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

Abstract

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: 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).

Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys

“…[23]. The task is sensitive to cholinergic modulation as indicated by its enhancement by cholinesterase inhibitors [24,25], as well as cholinergic receptor agonists [26,27], and it is sensitive to impairments of performance by cholinergic antagonists [15,28]. Intermittent stimulation of the Nucleus Basalis led to short term improvement in the task, while continuous stimulation suppressed performance.…”

“…All behavioral software was based on prior work [26], and available from PBTLI Prime Behavior Testing Laboratories, Inc, http://www.pbtli.com/, Augusta, GA. The behavioral task, shown in Figure 1, initiated with a colored square cue in the center-top part of the touchscreen.…”

Chronic Nicotine Exposure Initiated in Adolescence and Unpaired to Behavioral Context Fails to Enhance Sweetened Ethanol Seeking

“…For example, when administered in adolescence, repeated nicotine increases β2 subunit-containing nicotinic receptors (Counotte et al, 2012a ). In turn, compounds that selectively target β2 subunit-containing receptors can enhance behavioral flexibility in humans and primates withdrawn from drugs of abuse (Gould et al, 2013 ; Terry et al, 2016 ; Lesage et al, 2017 ). Therefore, the administration of nicotine outside of the behavioral context may have enhanced behavioral flexibility and, therefore, rendered animals in our study resistant to habit-directed behavior.…”

Double Dissociation of Nicotinic α7 and α4/β2 Sub-receptor Agonists for Enhancing Learning and Attentional Filtering of Distraction

“…We conjectured that such a combined learning and attention paradigm is needed to clarify open questions about subreceptor specific functions. In particular, an exhaustive literature survey of attention effects of fourteen studies applying systemically α7 agonists (Table S1) (Briggs CA et al 1997;Hahn B et al 2003;Buccafusco JJ et al 2007;Buccafusco JJ and AV Terry, Jr. 2009;Rezvani AH et al 2009; Wallace TL, PM Callahan, et al 2011;McLean SL et al 2012;Gould RW et al 2013;Yang Y et al 2013;Young JW et al 2013;Jones KM et al 2014;Kolisnyk B et al 2015;Wood C et al Nicotinic sub-receptor specific modulation of learning and attention 2016;Wadenberg MG et al 2017), and thirteen studies using α4β2 agonists (Table S2) (Buccafusco JJ et al 1995;Decker MW et al 1997;Schneider JS et al 1999;Schneider JS et al 2003;Decamp E and JS Schneider 2006;Buccafusco JJ et al 2007;Howe WM et al 2010;Gould RW et al 2013;Paolone G et al 2013;Kolisnyk B et al 2015;Terry AV, Jr. et al 2016;Wood C et al 2016) failed to reveal sub-receptor specific contributions to working memory and distractor filtering functions in the NHP animal model.…”