Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABAA/α1 receptors

Abstract

Our findings provide evidence for a key role of GABA(A)/alpha(1) receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABA(A)/alpha(1) receptors is required for BZ agonists to reproduce these discriminative stimulus effects.

Contribution of GABAAReceptor Subtypes to the Anxiolytic-Like, Motor, and Discriminative Stimulus Effects of Benzodiazepines: Studies with the Functionally Selective Ligand SL651498 [6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one]

“…In the equation, "B" is the dose of ␤-CCT in moles per kilogram and "DR" is the ED 50 of agonist combined with antagonist divided by the ED 50 of agonist alone. Mean apparent pK B values and 95% confidence intervals were calculated to make comparisons with previous findings (e.g., Lelas et al, 2002;Rowlett et al, 2003).…”

“…Altogether, these data suggest that the receptor mechanisms underlying the behavioral effects of the BZ agonist SL651498 likely reflect its relative efficacy at the various ␣ Rowlett et al (2003). b Calculated from Lelas et al (2002).…”

“…To evaluate the role of ␣ 1 GABA A receptors in this effect, we examined the ability of the ␣ 1 GABA A receptor-preferring antagonist ␤-CCT to block the partial triazolam-like subjective effects of SL651498. ␤-CCT, at doses that antagonized the discriminative stimulus effects of both triazolam and the ␣ 1 GABA A -preferring agonist zolpidem (Lelas et al, 2002;Rowlett et al, 2003), dose-dependently prevented SL651498's partial substitution for triazolam. The apparent pK B value for antagonism of the triazolam-like discriminative stimulus effects of SL651498 was similar to those calculated from previous studies examining ␤-CCT antagonism of zolpidem-and triazolam-like discriminative effects (Lelas et al, 2002;Rowlett et al, 2003).…”

“…␤-CCT, at doses that antagonized the discriminative stimulus effects of both triazolam and the ␣ 1 GABA A -preferring agonist zolpidem (Lelas et al, 2002;Rowlett et al, 2003), dose-dependently prevented SL651498's partial substitution for triazolam. The apparent pK B value for antagonism of the triazolam-like discriminative stimulus effects of SL651498 was similar to those calculated from previous studies examining ␤-CCT antagonism of zolpidem-and triazolam-like discriminative effects (Lelas et al, 2002;Rowlett et al, 2003). This analysis suggests that ␤-CCT blocked the discriminative stimulus effects of SL651498, zolpidem, and triazolam via a similar population of receptors, presumably ␣ 1 GABA A receptors.…”

Contribution of α1GABAAand α5GABAAReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

“…Zolpidem binds preferentially at ␣ 1 GABA A receptors and has little or no affinity at ␣ 5 GABA A receptors (Huang et al, 2000), and zaleplon displays ϳ27-fold selectivity for ␣ 1 GABA A receptors compared with ␣ 5 GABA A receptors (Damgen and Luddens, 1999). In addition, both zolpidem and zaleplon have been shown to exhibit a unique profile of behavioral effects that appear to be mediated principally by stimulation of ␣ 1 GABA A receptors (e.g., Crestani et al, 2000;Noguchi et al, 2002;Rowlett et al, 2003). CL 218,872 exhibits lower efficacy than either zolpidem or zaleplon but demonstrates high selectivity for ␣ 1 GABA A receptors versus ␣ 5 GABA A receptors (ϳ100-fold; Wafford et al, 1993;Atack et al, 1999).…”