D_2/3Agonist during Learning Potentiates Cued Risky Choice

Abstract

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. Here we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug’s effect on risk preference.Ex vivocFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.Significance Statement:D2/3receptor agonists, used to treat Parkinson’s disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.

Sexually dimorphic development of the mesolimbic dopamine system is associated with nuanced sensitivity to adolescent alcohol use

“…This pattern contrasts with males where dopamine excitability is elevated during late adolescence and drops in adulthood, but with alcohol use during this time, the elevated excitability is sustained into adulthood and animals exhibit a higher risk attitude during probabilistic (economic) decision making. While these concomitant neurochemical and behavioral findings are correlational, there has been a wealth of reports linking the NAcc (Kuhnen and Knutson, 2005;Zalocusky et al, 2016) and dopamine transmission (Fiorillo et al, 2003;Clark et al, 2012;Hart et al, 2015;Mortazavi et al, 2023) to risk taking, providing well-founded evidence for a causal relationship.…”

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

“…To investigate how our pharmacological manipulations may have influenced the tendency to switch choice strategies following a certain task outcome, we performed trial-by-trial analyses on the Latin square data (Mortazavi et al 2023 ). For each trial, behaviour was classified as either a win-stay or lose-shift depending on the choice category (safe: P1/P2, or risky: P3/P4) and outcome (win or loss) of the previous trial, and whether the animal chose from the same choice category on the following trial.…”

Dopamine activity in the nigrostriatal pathway alters cue‐induced risky choice patterns in female rats

“…On the rGT, these low‐risk, low‐reward options result in less frequent and shorter time‐out penalties, and therefore, more sugar pellets are earned overall. Adding salient audiovisual cues concurrent with reward delivery to this task results in a higher proportion of rats preferring the disadvantageous risky options and renders decision making more sensitive to dopamine manipulations (Barrus & Winstanley, 2016; Mortazavi et al, 2023). The impact of reward‐paired cues on risky choice has also been observed in humans (Cherkasova et al, 2018).…”