O'Brien D P, White F J
Department of Veterinary Bioscience, University of Illinois, Champaign 61820.
Eur J Pharmacol. 1987 Oct 27;142(3):343-54. doi: 10.1016/0014-2999(87)90072-0.
Previous electrophysiological studies have demonstrated that non-dopaminergic (non-DA) neurons within the substantia nigra pars reticulata (SNR) are extremely sensitive to the inhibitory effects of GABA and GABA-mimetic drugs, including benzodiazepines, whereas dopaminergic (DA) neurons in the substantia nigra pars compacta (SNC) are less sensitive to these compounds and may be influenced indirectly by SNR neurons. The interactions between A10 DA and non-DA neurons within the adjacent ventral tegmental area (VTA) are not as well characterized. In the present experiments, single unit recording and microiontophoretic techniques were used to determine the effects of benzodiazepines on DA and non-DA neurons in the VTA of chloral hydrate anesthetized rats. Diazepam, administered intravenously (i.v.), potently inhibited non-DA, SNR-like cells within the VTA. The effects of diazepam on A10 DA cells were more variable than those observed on non-DA, SNR-like cells in this region, but 77% of such cells showed moderate to marked excitation. Both of these effects were reversed by the benzodiazepine antagonist Ro 15-1788; on many cells, this agent produced marked rebound effects beyond the original basal firing rates. However, when administered alone, Ro 15-1788 exerted no effect on either cell population. Microiontophoretic administration of the benzodiazepines chlordiazepoxide and flurazepam resulted in marked inhibition of non-DA SNR-like cells, but produced either mild inhibition or no effect on A10 DA cells; excitation of DA cells was never observed even though the same neuron was excited by i.v. diazepam. These findings suggest that benzodiazepines act directly upon non-DA, SNR-like cells in the VTA to produce inhibition of activity and a disinhibition of A10 DA cells. This relationship makes it unlikely that benzodiazepines would enhance feedback inhibition of DA cells following neuroleptic administration. In fact, when administered following haloperidol, i.v. diazepam failed to reverse haloperidol-induced increases of A10 DA cell firing; if anything, diazepam further depolarized the cell. If antipsychotic drugs produce their clinical effects, in part, by inducing depolarization inactivation of DA cells, then benzodiazepines might be a useful adjunctive therapy in the treatment of schizophrenia.
以往的电生理学研究表明，黑质网状部（SNR）内的非多巴胺能（non-DA）神经元对γ-氨基丁酸（GABA）和GABA模拟药物（包括苯二氮䓬类药物）的抑制作用极为敏感，而黑质致密部（SNC）中的多巴胺能（DA）神经元对这些化合物的敏感性较低，可能受到SNR神经元的间接影响。相邻腹侧被盖区（VTA）内A10 DA神经元与非DA神经元之间的相互作用尚未得到充分表征。在本实验中，采用单细胞记录和微离子电泳技术，以确定苯二氮䓬类药物对水合氯醛麻醉大鼠VTA中DA和非DA神经元的影响。静脉注射（i.v.）地西泮可有效抑制VTA内非DA、类似SNR的细胞。地西泮对A10 DA细胞的作用比该区域内非DA、类似SNR的细胞更具变异性，但77% 的此类细胞表现出中度至明显的兴奋。这两种作用均被苯二氮䓬类拮抗剂Ro 15-1788逆转；在许多细胞上，该药物产生了超过原始基础放电率的明显反弹效应。然而，单独给药时，Ro 15-1788对这两种细胞群体均无作用。微离子电泳给予苯二氮䓬类药物氯氮䓬和氟西泮可导致对非DA、类似SNR的细胞产生明显抑制，但对A10 DA细胞产生轻度抑制或无作用；即使同一神经元被静脉注射地西泮兴奋，也从未观察到DA细胞的兴奋。这些发现表明，苯二氮䓬类药物直接作用于VTA内非DA、类似SNR的细胞，从而抑制其活动并解除对A10 DA细胞的抑制。这种关系使得苯二氮䓬类药物不太可能增强抗精神病药物给药后对DA细胞的反馈抑制。事实上，在氟哌啶醇给药后注射地西泮，未能逆转氟哌啶醇诱导的A10 DA细胞放电增加；如果有什么不同的话，地西泮使细胞进一步去极化。如果抗精神病药物部分通过诱导DA细胞的去极化失活产生临床效果，那么苯二氮䓬类药物可能是治疗精神分裂症的一种有用辅助疗法。
