Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making.

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation, and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine's potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine's antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.

Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

Chronic high-dose testosterone impairs economic decision making, but has no effect on memory in male rats.

The goal is to understand consequences of anabolic-androgenic steroid (AAS) abuse on cognitive function, using rats as a model. Economic decision making was evaluated in an operant test of effort value discounting, where subjects choose between 2 levers that deliver large and small rewards differing in maximum value and reward contrast. The hypothesis is that chronic high-dose testosterone increases preference for large rewards. Male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle. Initially, all rats preferred the large reward lever when large and small rewards remained fixed at 3 and 1 sugar pellets, respectively. When different reward values were introduced, and with increasing response requirements, testosterone-treated rats made fewer responses for the large reward, and increased omissions. They earned fewer rewards overall. To determine if testosterone impairs memory, rats were tested for recognition memory with the novel object recognition and social transmission of food preference tasks, and for spatial memory with the radial arm maze and Morris water maze. There was not effect of chronic high-dose testosterone on any memory task. These results suggest that testosterone shifts economic decision making towards larger rewards even when they are disadvantageous, but does not alter memory in rats.

Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 µg/µl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Prior cocaine self-administration does not impair the ability to delay gratification in rats during diminishing returns.

Previous exposure to drugs of abuse produces impairments in studies of reversal learning, delay discounting and response inhibition tasks. While these studies contribute to the understanding of normal decision-making and how it is impaired by drugs of abuse, they do not fully capture how decision-making impacts the ability to delay gratification for greater long-term benefit. To address this issue, we used a diminishing returns task to study decision-making in rats that had previously self-administered cocaine. This task was designed to test the ability of the rat to choose to delay gratification in the short-term to obtain more reward over the course of the entire behavioral session. Rats were presented with two choices. One choice had a fixed amount of time delay needed to obtain reward [i.e. fixed delay (FD)], while the other choice had a progressive delay (PD) that started at 0 s and progressively increased by 1 s each time the PD option was selected. During the 'reset' variation of the task, rats could choose the FD option to reset the time delay associated with the PD option. Consistent with previous results, we found that prior cocaine exposure reduced rats' overall preference for the PD option in post-task reversal testing during 'no-reset' sessions, suggesting that cocaine exposure made rats more sensitive to the increasing delay of the PD option. Surprisingly, however, we found that rats that had self-administered cocaine 1-month prior, adapted behavior during 'reset' sessions by delaying gratification to obtain more reward in the long run similar to control rats.

Hydrocortisone reduces altruistic punishment in healthy men.

Psychosocial stress modulates social cognition and behavior in humans. One potentially mediating factor is cortisol as part of the human endocrine stress response. With a double-blind, placebo-controlled between-subject study design, we tested possible dose-dependent effects of hydrocortisone (0 mg, 5 mg and 20 mg) in 85 healthy males. During a socio-economic decision-making task we measured trust, trustworthiness, sharing, punishment, and non-social risk behavior. Social value orientation (SVO) was also assessed. We observed significantly lower levels of punishment after hydrocortisone, especially in the 20 mg group. Drug-induced salivary cortisol correlated negatively with punishment behavior. None of the other facets of social behavior or the SVO were affected by hydrocortisone. Our results suggest that hydrocortisone reduces the propensity to punish unfair behavior. Future studies are needed to further disentangle the role played by various psychobiological mechanisms within the stress response as well as their complex interplay on social behavior and cognition.

Recent Opioid Use Impedes Range Adaptation in Reinforcement Learning in Human Addiction.

BACKGROUND: Drugs like opioids are potent reinforcers thought to co-opt value-based decisions by overshadowing other rewarding outcomes, but how this happens at a neurocomputational level remains elusive. Range adaptation is a canonical process of fine-tuning representations of value based on reward context. Here, we tested whether recent opioid exposure impacts range adaptation in opioid use disorder, potentially explaining why shifting decision making away from drug taking during this vulnerable period is so difficult. METHODS: Participants who had recently (<90 days) used opioids (n = 34) or who had abstained from opioid use for ≥ 90 days (n = 20) and comparison control participants (n = 44) completed a reinforcement learning task designed to induce robust contextual modulation of value. Two models were used to assess the latent process that participants engaged while making their decisions: 1) a Range model that dynamically tracks context and 2) a standard Absolute model that assumes stationary, objective encoding of value. RESULTS: Control participants and ≥90-days-abstinent participants with opioid use disorder exhibited choice patterns consistent with range-adapted valuation. In contrast, participants with recent opioid use were more prone to learn and encode value on an absolute scale. Computational modeling confirmed the behavior of most control participants and ≥90-days-abstinent participants with opioid use disorder (75%), but a minority in the recent use group (38%), was better fit by the Range model than the Absolute model. Furthermore, the degree to which participants relied on range adaptation correlated with duration of continuous abstinence and subjective craving/withdrawal. CONCLUSIONS: Reduced context adaptation to available rewards could explain difficulty deciding about smaller (typically nondrug) rewards in the aftermath of drug exposure.

