A multi-dosing regimen to enhance the spatial memory of normal rats with α5-containing GABAA receptor negative allosteric modulator L-655,708.

Rationale and objectives The reported inconsistent effects of negative allosteric modulators of α5-containing GABAA receptors on learning and memory may be attributed to receptor selectivity, effective plasma concentration maintenance, and administration time. This study aimed to compare the effects of L-655,708 administered by single-dosing regimen versus multi-dosing regimen on spatial memory, signaling molecules, and brain functional connectivity. Methods After comparing the maintenance time of the effective plasma concentration of L-655,708 between multi-dosing and single-dosing regimens, we further compared the effects of the administration of the two regimens at different phases (before-learning, during-learning, and before-probe) of the Morris water maze (MWM) test on the performance of learning and memory and the levels of signaling molecules related to learning and memory in hippocampal tissues. Functional connectivity analyses between hippocampal and cortical regions were performed to further clarify the effects of the multi-dosing regimen. Results The multi-dosing regimen could maintain the effective plasma concentration of L-655,708 much longer than the single-dosing regimen. Only the multi-dosing regimen for L-655,708 administration during the learning period led to significant improvement in spatial memory in the MWM test and increases in levels of glutamate receptors and phosphorylated signaling molecules (p-PKAα, p-CaMKII, and p-CREB-1). Compared with the vehicle control, the multi-dosing regimen increased the functional connectivity of the left hippocampal CA1 with cingulate and motor cortices. Conclusions A multi-dosing regimen for L-655,708 administered during the learning period is an effective strategy to improve spatial memory, increase signaling molecule levels, and enhance the functional connectivity of the hippocampus.