ArticleProceedings of the National Academy of Sciences of the United States of America2001
Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 86 citations in OpenAlex.
- Silymarin Reverses Seizure-Precipitating Effects of Alcohol and Associated Psychiatric Comorbidities, and Neurotoxicity in Pentylenetetrazol Pre-Kindled Mice.Neurotoxicity research · 2026Article
- Benzodiazepine Dependence: Clinical and Molecular Aspects, Preventive Strategies and Therapeutic Approaches.International journal of molecular sciences · 2026Review
- Increased NMDAR activity and GluN2A-NMDAR silent synapse expansion induced by chronic benzodiazepine treatment.Neuropharmacology · 2025Article
- Early life exposure to clonazepam has both short- and long-term effects on seizures induced with pentylenetetrazol (PTZ).Frontiers in pharmacology · 2025Article
- Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats-The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use.Pharmaceuticals (Basel, Switzerland) · 2023Article
- VALTOCONeurology international · 2021Review
- Psychopharmacological effects and safety of styryl-2-pyrones and dihydrostyryl-2-pyrones-rich fraction from Polygala sabulosa: absence of withdrawal syndrome and tolerance to anxiolytic-like and anticonvulsant effects.The Journal of pharmacy and pharmacology · 2018Article
- Neonatal Clonazepam Administration Induces Long-Lasting Changes in Glutamate Receptors.Frontiers in molecular neuroscience · 2018Article
- Cognate Ligand Chaperoning: a Novel Mechanism for the Post-translational Regulation of Neurotransmitter Receptor Biogenesis.Frontiers in cellular neuroscience · 2017Article
- Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA.Frontiers in cellular neuroscience · 2015Article
- Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats.Brain research bulletin · 2014Article
- GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area.Frontiers in pharmacology · 2014Article
- Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice.The international journal of neuropsychopharmacology · 2013Article
- Regulation of Ca²⁺/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal.Neural plasticity · 2012Article
- Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators?Advances in pharmacological sciences · 2012Article
- A neurochemical basis for an epigenetic vision of psychiatric disorders (1994-2009).Pharmacological research · 2011Review
- Down-regulation of synaptic GluN2B subunit-containing N-methyl-D-aspartate receptors: a physiological brake on CA1 neuron α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hyperexcitability during benzodiazepine withdrawal.The Journal of pharmacology and experimental therapeutics · 2011Article
- Tolerance to the rate-increasing and not rate-decreasing effects of pregnanolone in rats.Behavioural pharmacology · 2010Article
- Immunogold electron microscopic evidence of differential regulation of GluN1, GluN2A, and GluN2B, NMDA-type glutamate receptor subunits in rat hippocampal CA1 synapses during benzodiazepine withdrawal.The Journal of comparative neurology · 2010Article
- Calcium/calmodulin-dependent protein kinase II mediates hippocampal glutamatergic plasticity during benzodiazepine withdrawal.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2010Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Protracted administration of diazepam elicits tolerance, whereas discontinuation of treatment results in signs of dependence. Tolerance to the anticonvulsant action of diazepam is present in an early phase (6, 24, and 36 h) but disappears in a late phase (72-96 h) of withdrawal. In contrast, signs of dependence such as decrease in open-arm entries on an elevated plus-maze and increased susceptibility to pentylenetetrazol-induced seizures were apparent 96 h (but not 12, 24, or 48 h) after diazepam withdrawal. During the first 72 h of withdrawal, tolerance is associated with changes in the expression of GABA(A) (gamma-aminobutyric acid type A) receptor subunits (decrease in gamma(2) and alpha(1); increase in alpha(5)) and with an increase of mRNA expression of the most abundant form of glutamic acid decarboxylase (GAD), GAD(67). In contrast, dl-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit mRNA and cognate protein, which are normal during the early phase of diazepam withdrawal, increase by approximately 30% in cortex and hippocampus in association with the appearance of signs of dependence 96 h after diazepam withdrawal. Immunohistochemical studies of GluR1 subunit expression with gold-immunolabeling technique reveal that the increase of GluR1 subunit protein is localized to layer V pyramidal neurons and their apical dendrites in the cortex, and to pyramidal neurons and in their dendritic fields in hippocampus. The results suggest an involvement of GABA-mediated processes in the development and maintenance of tolerance to diazepam, whereas excitatory amino acid-related processes (presumably via AMPA receptors) may be involved in the expression of signs of dependence after withdrawal.
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