Ali Ziad, Roque Autumn, El-Mallakh Rif S
Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, United States.
Center for Mindfulness and CBT, 10845 Olive Blvd, St. Louis, MO 63141, United States.
Med Hypotheses. 2020 Mar 16;140:109682. doi: 10.1016/j.mehy.2020.109682.
Chronic treatment with dopamine D2 receptor antagonists has been proposed to lead to dopamine receptor supersensitivity. Frequently, this is conceptualized as upregulation or changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity are probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis.
Recent data suggest that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes.
Presynaptic increase in dopamine release occurs when super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated.
TD likely develops due to changes across the synapse and terminology such as 'dopamine receptor supersensitivity' can be misleading. 'Synaptic upregulation' may be a more correct term.
有人提出，长期使用多巴胺D2受体拮抗剂会导致多巴胺受体超敏。通常，这被概念化为突触后D2受体结构或功能的上调或改变。然而，所测得的D2受体密度增加1.4倍以及缺乏实际的受体超敏，可能不足以解释诸如迟发性运动障碍（TD）和多巴胺超敏性精神病等结果。
最近的数据表明，TD可能是由突触前、突触和突触后变化共同导致的。
当突触后D2受体受到超治疗剂量的阻断，导致突触中存在过量未结合的多巴胺，这些多巴胺最终通过多巴胺转运体被突触前神经元重新摄取时，就会发生突触前多巴胺释放增加。再循环多巴胺可用性的增加导致囊泡多巴胺浓度升高。由于释放的神经递质数量（称为量子）由突触前神经递质囊泡的数量决定，囊泡中多巴胺分子数量（浓度）的增加导致在连续的去极化事件中突触多巴胺浓度升高。在TD动物模型中已显示出突触变化，如穿孔突触的出现，这是新突触形成的早期步骤。最后，已证实突触后D2受体表达增加，但未表现出敏感性或效能增加。
TD可能是由于整个突触的变化而发展的，诸如“多巴胺受体超敏”这样的术语可能会产生误导。“突触上调”可能是一个更正确的术语。
