Convergent observations of MK-801-induced impairment in rat 5C-CPT performance across laboratories: reversal with a D but not nicotinic agonist.

Introduction: Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT). The 5-choice (5C)-CPT was developed as a translational cross-species version of this task. Given the association between glutamatergic abnormalities and cognitive dysfunction in schizophrenia, we hypothesized that the NMDA receptor antagonist MK-801 would impair 5C-CPT in rats across different laboratories, and determined whether the dopamine D receptor agonist SKF38393 or the nonspecific nicotinic agonist nicotine would remediate such deficits.

Method: Rats were trained in the 5C-CPT at Beacon Discovery and UCSD. These rats were then treated with MK-801, agonist treatment, and combinations of the two.

Results: MK-801 produced 5C-CPT deficits in the same domains of rats across sites at similar doses. Neither nicotine nor SKF38393 treatment alone improved performance. Importantly, SKF38393, but not nicotine, remediated the MK-801-induced deficits.

Conclusion: Convergent observation of MK-801-induced deficits in 5C-CPT was seen across laboratories, resulting in deficits consistent with those seen in people with schizophrenia. Treatment with SKF38393 but not nicotine reversed these deficits. More work is needed, but the 5C-CPT is a reliable method for detecting NMDA receptor disruption-induced deficits in attention.