Dopaminergic modulation of sensitivity to immediate and delayed punishment during decision-making.

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or "discounting," of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment. We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine's effects on decision-making, suggesting that cocaine's effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences.

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.

Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor.

While the cognitive enhancing effects of nicotine use have been well documented, it has also been shown to impair decision making. The goal of this study was to determine if exposure to nicotine vapor increases risky decision making. The study also aims to investigate possible long-term effects of nicotine vapor exposure on the expression of genes coding for cholinergic and dopaminergic receptors in brain. Thirty-two adult male Sprague Dawley rats were exposed to 24 mg/mL nicotine vapor or vehicle control, immediately followed by testing in the probability discounting task for 10 consecutive days. Fifty-four days after the 10-day vapor exposure, animals were sacrificed and expression of genes coding for the α4 and ß2 cholinergic receptor subunits, and dopamine D1 and D2 receptors, were analyzed using RT-PCR. Exposure to nicotine vapor caused an immediate and transient increase in risky choice. Analyses of gene expression identified significant reductions in CHRNB2 and DRD1 in the nucleus accumbens core and CHRNB2 and DRD2 in the medial prefrontal cortex of rats previously exposed to nicotine vapor, relative to vehicle controls. Results provide data on the negative cognitive effects of nicotine vapor exposure and identify cholinergic and dopaminergic mechanisms that may affected with repeated use.

Sex differences in reward- and punishment-guided actions.

Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

Action-outcome relationships are represented differently by medial prefrontal and orbitofrontal cortex neurons during action execution.

Internal representations of action-outcome relationships are necessary for flexible adaptation of motivated behavior in dynamic environments. Prefrontal cortex (PFC) is implicated in flexible planning and execution of goal-directed actions, but little is known about how information about action-outcome relationships is represented across functionally distinct regions of PFC. Here, we observe distinct patterns of action-evoked single unit activity in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) during a task in which the relationship between outcomes and actions was independently manipulated. The mPFC encoded changes in the number of actions required to earn a reward, but not fluctuations in outcome magnitude. In contrast, OFC neurons decreased firing rates as outcome magnitude was increased, but were insensitive to changes in action requirement. A subset of OFC neurons also tracked outcome availability. Pre-outcome anticipatory activity in both mPFC and OFC was altered when reward expectation was reduced, but did not differ with outcome magnitude. These data provide novel evidence that PFC regions encode distinct information about the relationship between actions and impending outcomes during action execution.

Lateral Orbitofrontal Cortex Encodes Presence of Risk and Subjective Risk Preference During Decision-Making.

Adaptive decision-making requires consideration of objective risks and rewards associated with each option, as well as subjective preference for risky/safe alternatives. Inaccurate risk/reward estimations can engender excessive risk-taking, a central trait in many psychiatric disorders. The lateral orbitofrontal cortex (lOFC) has been linked to many disorders associated with excessively risky behavior and is ideally situated to mediate risky decision-making. Here, we used single-unit electrophysiology to measure neuronal activity from lOFC of freely moving rats performing in a punishment-based risky decision-making task. Subjects chose between a small, safe reward and a large reward associated with either 0% or 50% risk of concurrent punishment. lOFC activity repeatedly encoded current risk in the environment throughout the decision-making sequence, signaling risk before, during, and after a choice. In addition, lOFC encoded reward magnitude, although this information was only evident during action selection. A Random Forest classifier successfully used neural data accurately to predict the risk of punishment in any given trial, and the ability to predict choice via lOFC activity differentiated between and risk-preferring and risk-averse rats. Finally, risk preferring subjects demonstrated reduced lOFC encoding of risk and increased encoding of reward magnitude. These findings suggest lOFC may serve as a central decision-making hub in which external, environmental information converges with internal, subjective information to guide decision-making in the face of punishment risk.

Prefrontal cortical-striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity.

Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.

Effort-related decision making and cannabis use among college students.

Cannabis exerts an indirect effect on dopamine (DA) output in the mesolimbic projection, a circuit implicated in reward processing and effort expenditure, and thus may be associated with aberrant effort-based decision making. The "amotivation syndrome" hypothesis suggests that regular cannabis use results in impaired capacity for goal-directed behavior. However, investigations of this hypothesis have used divergent methodology and have not controlled for key confounding variables. The present study extends these findings by examining the relation between cannabis use and effort-related decision making in a sample of college students. Cannabis using (n = 25; 68% meeting criteria for Cannabis Use Disorder) and noncannabis using (n = 22) students completed the Effort Expenditure for Rewards Task (EEfRT). In generalized estimating equation models, reward magnitude, reward probability, and expected value predicted greater likelihood of selecting a high-effort trial. Furthermore, past-month cannabis days and cannabis use disorder symptoms predicted the likelihood of selecting a high-effort trial, such that greater levels of both cannabis use days and symptoms were associated with an increased likelihood after controlling for Attention Deficit/Hyperactivity Disorder (ADHD) symptoms, distress tolerance, income, and delay discounting. The results provide preliminary evidence suggesting that college students who use cannabis are more likely to expend effort to obtain reward, even after controlling for the magnitude of the reward and the probability of reward receipt. Thus, these results do not support the amotivational syndrome hypothesis. Future research with a larger sample is required to evaluate possible associations between cannabis use and patterns of real-world effortful behavior over time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes-risky decision-making and impulsivity-are amplified in individuals with SUD and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these behavioral patterns is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats-LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrains to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/NHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in the differential reinforcement of low rates of responding task. These phenotypic differences were more pronounced in females than males. We defined a total of ∼9,000 polymorphisms between these substrains at 40× whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of Chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these, 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross should enable identification of one or more variants underlying multiple complex addiction-relevant behaviors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dopaminergic modulation of risky decision-making.

Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a "Risky Decision-making Task" that involves choices between small "safe" rewards and large "risky" rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal cortical-striatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences.