Otago Centre for Theoretical Studies in Psychiatry and Neuroscience (OCTSPAN), Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, P.O.Box 913, Dunedin, New Zealand.
Curr Neuropharmacol. 2009 Dec;7(4):302-14. doi: 10.2174/157015909790031229.
Many issues remain unresolved about antipsychotic drugs. Their therapeutic potency scales with affinity for dopamine D2 receptors, but there are indications that they act indirectly, with dopamine D1 receptors (and others) as possible ultimate targets. Classical neuroleptic drugs disinhibit striatal cholinergic interneurones and increase acetyl choline release. Their effects may then depend on stimulation of muscarinic receptors on principle striatal neurones (M4 receptors, with reduction of cAMP formation, for therapeutic effects; M1 receptors for motor side effects). Many psychotic patients do not benefit from neuroleptic drugs, or develop resistance to them during prolonged treatment, but respond well to clozapine. For patients who do respond, there is a wide (>ten-fold) range in optimal doses. Refractoriness or low sensitivity to antipsychotic effects (and other pathologies) could then arise from low density of cholinergic interneurones. Clozapine probably owes its special actions to direct stimulation of M4 receptors, a mechanism available when indirect action is lost.
许多关于抗精神病药物的问题仍未得到解决。它们的治疗效力与多巴胺 D2 受体的亲和力成正比，但有迹象表明它们是间接作用的，多巴胺 D1 受体（和其他受体）可能是最终的靶点。经典的神经阻滞剂药物抑制纹状体胆碱能中间神经元并增加乙酰胆碱的释放。它们的作用可能取决于对纹状体主要神经元上毒蕈碱受体的刺激（M4 受体，通过减少 cAMP 的形成来产生治疗效果；M1 受体则会引起运动副作用）。许多精神病患者不能从神经阻滞剂药物中受益，或者在长期治疗过程中对其产生耐药性，但对氯氮平反应良好。对于有反应的患者，最佳剂量范围很宽（>十倍）。那么，对抗精神病作用（和其他病理）的反应迟钝或低敏感性可能源于胆碱能中间神经元的密度低。氯氮平可能因其对 M4 受体的直接刺激作用而具有特殊作用，当间接作用丧失时，这种机制就会发挥作用。