Influences of social uncertainty and serotonin on gambling decisions.

In many instances in life, our decisions' outcomes hinge on someone else's choices (i.e., under social uncertainty). Behavioral and pharmacological work has previously focused on different types of uncertainty, such as risk and ambiguity, but not so much on risk behaviors under social uncertainty. Here, in two different studies using a double-blind, placebo-controlled, within-subject design, we administrated citalopram (a selective-serotonin-reuptake inhibitor) to male participants and investigated decisions in a gambling task under social and nonsocial uncertainty. In the social condition, gamble outcomes were determined by another participant. In the nonsocial condition, gamble outcomes were determined by a coin toss. We observed increased gamble acceptance under social uncertainty, especially for gambles with lower gains and higher losses, which might be indicative of a positivity bias in social expectations in conditions of high uncertainty about others' behaviors. A similar effect was found for citalopram, which increased overall acceptance behavior for gambles irrespective of the source of uncertainty (social/nonsocial). These results provide insights into the cognitive and neurochemical processes underlying decisions under social uncertainty, with implications for research in risk-taking behaviors in healthy and clinical populations.

Effects of the psychoactive compounds in green tea on risky decision-making.

Epigallocatechin-3-gallate (EGCG) and caffeine are the two primary compounds found in green tea. While EGCG has anxiolytic and anti-inflammatory effects, its acute effects on cognition are not well understood. Furthermore, despite widespread green tea consumption, little is known about how EGCG and caffeine co-administration impacts behavior. Here, we investigated the effects of multiple doses of either EGCG or caffeine on a rat model of risk-taking. This was assessed using the risky decision-making task (RDT), in which rats choose between a small, well-tolerated reward and a large reward with escalating risk of mild footshock. Rats were tested in RDT after acute systemic administration of EGCG, caffeine or joint EGCG and caffeine. EGCG caused a dose-dependent reduction in risk-taking without affecting reward discrimination or task engagement. Caffeine did not impact risk-taking, but elevated locomotor activity and reduced task engagement at high doses. Finally, exposure to both EGCG and caffeine had no effect on risk-taking, suggesting that low-dose caffeine is sufficient to mask the risk-aversion caused by EGCG. These data suggest EGCG as a potential therapeutic treatment for psychological disorders that induce compulsive risky decision-making.

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model.

Activity in numerous brain regions drives heroin seeking, but no circuits that limit heroin seeking have been identified. Furthermore, the neural circuits controlling opioid choice are unknown. In this study, we examined the role of the infralimbic cortex (IL) to nucleus accumbens shell (NAshell) pathway during heroin choice and relapse. This model yielded subpopulations of heroin versus food preferring rats during choice, and choice was unrelated to subsequent relapse rates to heroin versus food cues, suggesting that choice and relapse are distinct behavioral constructs. Supporting this, inactivation of the IL with muscimol produced differential effects on opioid choice versus relapse. A pathway-specific chemogenetic approach revealed, however, that the IL-NAshell pathway acts as a common limiter of opioid choice and relapse. Furthermore, dendritic spines in IL-NAshell neurons encode distinct aspects of heroin versus food reinforcement. Thus, opioid choice and relapse share a common addiction-limiting circuit in the IL-NAshell pathway.

Acute effects of high-potency cannabis flower and cannabis concentrates on everyday life memory and decision making.

Statewide legislation has increased public access to high-potency cannabis flower and concentrates, yet federal restrictions limit researchers' access to relatively low-potency whole-plant cannabis. The goal of this study was to examine the acute effects of high-potency cannabis on cognition using a novel methodology. We further sought to compare cognitive effects of high-potency cannabis flower with and without cannabidiol (CBD), as well as cannabis concentrates to cannabis flower. 80 cannabis users were randomly assigned to stay sober or use their funds to purchase one of three high-potency cannabis products: (1) high-potency flower (≥ 20% THC) without CBD, (2) high-potency flower with CBD, (3) high-potency concentrates (≥ 60% THC) with CBD. Participants were observed over Zoom videoconferencing while inhaling their product or remaining sober and then were administered tests of everyday life memory (prospective, source, temporal order, and false memory) and decision making (risky choice framing, consistency in risk perception, resistance to sunk cost, and over/under confidence) over Zoom. High-potency cannabis flower with CBD impaired free recall, high-potency flower without CBD and concentrates had detrimental effects on source memory, and all three products increased susceptibility to false memories. CBD did not offset impairments and concentrates were self-titrated producing comparable intoxication and impairment as flower.

