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Rapid Seizure-Induced Reduction of Benzodiazepine and Zn 2+ Sensitivity of Hippocampal Dentate Granule Cell GABA A Receptors
Open accessAbstract
Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABAA receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn2+) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn2+. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn2+ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.
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“Seizure threshold shows a hyperbolic relationship to dose in zebrafish (Gupta, Khobragade, & Shingatgeri, 2014), rats (Kapur & Macdonald, 1997), and non-human primates (Bottlaender et al., 1994) (Figure 3b).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Kapur & Macdonald, 1997
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Metadata
- Authors
- Kapur, J., & Macdonald, R. L.
- Affiliations
- Pediatrics and Genetics (US)
- University of Michigan (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1997-10-01
- Volume
- 17
- Issue
- 19
- Pages
- 7532-7540
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2892718
- OpenAlex
- W1909177474
- Cited by
- 427
- References
- 61
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 11 · 2019: 16 · 2018: 21 · 2017: 28 · 2016: 18 · 2015: 26 · 2014: 14 · 2013: 11 · 2012: 18
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Epilepsy Foundation
- U.S. Public Health Service (R01 33300)
- National Institute of Neurological Disorders and Stroke (KO8-NS01748, K08NS001748, R01NS033300)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- GABAA receptor, status epilepticus, benzodiazepine sensitivity, diazepam, zinc, allosteric modulation, barbiturates, pentobarbital, functional plasticity, chronic epilepsy
- MeSH terms
- Animals, Benzodiazepines, Diazepam, Electric Conductivity, Female, Male, Neurons, Pentobarbital, Receptors, GABA-A, Seizures, Time Factors, Zinc, Rats, Sprague-Dawley, Dentate Gyrus, Rats, GABA-A Receptor Antagonists
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