McBride W J, Murphy J M, Gatto G J, Levy A D, Yoshimoto K, Lumeng L, Li T K
Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, USA.
Alcohol Alcohol Suppl. 1993;2:463-7.
Neurochemical and neuropharmacological studies were undertaken to examine the possible involvement of the ventral tegmental area (VTA) dopamine (DA) system and the dorsal raphe nucleus (DRN) serotonin (5-HT) system in regulating oral alcohol self-administration. In vivo microdialysis studies demonstrated that either i.p. ethanol administration (1.0-2.0 g/kg) or local perfusion with ethanol (100 mM) could enhance the extracellular concentrations of both DA and 5-HT in the nucleus accumbens (ACB). Furthermore, the effects of local perfusion with ethanol on DA release in the ACB could be blocked by co-perfusion with a 5-HT3 antagonist. In the selectively-bred alcohol preferring P line of rats, there appears to be abnormal 5-HT and/or DA systems in certain limbic structures, i.e., ACB, olfactory tubercles (OTU) and medial prefrontal cortex (MPF). This is indicated by (a) lower contents of DA and 5-HT; (b) fewer 5-HT immunostained fibers; (c) lower densities of 5-HT1B, 5-HT2 and D2 receptors; and (d) higher densities of 5-HT1A receptors in the CNS of P rats compared to the alcohol-nonpreferring NP line of rats. Neuropharmacological studies demonstrated that local microinfusion of the D2 antagonist, sulpiride, or, at low doses, the DA releaser, d-amphetamine, could increase alcohol drinking by P rats. Intracranial self-administration (ICSA) studies showed that the P line of rats, but not the NP line, will self-administer 50-150 mg% ethanol directly into the VTA. Overall, these results suggest an innate abnormal functioning of the VTA DA and DRN 5-HT systems may be key factors facilitating the rewarding actions of ethanol in the CNS of P rats.
开展了神经化学和神经药理学研究，以检验腹侧被盖区（VTA）多巴胺（DA）系统和中缝背核（DRN）5-羟色胺（5-HT）系统在调节口服酒精自我给药过程中可能发挥的作用。体内微透析研究表明，腹腔注射乙醇（1.0 - 2.0 g/kg）或局部灌注乙醇（100 mM）均可提高伏隔核（ACB）中DA和5-HT的细胞外浓度。此外，与5-HT3拮抗剂共同灌注可阻断局部灌注乙醇对ACB中DA释放的影响。在选择性培育的嗜酒P品系大鼠中，某些边缘结构（即ACB、嗅结节（OTU）和内侧前额叶皮质（MPF））中似乎存在5-HT和/或DA系统异常。这表现为：（a）DA和5-HT含量较低；（b）5-HT免疫染色纤维较少；（c）5-HT1B、5-HT2和D2受体密度较低；以及（d）与不嗜酒的NP品系大鼠相比，P大鼠中枢神经系统中5-HT1A受体密度较高。神经药理学研究表明，局部微量注射D2拮抗剂舒必利，或低剂量的DA释放剂d-苯丙胺，可增加P大鼠的酒精摄入量。颅内自我给药（ICSA）研究表明，P品系大鼠而非NP品系大鼠会将50 - 150 mg%的乙醇直接自我注射到VTA中。总体而言，这些结果表明，VTA DA和DRN 5-HT系统的先天性功能异常可能是促进乙醇在P大鼠中枢神经系统中产生奖赏作用的关键因素。
