Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys

Rationale: Due to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing). Objectives: The purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition. Methods: Oral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task. Results: In dose-effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized "optimal doses" were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated. Conclusions: While the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer's disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia).