Pharmacological evidence of a cholinergic contribution to elevated impulsivity and risky decision-making caused by adding win-paired cues to a rat gambling task.

BACKGROUND: Pairing rewards with sensory stimulation, in the form of auditory and visual cues, increases risky decision-making in both rats and humans. Understanding the neurobiological basis of this effect could help explain why electronic gambling machines are so addictive, and inform treatment development for compulsive gambling and gaming. Numerous studies implicate the dopamine system in mediating the motivational influence of reward-paired cues; recent data suggest the cholinergic system also plays a critical role. Previous work also indicates that cholinergic drugs alter decision-making under uncertainty. AIMS: We investigated whether the addition of reward-concurrent cues to the rat gambling task (crGT) altered the effects of peripherally administered cholinergic compounds. METHODS: Muscarinic and nicotinic agonists and antagonists were administered to 16 male, Long-Evans rats trained on the crGT. Measures of optimal/risky decision-making and motor impulsivity were the main dependent variables of interest. RESULTS: The muscarinic receptor antagonist scopolamine improved decision-making overall, decreasing selection of one of the risky options while increasing choice of the more advantageous options. The muscarinic agonist oxotremorine increased choice latency but did not significantly affect option preference. Neither the nicotinic antagonist mecamylamine nor the agonist nicotine affected choice patterns, but mecamylamine decreased premature responding, an index of motor impulsivity. CONCLUSIONS: These results contrast sharply from those obtained previously using the uncued rGT, and suggest that the deleterious effects of win-paired cues on decision-making and impulse control may result from elevated cholinergic tone.

Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity.

Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes; therefore, we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced changes in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.