L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

The in vitro and in vivo properties of L-655,708, a compound with higher affinity for GABAA receptors containing an α5 compared to an α1, α2 or α3 subunit have been examined further. This compound has weak partial inverse agonist efficacy at each of the four subtypes but, and consistent with the binding data, has higher functional affinity for the α5 subtype. In a mouse hippocampal slice model, L-655,708 was able to enhance the long-term potentiation produced by a theta burst stimulation, consistent with a potential role for the α5 subtype in processes involving synaptic plasticity, such as learning and memory. When administered in a formulation specifically designed to achieve relatively constant plasma drug concentrations, and therefore maintain selective occupancy of α5- compared to α1-, α2- and α3-containing receptors (75 ± 4% versus 22 ± 10%, respectively), L-655,708 did not alter the dose of pentylenetetrazole required to induce seizures, indicating that the inverse agonist effects of L-655,708 at the α5 subtype are not associated with a proconvulsant liability. In the Morris water maze, L-655,708 enhanced performance not only during acquisition but also in a probe trial, demonstrating that this compound has cognition enhancing effects. These data further support the potential of α5-containing GABAA receptors as a target for novel cognition enhancing drugs.