Blockade of the orexin 1 receptors in the nucleus accumbens' shell reversed the reduction effect of olanzapine on motivation for positive reinforcers.

Effort-based choice of high reward requires one to decide how much effort to expend for a certain amount of reward. Orexin is a crucial neuropeptide in the physiological aspect especially a variety of affective and cognitive processes. The nucleus accumbens (NAc) is a region of the neural system that serves effort-related high reward choices andthe Orexin 1 receptor (OX1R) is distributed extensively throughout the nucleus accumbens shell (AcbS). Olanzapine (OLZ), a typical antipsychotic drug, has a high affinity to D2 as an antagonist, and also partial agonistic-like action at D2 receptors has been reported. We examined the interaction of OLZ with the orexinergic receptor 1 in AcbS on effort- related high reward choice when two goal arms were different in the amount of accessible reward. The animals had to pass the barrier for receiving a high reward in one arm (HRA) or obtain a low reward in the other arm without any cost. Before surgery, all animals were selecting the HRA on almost every trial.During test days, the rats received local injections of either DMSO 20% /0.5 µl, as vehicle or SB334867 (30, 100, 300 nM/0.5 µl), as selective OX1R antagonist, within the AcbS. Other group received OLZ (32 µM/0.5 µl DMSO20%) / vehicle alone or 5 min after administration of SB334867 (300 nM/0.5 µl). The results showed that administration of OLZ in the AcbS alters rat's preference for high reward. On the other hand, blocked of the OX1R (300 nM/0.5 µl) in this region could reverse the effect of OLZ, however, administration of the OX1R antagonists alone in the AcbS led to decreasing rat's preference for high reward. This result indicates that the orexin-1 antagonist might affect some effects of antipsychotic drugs.

Contrasting effects of d-amphetamine and atomoxetine on measures of impulsive action and choice.

Amphetamine (AMP) and atomoxetine (ATX) represent two of the most widely studied drug treatments used in the investigation of impulsive behaviour. While both drugs have relatively well defined effects in tests designed to investigate impulsive action (e.g. 5-choice task; 5-CSRTT), the effects of both drugs in tests of impulsive choice (e.g. delay discounting) are less consistent. In the present study both AMP and ATX were tested in a rodent gambling task (rGT) and delay discounting in rats separately trained to either an ascending or descending delay schedule. Effects of both drugs were compared to measures of impulsive action (premature (PREM) responses) and perseverative (PSV) responses measured in the 5-choice and rGT tasks. Consistent with previous studies, AMP (0.1-1 mg/kg) increased both PREM and PSV responses, and ATX (0.5-2 mg/kg) reduced both measures in the 5-choice and rGT tasks. At equivalent doses ATX had no reliable effect on choice behaviour in either the rGT or delay discounting suggesting a null effect of this drug on impulsive choice and risky decision making. The effects of AMP were more complex, with a subtle shift in preference to a low risk (P1) choice in the rGT, and an effect on discounting that was unrelated to reinforcer value, but instead dependent on delay sequence and baseline choice preference. One aspect to these outcomes is to highlight the importance of multiple methodological factors when assessing drug effects on complex behaviours such as impulsive choice, and question what are the most appropriate test conditions under which to examine these drugs on discounting.

Impact of EPclin on adjuvant therapeutic decision making and comparison of EPclin to the PREDICT tool.

PURPOSE: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. METHODS: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT's tool scores. RESULTS: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians' decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). CONCLUSION: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

The role of oxytocin in delay of gratification and flexibility in non-social decision making.

Oxytocin is well-known for its impact on social cognition. This specificity for the social domain, however, has been challenged by findings suggesting a domain-general allostatic function for oxytocin by promoting future-oriented and flexible behavior. In this pre-registered study, we tested the hypothesized domain-general function of oxytocin by assessing the impact of intranasal oxytocin (24 IU) on core aspects of human social (inequity aversion) and non-social decision making (delay of gratification and cognitive flexibility) in 49 healthy volunteers (within-subject design). In intertemporal choice, patience was higher under oxytocin than under placebo, although this difference was evident only when restricting the analysis to the first experimental session (between-group comparison) due to carry-over effects. Further, oxytocin increased cognitive flexibility in reversal learning as well as generosity under conditions of advantageous but not disadvantageous inequity. Our findings show that oxytocin affects both social and non-social decision making, supporting theoretical accounts of domain-general functions of oxytocin.

