Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies

Psychopharmacology (Berl). 1996 Nov;128(1):1-16. doi: 10.1007/s002130050103.

Abstract

The purpose of this review was to establish in vivo apparent pA2 and pKB values for antagonism of the discriminative stimulus effects of benzodiazepine ligands, and to compare these values to those obtained from other behavioral procedures. Articles were chosen from the Medline data base from January 1976 to August 1995. This literature consisted of studies with flumazenil (Ro 15-1788) as the antagonist, as well as other benzodiazepine ligands (beta-carbolines, CGS 9896, CGS 8216). The dose which occasioned 50% of the maximal response (ED50) was obtained from values estimated from the graphs presented in each article. These ED50 values were used to conduct apparent pKB and apparent pA2 analyses. Apparent pA2 values for antagonism of the discriminative stimulus effects of diazepam in rats were the following (antagonist, pA2, slope): flumazenil, 4.7, -1.5; beta-CCE, 4.0, -3.0; beta-CCtB, 5.0, -2.2. The apparent pA2 value for CGS 8216 antagonism of the discriminative stimulus effects of diazepam in rats was 5.74, -2.22 (reported in Shannon and Davis 1984). The mean apparent pA2 value for flumazenil antagonism of the discriminative stimulus effects of diazepam in rhesus monkeys was 6.55, with a mean slope of -1.42. Analysis of baboon data from Ator and Griffiths (1986) revealed apparent pKB values for flumazenil antagonism of the discriminative stimulus effects of lorazepam that were lower than the pKB values for either zopiclone or CL 218,872. Analyses of the pKB data also revealed the following: no effect of route of administration (rat, PO versus IP; baboon, PO versus IM), no effect of pretreatment time (grouped into two categories: 10-20 min and 40-70 min, in rats and non-human primates), and a species effect (pKB values for rats were reliably lower than either non-human primates or pigeons, rhesus monkeys were lower than baboons). The apparent pA2 and pKB values obtained in the present review were similar across behavioral assays, except that, in squirrel monkeys, flumazenil pKB values for antagonism of benzodiazepine-induced decreases in schedule-controlled behavior were lower than pKB values obtained from drug discrimination studies. This review provides apparent pA2 values for antagonism of the discriminative stimulus effects of benzodiazepine ligands and provides evidence from pKB analyses consistent with functional heterogeneity of benzodiazepine receptors in vivo.

Publication types

  • Meta-Analysis
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Benzodiazepines / pharmacology*
  • Discrimination Learning / drug effects*
  • Flumazenil / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists*
  • Pyrazoles / pharmacology

Substances

  • Anti-Anxiety Agents
  • GABA Modulators
  • GABA-A Receptor Agonists
  • Pyrazoles
  • Benzodiazepines
  • Flumazenil
  • 2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one