ASSESSMENT OF BENZODIAZEPINE RECEPTOR HETEROGENEITY IN-VIVO - APPARENT PA(2) AND PK(B) ANALYSES FROM BEHAVIORAL-STUDIES

The purpose of this review was to establish in vivo apparent pA(2) and pK(B) 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 Medli ne data base from January 1976 to August 1995. This literature consist ed 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 (ED(50)) was ob tained from Values estimated from the graphs presented in each article . These ED(50) values were used to conduct apparent pK(B) and apparent pA(2) analyses. Apparent pA(2) values for antagonism of the discrimin ative stimulus effects of diazepam in rats were the following (antagon ist, pA(2), slope): flumazenil, 4.7,-1.5; beta-CCE, 4.0, -3.0; beta-CC tB, 5.0, -2.2. The apparent pA(2) 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 pA(2) value for flumazenil antagonism of the discriminative stimulus effects of diaze pam in rhesus monkeys was 6.55, with a mean slope of -1.42. Analysis o f baboon data from Ator and Griffiths (1986) revealed apparent pK(B) V alues for flumazenil antagonism of the discriminative stimulus effects of lorazepam that were lower than the pK(B) values for either zopiclo ne or CL 218,872. Analyses of the pK(B) data also revealed the followi ng: no effect of route of administration (rat, PO versus IF; baboon, P O Versus IM), no effect of pretreatment time (grouped into two categor ies: 10-20 min and 40-70 min, in rats and non-human primates), and a s pecies effect (pK(B) values for rats were reliably lower than either n on-human primates or pigeons, rhesus monkeys were lower than baboons). The apparent pA(2) and pK(B) values obtained in the present review we re similar across behavioral assays, except that, in squirrel monkeys, flumazenil pK(B) values for antagonism of benzodiazepine-induced decr eases in schedule-controlled behavior were lower than pK(B) values obt ained from drug discrimination studies. This review provides apparent pA(2) values for antagonism of the discriminative stimulus effects of benzodiazepine ligands and provides evidence from pK(B) analyses consi stent with functional heterogeneity of benzodiazepine receptors in viv o.