Quantifying value-based determinants of drug and non-drug decision dynamics.

RATIONALE: A growing body of research suggests that substance use disorder (SUD) may be characterized as disorders of decision making. However, drug choice studies assessing drug-associated decision making often lack more complex and dynamic conditions that better approximate contexts outside the laboratory and may lead to incomplete conclusions regarding the nature of drug-associated value. OBJECTIVES: The current study assessed isomorphic (choice between identical food options) and allomorphic (choice between remifentanil [REMI] and food) choice across dynamically changing reward probabilities, magnitudes, and differentially reward-predictive stimuli in male rats to better understand determinants of drug value. Choice data were analyzed at aggregate and choice-by-choice levels using quantitative matching and reinforcement learning (RL) models, respectively. RESULTS: Reductions in reward probability or magnitude independently reduced preferences for food and REMI commodities. Inclusion of reward-predictive cues significantly increased preference for food and REMI rewards. Model comparisons revealed that reward-predictive stimuli significantly altered the economic substitutability of food and REMI rewards at both levels of analysis. Furthermore, model comparisons supported the reformulation of reward value updating in RL models from independent terms to a shared, relative term, more akin to matching models. CONCLUSIONS: The results indicate that value-based quantitative choice models can accurately capture choice determinants within complex decision-making contexts and corroborate drug choice as a multidimensional valuation process. Collectively, the present study indicates commonalities in decision-making for drug and non-drug rewards, validates the use of economic-based SUD therapies (e.g., contingency management), and implicates the neurobehavioral processes underlying drug-associated decision-making as a potential avenue for future SUD treatment.

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. OBJECTIVE: We wished to investigate the role of NA in our rodent assay of decision making and impulsivity, the cued rat gambling task (crGT). Given that sex differences are prominent in addiction disorders, and increasingly reported in the monoaminergic regulation of behaviour, we also prioritised evaluating noradrenergic drugs in both sexes. METHODS: Female and male rats were trained to stability on the crGT and then given intraperitoneal injections of the noradrenaline reuptake inhibitor atomoxetine, the α2A receptor agonist guanfacine, the beta receptor antagonist propranolol, and the α2 receptor antagonist yohimbine. RESULTS: Atomoxetine dose-dependently improved decision-making score. Guanfacine selectively enhanced decision making in risk-preferring males and optimal performing females. Propranolol and yohimbine did not influence decision making. Atomoxetine and guanfacine reduced premature responses, while yohimbine bi-phasically affected this index of motor impulsivity. CONCLUSIONS: These results support the hypothesis that NA is an important neuromodulator of the cue-induced deficits in decision making observed in laboratory-based gambling paradigms, and suggest that NAergic drugs like atomoxetine and guanfacine may be useful in treating GD.

Selective effects of serotonin on choices to gather more information.

BACKGROUND: Gathering and evaluating information leads to better decisions, but often at cost. The balance between information seeking and exploitation features in neurodevelopmental, mood, psychotic and substance-related disorders. Serotonin's role has been highlighted by experimental reduction of its precursor, tryptophan. AIMS: We tested the boundaries and applicability of this role by asking whether changes to information sampling would be observed following acute doses of serotonergic and catecholaminergic clinical treatments. We used a variant of the Information Sampling Task (IST) to measure how much information a person requires before they make a decision. This task allows participants to sample information until satisfied to make a choice. METHODS: In separate double-blind placebo-controlled experiments, we tested 27 healthy participants on/off 20 mg of the serotonin reuptake inhibitor (SRI) citalopram, and 22 participants on/off 40 mg of the noradrenergic reuptake inhibitor atomoxetine. The IST variant minimised effects of temporal impulsivity and loss aversion. Analyses used a variety of participant prior expectations of sampling spaces in the IST, including a new prior that accounts for learning of likely states across trials. We analysed behaviour by a new method that also accounts for baseline individual differences of risk preference. RESULTS: Baseline preferences demonstrated risk aversion. Citalopram decreased the expected utility of choices and probability of being correct based on informational content of samples collected, suggesting participants collected less useful information before making a choice. Atomoxetine did not influence information seeking. CONCLUSION: Acute changes of serotonin activity by way of a single SRI dose alter information-seeking behaviour.

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.