High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high-fat or high-sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats' performance in the five-choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high-fat diet (HFD) were more impulsive, whereas the high-sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2 R), cAMP response element-binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2 R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high-fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions - findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge-eating disorder.

These findings demonstrate that the 5-HT receptor-mediated regulation of risky decision making and motor impulsivity can be pharmacologically dissociated and further show that the presence of highly salient reward-paired cues critically alters the neurochemical regulation of the choice process. Importantly, these results suggest that 5-HT receptor antagonists may be of use in disrupting maladaptive patterns of decision making.

Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity and motivation. Moderately-and severely-injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks post-injury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment ("TBI-resilient"), some demonstrated initial deficits that recovered ("TBI-vulnerable") and some never recovered ("chronically-impaired"). Three clinically-relevant treatments for impulsecontrol or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically-impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing.Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury.

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. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine. Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associatedwithgreaterriskofrelapseandtreatmentfailureinsubstanceusedisorder.Understandingfactorsthatenhancepreferencefor risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

D 2/3 receptor agonists are effective treatments for Parkinson's disease (PD), but can precipitate impulse control disorders (ICDs) including gambling disorder (GD). The neurobiological mechanisms underlying this devastating side-effect of dopamine agonist replacement therapy (DRT), and any dependence on the dopamine depletion caused by PD, are unclear. It is also unclear whether previous biases towards risk or uncertainty are a risk factor for developing these ICDs. We investigated whether chronic D 2/3 agonist administration (5 mg/kg/day ropinirole for 28 days) altered performance of a rat model of gambling-like behaviour, the rodent betting task (rBT), and examined if baseline behaviour predicted this behavioural change. The rBT captures individual differences in subjective preference for uncertain outcomes: animals choose between guaranteed or probabilistic reinforcement of equal expected value. Chronic ropinirole dramatically increased selection of the uncertain option in two-thirds of animals, regardless of baseline preferences. The effect on choice in the rBT was replicated in a dorsolateral striatal 6-hydroxydopamine (6-OHDA) rat model of early PD. These studies are the first to look at individual differences in response to chronic, rather than pulsatile, dosing of DRT in a rodent model of gambling behaviour. These findings suggest that DRT-induced PG may stem from increases in subjective valuation of uncertainty. Such symptoms likely arise because of changes in dopaminergic striatal signalling caused by DRT rather than from an interaction between pre-morbid behaviours or PD itself.