The GABAA receptor as a potential target for the treatment of cognitive dysfunction

Drug treatment of Alzheimer's disease and other dementias represents a major unmet medical need, with no preventive or curative therapies available. The currently approved therapies are directed toward symptomatic relief of impaired cognition but have modest utility. In the quest for novel cognition enhancers, the observation that classical benzodiazepines (BZ) are amnesic highlighted the GABA(A) receptor as a potential therapeutic target. In contrast to the amnesic BZ agonists which potentiate GABA(A) receptor function, the BZ inverse agonists, which attenuate GABAA receptor function, have been shown to improve performance in animal models of memory formation. Unfortunately, such nonselective ligands are also anxiogenic and proconvulsant and therefore cannot be used clinically to treat dementia. More recently, novel ligands have been developed that demonstrate functional selectivity for and high inverse agonism at the alpha 5 GABA(A) receptor subtype. These alpha 5-selective inverse agonists enhance learning and memory in animal models but are devoid of the adverse effects associated with other GABA(A) receptor subtypes. In a preliminary clinical study, an alpha 5-selective inverse agonist was reported to prevent alcohol-induced memory deficits in healthy volunteers. If the preclinical efficacy and safety profiles continue to translate into the clinic, these recently developed, functionally selective alpha 5 inverse agonists may present attractive new therapeutic options for dementia.