Allosteric modulation of GAB _AA receptor subtypes: Effects on visual recognition and visuospatial working memory in rhesus monkeys

Non-selective positive allosteric modulators (PAMs) of GABA_A receptors (GABA_ARs) are known to impair anterograde memory. The role of the various GABA_AR subtypes in the memory-impairing effects of non-selective GABA_AR PAMs has not been fully elucidated. The current study assessed, in rhesus monkeys, effects of modulation of alpha;1, alpha;2/3, and alpha;5GABA_ARs on visual recognition and spatial working memory using delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) procedures, respectively. The DMTS procedure (n=8) involved selecting a previously presented 'sample' image from a set of multiple images presented after a delay. The SOSS procedure (n=6) involved touching a number of boxes without repeats. The non-selective GABA_AR PAM triazolam and the α1GAB_AA preferential PAMS zolpidem and zaleplon reduced accuracy in both procedures, whereas the α5GAB_AA preferential PAMs SH-053-20F-R-CH₃ and SH-053-20F-S-CH₃, and the α2/3GAB_AA preferential PAM TPA023B were without effects on accuracy or trial completion. The low-efficacy α5GABA_AR negative allosteric modulator (NAM) PWZ-029 slightly increased only DMTS accuracy, whereas the high-efficacy α5GABA_AR NAMs RY-23 and RY-24 did not affect accuracy under either procedure. Finally, the slopes of the accuracy dose-effect curves for triazolam, zolpidem, and zaleplon increased with box number in the SOSS procedure, but were equivalent across DMTS delays. The present results suggest that (1) a1GABAARs, compared with α2/3 and α5GABA_ARs, are primarily involved in the impairment, by non-selective GABA_AR PAMs, of visual recognition and visuospatial working memory in nonhuman primates; and (2) relative cognitive impairment produced by positive modulation of GABA_ARs increases with number of locations to be remembered, but not with the delay for remembering.