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 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.
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 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.
Authors: David A Lewis; Raymond Y Cho; Cameron S Carter; Kevin Eklund; Sarah Forster; Mary Ann Kelly; Debra Montrose Journal: Am J Psychiatry Date: 2008-10-15 Impact factor: 18.112
Authors: Michael R Weed; Mark Bookbinder; Joseph Polino; Deborah Keavy; Rudolf N Cardinal; Jean Simmermacher-Mayer; Fu-ni L Cometa; Dalton King; Srinivasan Thangathirupathy; John E Macor; Linda J Bristow Journal: Neuropsychopharmacology Date: 2015-06-24 Impact factor: 7.853
Authors: S A Castner; N V Murthy; K Ridler; H Herdon; B M Roberts; D P Weinzimmer; Y Huang; M Q Zheng; E A Rabiner; R N Gunn; R E Carson; G V Williams; M Laruelle Journal: Neuropsychopharmacology Date: 2014-02-03 Impact factor: 7.853
Authors: Rouba Kozak; Tamás Kiss; Keith Dlugolenski; David E Johnson; Roxanne R Gorczyca; Kyle Kuszpit; Brian D Harvey; Polina Stolyar; Stacey J Sukoff Rizzo; William E Hoffmann; Dmitri Volfson; Mihaly Hajós; Jennifer E Davoren; Amanda L Abbott; Graham V Williams; Stacy A Castner; David L Gray Journal: Front Pharmacol Date: 2020-07-07 Impact factor: 5.810
Authors: Jodi E Gresack; Patricia A Seymour; Christopher J Schmidt; Victoria B Risbrough Journal: Psychopharmacology (Berl) Date: 2013-12-21 Impact factor: 4.530
Authors: Rouba Kozak; Brian M Campbell; Christine A Strick; Weldon Horner; William E Hoffmann; Tamas Kiss; Douglas S Chapin; Dina McGinnis; Amanda L Abbott; Brooke M Roberts; Kari Fonseca; Victor Guanowsky; Damon A Young; Patricia A Seymour; Amy Dounay; Mihaly Hajos; Graham V Williams; Stacy A Castner Journal: J Neurosci Date: 2014-08-06 Impact factor: 6.167