与了吗啡诱导的对滥用药物和应激源的长期行为敏化的表达。
