Reversal of ketamine-induced working memory impairments by the GABAAalpha2/3 agonist TPA023.
BACKGROUND
Ketamine 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 gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) 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 GABA(Aalpha2/3) 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.


METHODS
Rhesus 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 approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection.


RESULTS
Ketamine 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.


CONCLUSIONS
Acute GABA(Aalpha2/3) 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.
Castner
Stacy A
SA
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Arriza
Jeffrey L
JL
Roberts
John C
JC
Mrzljak
Ladislav
L
Christian
Edward P
EP
Williams
Graham V
GV
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058785:GABA-A Receptor Agonists; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008253:Macaca mulatta; D008569:Memory Disorders / Q000139:chemically induced*; D008570:Memory, Short-Term / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D058785:GABA-A Receptor Agonists; D011724:Pyridazines; D014230:Triazoles; D007649:Ketamine