Johnson S W, North R A
Vollum Institute, Oregon Health Sciences University, Portland 97201.
J Neurosci. 1992 Feb;12(2):483-8. doi: 10.1523/JNEUROSCI.12-02-00483.1992.
Increased activity of dopamine-containing neurons in the ventral tegmental area is necessary for the reinforcing effects of opioids and other abused drugs. Intracellular recordings from these cells in slices of rat brain in vitro showed that opioids do not affect the principal (dopamine-containing) neurons but hyperpolarize secondary (GABA-containing) interneurons. Experiments with agonists and antagonists selective for opioid receptor subtypes indicated that the hyperpolarization of secondary cells involved the mu-receptor. Most principal cells showed spontaneous bicuculline-sensitive synaptic potentials when the extracellular potassium concentration was increased from 2.5 to 6.5 or 10.5 mM; these were prevented by TTX and assumed to result from action potentials arising in slightly depolarized local interneurons. The frequency of these synaptic potentials, but not their amplitudes, was reduced by opioids selective for mu-receptors. It is concluded that hyperpolarization of the interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the dopamine cells. In vivo, this would lead to excitation of the dopamine cells by disinhibition, which would be expected to contribute to the positive reinforcement seen with mu-receptor agonists such as morphine and heroin.
腹侧被盖区中含多巴胺神经元的活性增加，是阿片类药物和其他滥用药物产生强化作用所必需的。在体外对大鼠脑切片中的这些细胞进行细胞内记录显示，阿片类药物并不影响主要的（含多巴胺的）神经元，而是使次级的（含γ-氨基丁酸的）中间神经元超极化。对阿片受体亚型具有选择性的激动剂和拮抗剂实验表明，次级细胞的超极化涉及μ受体。当细胞外钾浓度从2.5 mM增加到6.5 mM或10.5 mM时，大多数主要细胞表现出自发性荷包牡丹碱敏感的突触电位；这些电位可被河豚毒素阻断，并被认为是由轻度去极化的局部中间神经元产生的动作电位所致。对μ受体具有选择性的阿片类药物可降低这些突触电位的频率，但不影响其幅度。得出的结论是，阿片类药物使中间神经元超极化，减少了由γ-氨基丁酸介导的对多巴胺能细胞的自发性突触输入。在体内，这将导致多巴胺能细胞通过去抑制作用而兴奋，这有望促成如吗啡和海洛因等μ受体激动剂所产生的正性强化作用。
