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Selective changes in sensitivity to benzodiazepines, and not other positive GABAA modulators, in rats receiving flunitrazepam chronically

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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 GABAA receptors might not occur.

Objectives

The current study evaluated changes in sensitivity to positive GABAA 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 GABAA 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 GABAA modulators, the differential development of cross tolerance suggests that adaptations at GABAA 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 GABAA modulators.

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Acknowledgments

The author thanks R. Lopez, O. Dominguez, J. Kite, and D. Mojica for their excellent technical assistance.

Animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council [Department of Health, Education and Welfare, publication No. (NIH) 85-23, revised 1996].

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Authors and Affiliations

  1. 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

    Lisa R. Gerak

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  1. Lisa R. Gerak
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Correspondence to Lisa R. Gerak.

Additional information

These studies were supported by United States Public Health Service Grant DA017240. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

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Gerak, L.R. Selective changes in sensitivity to benzodiazepines, and not other positive GABAA modulators, in rats receiving flunitrazepam chronically. Psychopharmacology 204, 667–677 (2009). https://doi.org/10.1007/s00213-009-1497-4

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  • DOI: https://doi.org/10.1007/s00213-009-1497-4

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