Reversal of Ketamine-Induced Working Memory Impairments by the GABAAα2/3 Agonist TPA023

BackgroundKetamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in γ-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits α2/α3 (GABAAα2/3) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABAAα2/3 agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms.MethodsRhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at ∼5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection.ResultsKetamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms.ConclusionsAcute GABAAα2/3 agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.