Clinical and behavioral studies have demonstrated that chronic administration of benzodiazepines results in tolerance to many of the therapeutic actions of these drugs. Benzodiazepines are the drugs of first choice for the treatment of status epilepticus and are potential anticonvulsants against a variety of seizure types. However, significant tolerance develops to the anticonvulsant effects of all of the benzodiazepines currently available for clinical use, limiting their usefulness in maintenance therapy. Although the cellular basis for decreasing effectiveness with chronic exposure is not well understood, present knowledge of benzodiazepine function points to involvement of GABAergic processes. We have proposed that tolerance to the benzodiazepines is mediated by changes in the GABA/Bz receptor complex. Work during the present funding period has been directed toward testing this hypothesis. The present proposal will extend these studies, incorporating recent findings that changes in GABA sensitivity seen after chronic diazepam are regionally specific. The hypothesis that differences in GABAergic innervation of the dorsal raphe and substantia nigra pars reticulata underlie differences in GABA sensitivity following chronic diazepam exposure will be tested. Evaluations of GABA sensitivity changes following chronic benzodiazepine exposure to other brain areas using electrophysiological and biochemical (chloride flux) measures will be carried out. Exposure of tolerant animals to a benzodiazepine antagonist has been shown to rapidly restore GABA sensitivity, anticonvulsant efficacy and to diminish physical dependence. This effect will be further investigated and extended to an examination of benzodiazepine ligands of differing efficacy for their tolerance-inducing potency. Possible molecular mechanisms underlying the development of tolerance will be examined by measuring the state of phosphorylation of identified GABA/Bz receptor subunits and by comparing steady state levels of mRNA coding for the receptor complex in naive and tolerant animals. This research will help us understand neural adaptations associated with chronic benzodiazepine exposure and may lead to the development of new chronic therapeutic strategies utilizing these drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023321-06
Application #
3406630
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1986-02-01
Project End
1992-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Hernandez, T D; Gallager, D W (1992) Development of long-term subsensitivity to GABA in dorsal raphe neurons of amygdala-kindled rats. Brain Res 582:221-5
Marley, R J; Heninger, C; Hernandez, T D et al. (1991) Chronic administration of beta-carboline-3-carboxylic acid methylamide by continuous intraventricular infusion increases GABAergic function. Neuropharmacology 30:245-51
Gallager, D W; Tallman, J F (1990) Relationship of GABAa receptor heterogeneity to regional differences in drug response. Neurochem Res 15:113-8
Hernandez, T D; Rosen, J B; Gallager, D W (1990) Long-term changes in sensitivity to GABA in dorsal raphe neurons following amygdala kindling. Brain Res 517:294-300
Hernandez, T D; Heninger, C; Wilson, M A et al. (1989) Relationship of agonist efficacy to changes in GABA sensitivity and anticonvulsant tolerance following chronic benzodiazepine ligand exposure. Eur J Pharmacol 170:145-55
Wilson, M A; Gallager, D W (1989) Responses of substantia nigra pars reticulata neurons to benzodiazepine ligands after acute and prolonged diazepam exposure. II. Modulation of firing rate. J Pharmacol Exp Ther 248:886-91
Wilson, M A; Gallager, D W (1989) Responses of substantia nigra pars reticulata neurons to benzodiazepine ligands after acute and prolonged diazepam exposure. I. Modulation of gamma-aminobutyric acid sensitivity. J Pharmacol Exp Ther 248:879-85
Heninger, C; Gallager, D W (1988) Altered gamma-aminobutyric acid/benzodiazepine interaction after chronic diazepam exposure. Neuropharmacology 27:1073-6
Davis, M; Gallager, D W (1988) Continuous slow release of low levels of diazepam produces tolerance to its depressant and anxiolytic effects on the startle reflex. Eur J Pharmacol 150:23-33

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