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Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys.
Behav Pharmacol. 2011 Feb; 22(1):49-57.BP

Abstract

Benzodiazepines and neuroactive steroids are positive c-aminobutyric acid(A) (GABA(A)) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABA(A) modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABA(A) receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepam-treated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenil-lever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABA(A) modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, mail code 7764, San Antonio, TX 78229-3900, USA. gerak@uthscsa.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21516176

Citation

Gerak, Lisa R., and Charles P. France. "Chronic Benzodiazepine Treatment Does Not Alter Interactions Between Positive GABA(A) Modulators and Flumazenil or Pentylenetetrazole in Monkeys." Behavioural Pharmacology, vol. 22, no. 1, 2011, pp. 49-57.
Gerak LR, France CP. Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys. Behav Pharmacol. 2011;22(1):49-57.
Gerak, L. R., & France, C. P. (2011). Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys. Behavioural Pharmacology, 22(1), 49-57. https://doi.org/10.1097/FBP.0b013e3283425aa0
Gerak LR, France CP. Chronic Benzodiazepine Treatment Does Not Alter Interactions Between Positive GABA(A) Modulators and Flumazenil or Pentylenetetrazole in Monkeys. Behav Pharmacol. 2011;22(1):49-57. PubMed PMID: 21516176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys. AU - Gerak,Lisa R, AU - France,Charles P, PY - 2011/4/26/entrez PY - 2011/4/26/pubmed PY - 2012/4/7/medline KW - GABAA modulators KW - diazepam KW - drug discrimination KW - flumazenil KW - monkey KW - monkeys KW - neuroactive steroids KW - pentylenetetrazole KW - pregnanolone SP - 49 EP - 57 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 22 IS - 1 N2 - Benzodiazepines and neuroactive steroids are positive c-aminobutyric acid(A) (GABA(A)) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABA(A) modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABA(A) receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepam-treated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenil-lever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABA(A) modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids. SN - 1473-5849 UR - https://www.unboundmedicine.com/medline/citation/21516176/Chronic_benzodiazepine_treatment_does_not_alter_interactions_between_positive_GABA_A__modulators_and_flumazenil_or_pentylenetetrazole_in_monkeys_ L2 - https://doi.org/10.1097/FBP.0b013e3283425aa0 DB - PRIME DP - Unbound Medicine ER -