Selective changes in sensitivity to benzodiazepines, and not other positive GABA(A) modulators, in rats receiving flunitrazepam chronically.
BACKGROUND
Tolerance and dependence can develop during chronic benzodiazepine treatment; however, cross tolerance and cross dependence to positive modulators acting at other sites on GABA(A) receptors might not occur.


OBJECTIVE
The current study evaluated changes in sensitivity to positive GABA(A) modulators during chronic treatment with the benzodiazepine flunitrazepam to determine whether cross tolerance and cross dependence varied as a function of site of action.


METHODS
Eight rats responded under a fixed ratio 20 schedule of food presentation. Dose-effect curves were determined before, during and after chronic treatment with one or two daily injections of 1 mg/kg of flunitrazepam.


RESULTS
Prior to chronic treatment, benzodiazepines (flunitrazepam, midazolam), a barbiturate (pentobarbital), a neuroactive steroid (pregnanolone), and drugs with primary mechanisms of action at receptors other than GABA(A) receptors (morphine, ketamine) dose-dependently decreased responding. Twice daily treatment with flunitrazepam produced 9.5- and 23-fold shifts to the right in the flunitrazepam and midazolam dose-effect curves, respectively. In contrast, dose-effect curves for other drugs either were not changed or were shifted less than or equal to fourfold to the right.


CONCLUSIONS
Decreased sensitivity to benzodiazepines and not to a barbiturate or a neuroactive steroid during chronic flunitrazepam treatment indicates that tolerance and cross tolerance developed only to benzodiazepines. Despite similar acute behavioral effects among positive GABA(A) modulators, the differential development of cross tolerance suggests that adaptations at GABA(A) receptors produced by chronic benzodiazepine treatment differentially affect positive modulators depending on their site of action; such differences might be exploited to benefit patients treated daily with positive GABA(A) modulators.
Gerak
Lisa R
LR
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., mail code 7764, San Antonio, TX, 78229-3900, USA. gerak@uthscsa.edu
D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005445:Flunitrazepam / Q000008:administration & dosage / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010424:Pentobarbital / Q000008:administration & dosage / Q000494:pharmacology; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012055:Reinforcement Schedule; D019966:Substance-Related Disorders / Q000503:physiopathology
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005445:Flunitrazepam; D007649:Ketamine; D009020:Morphine; D011280:Pregnanolone; D010424:Pentobarbital; D008874:Midazolam