Jenner P, Boyce S, Marsden C D
University Department of Neurology, Institute of Psychiatry, London, U.K.
J Neural Transm Suppl. 1988;27:161-75. doi: 10.1007/978-3-7091-8954-2_14.
The underlying cause of the long term complications of L-DOPA or dopamine agonist therapy in Parkinson's disease remains unknown. Previous studies of repeated administration of L-DOPA or bromocriptine to rodents have shown increases, decreases or no change in brain dopaminergic activity. For this reason we have re-examined the effects of chronic L-DOPA or dopamine agonist administration on brain dopamine receptor function in rats. Repeated intraperitoneal administration of L-DOPA to rats for 21 days followed by 3 days drug withdrawal caused an enhancement of apomorphine-induced stereotypy but no apparent alteration in striatal dopamine receptor numbers or affinity (as judged by 3H-spiperone; 3H-NPA and 3H-piflutixol binding). Chronic oral administration of L-DOPA plus carbidopa to rats for one year was without effect on apomorphine-induced stereotypy or striatal D-2 dopamine receptors. Similarly, no effects were observed on striatal dopamine function following one year's administration of bromocriptine. Pergolide produced an enhancement of apomorphine-induced stereotypy but a decrease in D-2 receptor density as judged by 3H-spiperone binding. In rats with a unilateral 6-OHDA lesion of the medial forebrain bundle the oral administration of L-DOPA plus carbidopa for 4 weeks, followed by 4 days withdrawal, enhanced the rate of apomorphine-induced contraversive rotation. It appears difficult, at least in rats, to manipulate striatal dopamine receptors with L-DOPA or dopamine agonist drugs. An enhancement of motor behaviour can occur in the presence of no change or a decrease in dopamine receptor numbers identified by in vitro ligand binding to tissue homogenates.
左旋多巴或多巴胺激动剂治疗帕金森病的长期并发症的潜在原因仍然未知。先前对啮齿动物重复给予左旋多巴或溴隐亭的研究表明，脑多巴胺能活性有增加、降低或无变化。因此，我们重新研究了长期给予左旋多巴或多巴胺激动剂对大鼠脑多巴胺受体功能的影响。对大鼠重复腹腔注射左旋多巴21天，然后停药3天，导致阿扑吗啡诱导的刻板行为增强，但纹状体多巴胺受体数量或亲和力无明显改变（通过³H-螺哌隆、³H-NPA和³H-匹莫齐特结合判断）。对大鼠长期口服左旋多巴加卡比多巴一年，对阿扑吗啡诱导的刻板行为或纹状体D-2多巴胺受体无影响。同样，给予溴隐亭一年后，对纹状体多巴胺功能也无影响。培高利特使阿扑吗啡诱导的刻板行为增强，但通过³H-螺哌隆结合判断，D-2受体密度降低。在单侧内侧前脑束6-羟基多巴胺损伤的大鼠中，口服左旋多巴加卡比多巴4周，然后停药4天，提高了阿扑吗啡诱导的向对侧旋转的速率。至少在大鼠中，似乎难以用左旋多巴或多巴胺激动剂药物来操纵纹状体多巴胺受体。在通过体外配体与组织匀浆结合鉴定的多巴胺受体数量无变化或减少的情况下，运动行为仍可增强。
