Shoham Shai, Mazeh Hagi, Javitt Daniel C, Heresco-Levy Uriel
Research Department, Ezrath Nashim-Herzog Memorial Hospital, Jerusalem, Israel.
Brain Res. 2004 Apr 9;1004(1-2):142-7. doi: 10.1016/j.brainres.2004.01.022.
Presently there is no established treatment for antipsychotic drugs-induced tardive dyskinesia (TD), which remains a major clinical issue in psychiatry. Based on the principles of the glutamatergic hypothesis of schizophrenia, the amino acid glycine (GLY) and the antituberculosis drug D-cycloserine (DCS) have been assessed, during the last decade, as adjuvants to antipsychotic drugs. Observations stemming from these studies suggest that, in addition to improving schizophrenia symptoms, these compounds may also be beneficial against drug-induced dyskinesias. In order to investigate this hypothesis, GLY and DCS effects were studied using the putative TD analogue vacuous chewing movements (VCM) rat model. Following 24 weeks of treatment with haloperidol decanoate (0.38 mg/kg/4 weeks) rats (N=40) were randomized to receive one intraperitoneal injection with 1.6 g/kg GLY, 10 mg/kg ("low dose") DCS; 100 mg/kg ("high dose") DCS or saline ("placebo"), respectively. Behavior was videotaped at intervals during the experiment and all VCM, rearing, grooming and immobility episodes were analyzed and scored. A control group (N=9) received saline for 24 weeks. Haloperidol administration decreased motor activity and significantly induced VCM. High dose DCS significantly reduced VCM without affecting other motor parameters. GLY treatment resulted in significantly less VCM but also reduced rearing, grooming and mobility. In contrast, low dose DCS and placebo did not significantly affect any of these parameters. These findings indicate that the use of GLY and DCS results in attenuation of VCM in rats and may have an effect on TD in humans. Clinical trials with this type of compounds for patients suffering from TD are warranted.
目前，抗精神病药物所致迟发性运动障碍（TD）尚无既定的治疗方法，这仍是精神病学领域的一个主要临床问题。基于精神分裂症谷氨酸能假说的原理，在过去十年中，氨基酸甘氨酸（GLY）和抗结核药物D-环丝氨酸（DCS）已被评估为抗精神病药物的辅助药物。这些研究得出的观察结果表明，除了改善精神分裂症症状外，这些化合物可能对药物性运动障碍也有益处。为了研究这一假说，使用假定的TD类似物空嚼运动（VCM）大鼠模型研究了GLY和DCS的作用。用癸酸氟哌啶醇（0.38mg/kg/4周）治疗24周后，将大鼠（N=40）随机分为四组，分别腹腔注射1.6g/kg GLY、10mg/kg（“低剂量”）DCS、100mg/kg（“高剂量”）DCS或生理盐水（“安慰剂”）。在实验期间定期对行为进行录像，并对所有VCM、竖毛、理毛和不动发作进行分析和评分。一个对照组（N=9）接受24周的生理盐水注射。给予氟哌啶醇会降低运动活性并显著诱发VCM。高剂量DCS显著降低了VCM，而不影响其他运动参数。GLY治疗导致VCM明显减少，但也减少了竖毛、理毛和活动能力。相比之下，低剂量DCS和安慰剂对这些参数均无显著影响。这些发现表明，使用GLY和DCS可减轻大鼠的VCM，可能对人类TD有影响。有必要对这类化合物用于TD患者进行临床试验。
