Amelioration of ketamine-induced working memory deficits by dopamine D1 receptor agonists.
BACKGROUND
Ketamine has been used in humans to model cardinal symptoms of schizophrenia, including working memory impairments and behavioral disorganization. Translational studies with ketamine in nonhuman primates promise to extend the neurobiological understanding of this model.


OBJECTIVE
By establishing the dose-dependent effects of ketamine on spatial working memory and behavior, we sought to test and compare the capacity of antipsychotic and procognitive agents to reverse these symptoms.


METHODS
Behavioral observations were taken following administration of placebo/ketamine (0.1-1.7 mg/kg, intramuscularly) and animals were tested on the spatial delayed response task 15 min post-injection. Pretreatments with risperidone as well as full and partial D1 receptor agonists were tested for their ability to reverse ketamine-induced impairments.


RESULTS
Ketamine (median 1.0 mg/kg) produced a profound cognitive impairment and behavioral sequelae reminiscent of positive and negative symptoms. Risperidone within the therapeutic dose range failed to antagonize behavioral or cognitive consequences of acute ketamine but A77636 (0.1 and 1 microg/kg) and SKF38393 (0.1 microg/kg-100 microg/kg) ameliorated the spatial working memory deficit. This effect of A77636 was blocked by the D1 receptor antagonist, SCH39166 (1 and 10 microg/kg).


CONCLUSIONS
These findings establish a valuable ketamine platform relevant to the treatment of cognitive dysfunction in schizophrenia. The reversal of ketamine-induced working memory deficits by a D1 receptor agonist, but not a commonly prescribed atypical antipsychotic, provides behavioral evidence for significant D1/N-methyl-D: -aspartate receptor interactions in prefrontal dysfunction and concurs with suggestions that D1 agonists may be useful in the treatment of cognitive impairments in schizophrenia.
Roberts
Brooke M
BM
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
Seymour
Patricia A
PA
Schmidt
Christopher J
CJ
Williams
Graham V
GV
Castner
Stacy A
SA
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy; D018491:Dopamine Agonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000633:toxicity*; D008253:Macaca mulatta; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy
D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D007649:Ketamine
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