Egan M F, Chrapusta S, Karoum F, Lipska B K, Wyatt R J
Neuropsychiatry Branche, National Institute of Mental Health, Neuroscience Research Center at St. Elizabeth's, Washington, DC, USA.
J Neural Transm (Vienna). 1996;103(7):777-805. doi: 10.1007/BF01273358.
Antipsychotic medications appear to exert their therapeutic effects by blocking D2 receptors. While D2 blockade occurs rapidly, reduction in psychotic symptoms is often delayed. This time discrepancy has been attributed to the relatively slow development of depolarization inactivation (DI) of dopaminergic neurons. The reduced firing rates associated with DI has been hypothesized to reduce dopamine release and thus psychotic symptoms. Studies assessing changes in dopamine release during chronic neuroleptic treatment, using microdialysis and voltammetry, have been inconsistent. This may be due to methodological differences between studies, the invasive nature of these procedures, or other confounds. To investigate the effects of DI on dopamine release, 3-MT accumulation, an index of dopamine release that does not involve disruption of brain tissue, was measured during acute and chronic neuroleptic treatment. These results are compared with those using other techniques. 3-MT levels remained elevated after chronic treatment, suggesting that DI does not markedly reduce release. Regulation of dopamine release during DI was examined using two techniques known to block dopamine neuronal impulse flow. 3-MT levels were markedly reduced by both, implying that DI does not alter the portion of dopamine release mediated by neuronal impulse flow. Overall, studies to date suggest that the delayed therapeutic effects of neuroleptics are not due to reductions in impulse dependent dopamine release. Recent studies using a neurodevelopmental animal model of schizophrenia have pointed to altered pre- and post-synaptic indices of dopamine neurotransmission. The results suggest that neuroleptics may exert their therapeutic effects, in part, by limiting the fluctuations in dopamine release, and raise new issues for future research.
抗精神病药物似乎通过阻断D2受体发挥其治疗作用。虽然D2受体阻断迅速发生，但精神病症状的减轻往往延迟。这种时间差异归因于多巴胺能神经元去极化失活（DI）的发展相对缓慢。与DI相关的放电率降低被认为会减少多巴胺释放，从而减轻精神病症状。使用微透析和伏安法评估慢性抗精神病药物治疗期间多巴胺释放变化的研究结果并不一致。这可能是由于研究之间的方法学差异、这些程序的侵入性性质或其他混杂因素。为了研究DI对多巴胺释放的影响，在急性和慢性抗精神病药物治疗期间测量了3 - MT积累，这是一种不涉及脑组织破坏的多巴胺释放指标。将这些结果与使用其他技术得到的结果进行比较。慢性治疗后3 - MT水平仍然升高，表明DI并没有显著减少释放。使用已知可阻断多巴胺神经元冲动流的两种技术研究了DI期间多巴胺释放的调节。两种技术都使3 - MT水平显著降低，这意味着DI不会改变由神经元冲动流介导的多巴胺释放部分。总体而言，迄今为止的研究表明，抗精神病药物延迟的治疗效果并非由于依赖冲动的多巴胺释放减少。最近使用精神分裂症神经发育动物模型的研究指出，多巴胺神经传递的突触前和突触后指标发生了改变。结果表明，抗精神病药物可能部分通过限制多巴胺释放的波动发挥其治疗作用，并为未来研究提出了新问题。
