Effects of Intraseptal Zolpidem and Chlordiazepoxide on Spatial Working Memory and High-Affinity Choline Uptake in the Hippocampus

Abstract

Injection of GABAA/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABAA receptor are differentially localized to either GABAergic (α1/β2/γ2) or cholinergic (α3/β3/γ2) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague–Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 μg), or zolpidem (4, 8, or 12 μg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 μg). However, intraseptal injection of 8 μg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway.