Behavioral measurement of benzodiazepine tolerance and GABAergic subsensitivity in the substantia nigra pars reticulata

Abstract

Rotational behavior was elicited by unilateral microinjection of the benzodiazepine flurazepam, and the γ-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 μg) 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 a 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.