Effects of nicotinic cholinergic system manipulations on paired-associate learning (PAL) in mice

Rationale: The ability to perform on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associate learning (PAL) test is predictive of Alzheimer’s disease and Mild Cognitive Impairment. Recently, an automated computer touchscreen PAL task for mice has been developed. Pharmacological validation of this task is warranted to establish it as a useful tool in future drug discovery pertaining to Alzheimer’s disease and Mild Cognitive Impairment. Objectives: This investigation provides a systematic analysis of nicotinic involvement within the PAL task for mice. Particularly, the effects of systemic administration of nicotinic cholinergic agents (agonist and antagonist) on PAL task performance in C57BL/6 mice were investigated. This was done to detect whether bidirectional modification of performance is consequent upon these manipulations. Methods: Upon acquiring the PAL task, nicotine (nicotinic receptor agonist; 0.1, 0.5, and 1.0 mg/kg) and mecamylamine (nicotinic receptor antagonist; 0.3, 1.0, and 3.0 mg/kg) were administered intraperitoneally to the mice in a within-subjects design, prior to daily sessions in the PAL task. Results: Nicotine did not have any significant effect on PAL performance improvement at any doses. However, mecamylamine did increase perseverative responding and reaction time in the mice. Such impairment effects are interpreted as being attentional in nature. Conclusion: This investigation indicates that mice indeed acquire the rodent PAL task, deeming it a valuable tool for future drug discovery. Further, the nicotinic cholinergic system appears to be implicated in PAL task performance, with greater effects seen with deactivation rather than activation of the system, and with these effects appearing to be of an attentional nature. Keywords: paired-associate learning (PAL); Alzheimer’s disease; nicotinic cholingeric system; touchscreen