An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze

Rationale: Compounds selective for the GABA(A) receptors containing an alpha 5 subunit have been reported to enhance performance in the hippocampally mediated delayed-matching-to-position version of the Morris water maze, in which reduction in the time required to find a hidden platform relative to an initial trial is used as an index of learning and memory. Objective: In the present study, we have used one such compound, alpha 5IA-II, to examine whether these effects occur during the encoding, consolidation or recall phases of this paradigm. Methods: alpha 5IA-II was administered in the absence or presence of the benzodiazepine site antagonist flumazenil, so as to limit its action to periods associated with encoding, consolidation and recall. Drug doses and timings of administrations were defined using occupancy data derived from an in vivo [H-3]flumazenil binding assay. Similar experiments were carried out to study the memory-disruptive properties of chlordiazepoxide (CDP). Results: The trial 1 to trial 2 difference was increased when alpha 5IA-II was given before either trial 1 or trial 2, indicating an effect on the encoding and recall phases, respectively, of learning and memory. Conversely, alpha 5IA-II had no effect on performance when given immediately after trial 1, suggesting that it had no effect on the consolidation phase. In contrast to the facilitation of performance produced by the alpha 5-selective inverse agonist alpha 5IA-II given during the encoding and recall but not the consolidation phase, the non-selective agonist CDP impaired performance when given during the encoding and recall phases, whilst having no effect on the consolidation phase. Conclusions: These data further highlight the cognition-enhancing properties of GABA(A) alpha 5-selective inverse agonists and define the functional specificity of these effects in terms of encoding and recall processes in the Morris water maze.