Tietz E I, Rosenberg H C
Department of Pharmacology, Medical College of Ohio, Toledo 43699.
Brain Res. 1988 Jan 12;438(1-2):41-51. doi: 10.1016/0006-8993(88)91321-2.
Rotational behavior was elicited by unilateral microinjection of the benzodiazepine flurazepam, and the gamma-aminobutyric acid (GABA) agonist, muscimol, into the substantia nigra pars reticulata (SNpr). This response was used to quantitate benzodiazepine tolerance and GABAergic subsensitivity after chronic benzodiazepine treatment. Studies in naive rats established the dose requirements for inducing contralateral circling and demonstrated the reproducibility of the behavioral response as a measure of SNpr function. There was a large difference in potency between the two drugs for causing dose-related rotation. The response to microinjected flurazepam could be blocked by 16 mg/kg of the benzodiazepine antagonist, Ro15-1788. Tolerance to intranigral flurazepam (50 micrograms) was measured by a reduction in the turning response after a 1- or 4-week chronic flurazepam treatment. The time course for the reversal of tolerance after a 4-week benzodiazepine treatment correlates with the time course of the reversal of benzodiazepine receptor down-regulation in the SNpr. Subsensitivity of the GABAergic system was demonstrated by the decreased rotational response to muscimol (10 ng), confirming the idea that the GABAergic system is also functionally altered by chronic benzodiazepine treatment. The time course of the decreased sensitivity to muscimol does not coincide with the development and reversal of tolerance to the turning produced by flurazepam or with benzodiazepine receptor down-regulation. These data suggest differential regulation of SNpr sensitivity to benzodiazepine and GABA agonists following chronic benzodiazepine treatment and may provide a basis for differential tolerance; the development of tolerance to some but not other benzodiazepine actions.
通过向黑质网状部（SNpr）单侧微量注射苯二氮䓬类药物氟西泮和γ-氨基丁酸（GABA）激动剂蝇蕈醇来诱发旋转行为。该反应用于定量慢性苯二氮䓬治疗后的苯二氮䓬耐受性和GABA能亚敏感性。对未用药大鼠的研究确定了诱导对侧旋转的剂量要求，并证明了行为反应作为SNpr功能指标的可重复性。两种药物在引起剂量相关旋转方面的效力有很大差异。微量注射氟西泮的反应可被16mg/kg的苯二氮䓬拮抗剂Ro15-1788阻断。通过在1周或4周的慢性氟西泮治疗后旋转反应的降低来测量对黑质内氟西泮（50微克）的耐受性。4周苯二氮䓬治疗后耐受性逆转的时间进程与SNpr中苯二氮䓬受体下调逆转的时间进程相关。对蝇蕈醇（10纳克）的旋转反应降低证明了GABA能系统的亚敏感性，证实了慢性苯二氮䓬治疗也会使GABA能系统发生功能改变的观点。对蝇蕈醇敏感性降低的时间进程与对氟西泮产生的旋转耐受性的发展和逆转或与苯二氮䓬受体下调不一致。这些数据表明，慢性苯二氮䓬治疗后SNpr对苯二氮䓬和GABA激动剂的敏感性存在差异调节，这可能为差异耐受性提供基础；即对某些而非其他苯二氮䓬作用产生耐受性。
