Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions.

Rationale: Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding.

Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex.

Background: Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation.

D Agonist during Learning Potentiates Cued Risky Choice.

Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior.

Noradrenergic contributions to cue-driven risk-taking and impulsivity.

Rationale: The flashing lights and sounds of modern casinos are alluring and may contribute to the addictive nature of gambling. Such cues can have a profound impact on the noradrenaline (NA) system, which could therefore be a viable therapeutic target for gambling disorder (GD). While there is substantial evidence to support the involvement of NA in the impulsive symptoms of GD, its function in mediating the "pro-addictive" impact of cues is less understood.

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.

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.

GPR52 agonists attenuate ropinirole-induced preference for uncertain outcomes.

Dopamine D receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful.

Chemogenetic inhibition of dopaminergic projections to the nucleus accumbens has sexually dimorphic effects in the rat gambling task.

Women and men can differ in their propensity to take risks and develop impulse control and addiction disorders. Sexual dimorphisms in behavioral control by the mesolimbic dopaminergic reward system may underlie these phenomena, given its sensitivity to gonadal hormones. However, this is hard to test experimentally using humans.

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction.

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected.

Early life adversity potentiates expression of addiction-related traits.

Many individuals sporadically and circumstantially sample addictive drugs, yet few become addicted. The individual vulnerabilities underlying the development of addiction are not well understood. Correlational findings show that early life adversity is associated with a greater propensity to develop drug addiction.