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Selective changes in sensitivity to benzodiazepines, and not other positive GABA(A) modulators, in rats receiving flunitrazepam chronically.
Psychopharmacology (Berl). 2009 Jul; 204(4):667-77.P

Abstract

RATIONALE

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.

OBJECTIVES

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19274455

Citation

Gerak, Lisa R.. "Selective Changes in Sensitivity to Benzodiazepines, and Not Other Positive GABA(A) Modulators, in Rats Receiving Flunitrazepam Chronically." Psychopharmacology, vol. 204, no. 4, 2009, pp. 667-77.
Gerak LR. Selective changes in sensitivity to benzodiazepines, and not other positive GABA(A) modulators, in rats receiving flunitrazepam chronically. Psychopharmacology (Berl). 2009;204(4):667-77.
Gerak, L. R. (2009). Selective changes in sensitivity to benzodiazepines, and not other positive GABA(A) modulators, in rats receiving flunitrazepam chronically. Psychopharmacology, 204(4), 667-77. https://doi.org/10.1007/s00213-009-1497-4
Gerak LR. Selective Changes in Sensitivity to Benzodiazepines, and Not Other Positive GABA(A) Modulators, in Rats Receiving Flunitrazepam Chronically. Psychopharmacology (Berl). 2009;204(4):667-77. PubMed PMID: 19274455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective changes in sensitivity to benzodiazepines, and not other positive GABA(A) modulators, in rats receiving flunitrazepam chronically. A1 - Gerak,Lisa R, Y1 - 2009/03/10/ PY - 2008/03/14/received PY - 2009/02/14/accepted PY - 2009/3/11/entrez PY - 2009/3/11/pubmed PY - 2009/8/1/medline SP - 667 EP - 77 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 204 IS - 4 N2 - RATIONALE: 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. OBJECTIVES: 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/19274455/Selective_changes_in_sensitivity_to_benzodiazepines_and_not_other_positive_GABA_A__modulators_in_rats_receiving_flunitrazepam_chronically_ L2 - https://dx.doi.org/10.1007/s00213-009-1497-4 DB - PRIME DP - Unbound Medicine ER -