ArticlePloS one2012
GABA(A) receptor α subunits differentially contribute to diazepam tolerance after chronic treatment.
Article in PloS one, 2012. 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, 46 citations in OpenAlex.
- Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5-Subtype Selective GABAClinical pharmacology in drug development · 2021Trial
- Chronic Chrysin, but Not Diazepam, Induces Anxiolytic-like Effects Without Behavioral Tolerance.Molecules (Basel, Switzerland) · 2026Article
- Targeting γ-aminobutyric acid type A receptors to mitigate perioperative neurocognitive disorders: a narrative review.British journal of anaesthesia · 2026Review
- Benzodiazepine Dependence: Clinical and Molecular Aspects, Preventive Strategies and Therapeutic Approaches.International journal of molecular sciences · 2026Review
- Residual Effects of Acute and Subchronic Zolpidem Treatments on Attentional Processes in Aged Female Rats.Fundamental & clinical pharmacology · 2026Article
- Acute and chronic zolpidem administration changes hippocampal long-term potentiation (LTP) as a possible mechanism of memory impairment.Iranian journal of basic medical sciences · 2026Article
- Anxiolytic-Like Effects of Citronellal and Phytol, Possibly Through the GABAergic Interaction Pathway: In Vivo with Molecular Docking Studies.Molecular neurobiology · 2025Article
- Anxiolytic Activity of Morellic Acid: Modulation of Diazepam's Anxiolytic Effects, Possibly Through GABAergic Interventions.CNS neuroscience & therapeutics · 2025Article
- A novel combination treatment for fragile X syndrome predicted using computational methods.Brain communications · 2024Article
- Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.Neurobiology of disease · 2023Article
- GABAFrontiers in psychiatry · 2022Review
- Tolerance and dependence following chronic alprazolam treatment in rhesus monkeys: Role of GABADrug and alcohol dependence · 2021Article
- Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice.Frontiers in aging neuroscience · 2021Article
- Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of "Juvenile" and "Adult Stress" in Rats.International journal of molecular sciences · 2020Article
- Article
- Tolerance and dependence following chronic alprazolam treatment: quantitative observation studies in female rhesus monkeys.Psychopharmacology · 2020Article
- Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit-containing GABAPsychopharmacology · 2019Article
- The α5-Containing GABAJournal of molecular neuroscience : MN · 2019Review
- 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
- Valium without dependence? Individual GABANeuropsychiatric disease and treatment · 2018Review
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundWithin the GABA(A)-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABA(A)-receptor subtypes.
methodsWe investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABA(A)-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (α(1) selective) and TPA023 (α(2/3) selective). In-vivo binding studies with [(3)H]flumazenil confirmed compounds occupied CNS GABA(A) receptors.
resultsChronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects.
conclusionsOUR DATA INDICATE THAT: (i) GABA(A)-α(2)/α(3) subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABA(A)-α(1)/GABA(A)-α(5) receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABA(A) α(1), α(2) or α(5) subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABA(A) α(2), or α(3) receptors does not engender tolerance development, subtype-selective GABA(A) drugs might constitute a promising class of novel drugs.
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