Amelioration of ketamine-induced working memory deficits by dopamine D1 receptor agonists

Rationale 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. Objectives 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 µg/kg) and SKF38393 (0.1 µg/kg–100 µg/kg) ameliorated the spatial working memory deficit. This effect of A77636 was blocked by the D1 receptor antagonist, SCH39166 (1 and 10 µg/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.