Muscarinic receptor contributions to cost/benefit decision-making on the rat gambling task

The cholinergic system, encompassing the muscarinic and nicotinic receptor systems, plays a modulatory role in a variety of executive processes. However, its role in decision making is still unclear. Disorders characterized by disturbed muscarinic receptor functioning, such as schizophrenia, exhibit impaired performance on measures of real-world cost/benefit decision making, but whether this contributes to the choice deficits observed in the disorders is currently unknown. To address muscarinic receptor contributions to such processes, we investigated the effects of the broad-acting muscarinic receptor agonist oxotremorine (0.01, 0.03. 0.1 mg.kg) and antagonist scopolamine (0.01, 0.03, 0.1 mg.kg) on rodent Gambling Task (rGT) performance. Like the clinically administered Iowa Gambling Task (IGT), rodents must evaluate the costs and benefits of four nosepoke options that are each associated with the delivery of a different amount of reward, as well as different probabilities of receiving reward or a punishment time-out in which no reward can be earned. Rats quickly learn to select the advantageous options characterized by smaller rewards with lower penalties, and to avoid the large, high penalty reward options. Although systemic administration of oxotremorine had no effect, the highest dose of scopolamine impaired optimal performance by increasing choice of the option associated with the smallest reward and the lowest risk. This shift in choice is similar to that previously observed following administration of amphetamine, and suggests the drugs induce a hypersensitivity to loss. Given the functional connectivity of muscarinic and dopaminergic systems in the brain, and the antipsychotic-like profile of muscarinic agonists in amphetamine-induced animal models of schizophrenia, we then attempted to attenuate amphetamine’s choice impairments by prior administration of oxotremorine. Amphetamine (1.0 mg.kg) produced its characteristic choice impairments, despite pretreatment with oxotremorine. The results of this study suggest muscarinic receptor blockade can impair cost/benefit decision-making under conditions of risk and uncertainty, and prescribe a novel role to acetylcholine as a modulator of the decision process. Future work is required to pinpoint the mechanism driving amphetamine’s effect on the rGT, as cholinergic signaling through muscarinic receptors does not appear to be involved.Arts, Faculty ofPsychology, Department ofGraduat