Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

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12 Scopus citations

Abstract

Rationale: Benzodiazepine treatment can result in dependence as evidenced by signs of withdrawal upon discontinuation of use. Objective: Positive GABAA receptor modulators were examined for their capacity to attenuate flumazenil-like discriminative stimulus effects (i.e., withdrawal) that emerge upon discontinuation of chronic benzodiazepine treatment. Methods: Rhesus monkeys receiving chronic diazepam (5.6 mg-1 kg-1 24 h-1 p.o.) discriminated flumazenil (0.1 mg/kg s.c.) from vehicle. Results: Upon discontinuation of diazepam treatment, responding switched from the vehicle to the flumazenil lever, although at different times among monkeys. The shorter-acting benzodiazepine lorazepam (3.2 mg-1 kg-1 8 h-1) was substituted for diazepam and, 11 h after lorazepam, monkeys consistently responded on the flumazenil lever. Flumazenil-lever responding after acute lorazepam deprivation was attenuated not only by benzodiazepines (lorazepam and midazolam) but also by positive GABAA receptor modulators acting at neuroactive steroid (pregnanolone and alfaxalone) and barbiturate sites (pentobarbital). Deprivation-induced responding on the flumazenil lever was not attenuated by low efficacy positive GABAA modulators (bretazenil and L-838,417) or non-GABAA receptor ligands (ketamine and cocaine). Neuroactive steroids were relatively more potent than other positive GABAA receptor modulators in attenuating deprivation-induced flumazenil-lever responding, as compared to their relative potency in monkeys discriminating midazolam and otherwise not receiving benzodiazepine treatment. Conclusions: These results suggest that positive GABAA receptor modulators acting at different sites attenuate withdrawal induced by discontinuation of benzodiazepine treatment, consistent with previous studies suggesting that the same compounds attenuate flumazenil-precipitated withdrawal. Differences in the relative potency of positive modulators as a function of acute versus chronic benzodiazepine treatment suggest that neuroactive steroids, in particular, are especially potent in benzodiazepine-dependent animals.

Original languageEnglish (US)
Pages (from-to)135-145
Number of pages11
JournalPsychopharmacology
Volume192
Issue number1
DOIs
StatePublished - May 1 2007

Keywords

  • Barbiturate
  • Benzodiazepine
  • Dependence
  • Drug discrimination
  • Flumazenil
  • GABA receptor
  • Neuroactive steroid
  • Rhesus monkey
  • Withdrawal

ASJC Scopus subject areas

  • Pharmacology

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