Chronic flurazepam differentially regulates a behavioral effect of GABA agonists

Subsensitivity to gamma-aminobutyric acid (GABA) agonists was sought in rats treated 1 or 4 weeks with flurazepam (FZP). Sensitivity to GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) was assessed by measuring contralateral rotation following unilateral microinjection of drug into the substantia nigra pars reticulata (SNpr). Immediately and 48 h after chronic treatment GABA, 200 micrograms or THIP, 60 ng was infused into SNpr. Immediately, but not 48 h after 1 week of FZP treatment, GABA subsensitivity was shown by a significantly reduced total number of contralateral turns and peak rotation rate. There was no change in the response to THIP after 1 week FZP treatment. Following 4 week FZP treatment, no subsensitivity to GABA or THIP was evident. Previous results showed subsensitivity to muscimol after 4, but not 1 week of FZP treatment. Since muscimol and THIP are not subject to uptake, there may be increased uptake of GABA after 1 week of FZP treatment, though it may not persist during continued treatment. Differential regulation of GABA agonist effects in SNpr may be related to their acting at differing GABAA receptor subpopulations, and variable responses of these subpopulations to chronic BZ treatment.