Age moderates the effect of acute dopamine depletion on passive avoidance learning

Despite extensive links between reinforcement-based learning and dopamine (DA), studies to date have not found consistent effects of acute DA reduction on reinforcement learning in both men and women. Here, we tested the effects of reducing DA on reward- and punishment-based learning using the deterministic passive avoidance learning (PAL) task We tested 16 (5 female) adults (ages 22–40) in a randomized, cross-over design to determine whether reducing global DA by administering an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[−]), would affect performance on the PAL task. We found that P/T[−] beverage effects on PAL performance were modulated by age. In particular, we found that P/T depletion significantly improved learning from punishment with increasing participant age. Participants committed 1.49 fewer passive avoidance errors per additional year of age (95% CI, −0.71 – −2.27, r=−0.74, p=0.001). Moreover, in this small sample, P/T depletion improved learning from punishment in adults (ages 26–40) while it impaired learning from punishment in emerging adults (ages 22–25). We observed similar, but non-significant trends in learning from reward. While there was no overall effect of P/T-depletion on reaction time (RT), there was a relationship between the effect of P/T depletion on PAL performance and RT; those who responded more slowly on the P/T[−] beverage also made more errors on the P/T[−] beverage. When P/T-depletion slowed RT after a correct response, there was a worsening of PAL task performance; there was no similar relationship for the RT after an incorrect response and PAL task performance. Moreover, among emerging adults, changes in mood on the P/T[−] beverage negatively correlated with learning from reward on the P/T[−] beverage. Together, we found that both reward- and punishment-based learning are sensitive to central catecholamine levels, and that these effects of acute DA reduction vary with age

Addiction History Associates with the Propensity to Form Habits

Learned habitual responses to environmental stimuli allow efficient interaction with the environment, freeing cognitive resources for more demanding tasks. However, when the outcome of such actions is no longer a desired goal, established stimulus-response (S-R) associations, or habits, must be overcome. Among people with substance use disorders (SUDs), difficulty in overcoming habitual responses to stimuli associated with their addiction in favor of new, goal-directed behaviors, contributes to relapse. Animal models of habit learning demonstrate that chronic self-administration of drugs of abuse promotes habitual responding beyond the domain of compulsive drug seeking. However, whether a similar propensity toward domain-general habitual responding occurs in humans with SUDs has remained unclear. To address this question, we used a visuomotor S-R learning and re-learning task, the Hidden Association Between Images Task (HABIT), which employs abstract visual stimuli and manual responses. This task allows us to measure new S-R association learning, well-learned S-R association execution, and includes a response contingency change manipulation to quantify the degree to which responding is habit-based, rather than goal-directed. We find that people with SUDs learn new S-R associations as well as healthy control subjects do. Moreover, people with an SUD history slightly outperform controls in S-R execution. In contrast, people with SUDs are specifically impaired in overcoming well-learned S-R associations; those with SUDs make a significantly greater proportion of perseverative errors during well-learned S-R replacement, indicating the more habitual nature of their responses. Thus, with equivalent training and practice, people with SUDs appear to show enhanced domain-general habit formation

COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity

Effects of Acute Dopamine Precusor Depletion on Immediate Reward Selection Bias and Working Memory Depend on Catechol- O -methyltransferase Genotype

Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O-methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18–21) as adults. Moreover, many studies have included female subjects without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that among healthy adult males (ages 22–40), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[−]), and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance, but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA’s role in immediate reward bias in humans

Age modulates the effect of COMT genotype on delay discounting behavior

A form of impulsivity, the tendency to choose immediate over delayed rewards (delay-discounting) has been associated with a single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (COMTval158met; rs4680). However, existing data regarding the nature of this association conflicts. We have previously reported that adults homozygous for valine (val) at the COMTval158met SNP demonstrate greater delay-discounting than do methionine (met) allele carriers (Boettiger et al. 2007). In contrast, a recent study of adolescent males found that those with the met/met genotype demonstrate greater delay-discounting than do val-allele carriers (Paloyelis et al. 2010). Based on reported age-related changes in frontal dopamine function and COMT expression, we hypothesized that the association of COMT genotype with delay-discounting behavior is modulated by age from late adolescence to young adulthood

Neural Systems Underlying Individual Differences in Intertemporal Decision-making

Excessively choosing immediate over larger future rewards, or delay discounting (DD), associates with multiple clinical conditions. Individual differences in DD likely depend on variations in the activation of and functional interactions between networks, representing possible endophenotypes for associated disorders, including alcohol use disorders (AUDs). Numerous fMRI studies have probed the neural bases of DD, but investigations of large-scale networks remains scant. We addressed this gap by testing whether activation within large-scale networks during “Now/Later” decision-making predicts individual differences in DD. To do so, we scanned 95 social drinkers (18–40 years; 50 females) using fMRI during hypothetical choices between small monetary amounts available “today” or larger amounts available later. We identified neural networks engaged during Now/Later choice using independent component analysis (ICA) and tested the relationship between component activation and degree of DD. The activity of two components during Now/Later choice correlated with individual DD rates: a temporal lobe network positively correlated with DD, while a frontoparietal-striatal network negatively correlated with DD. Activation differences between these networks predicted individual differences in DD and their negative correlation during Now/Later choice suggests functional competition. A generalized psychophysiological interactions (gPPI) analysis confirmed a decrease in their functional connectivity during decision-making. The functional connectivity of these two networks negatively correlates with alcohol-related harm, potentially implicating these networks in AUDs. These findings provide novel insight into the neural underpinnings of individual differences in impulsive decision making with potential implications for addiction and related disorders in which impulsivity is a defining feature

Impulsivity, frontal lobes and risk for addiction

Alcohol and substance abuse disorders involve continued use of substances despite negative consequences, i.e. loss of behavioral control of drug use. The frontal cortical areas of brain oversee behavioral control through executive functions. Executive functions include abstract thinking, motivation, planning, attention to tasks and inhibition of impulsive responses. Impulsiveness generally refers to premature, unduly risky, poorly conceived actions. Dysfunctional impulsivity includes deficits in attention, lack of reflection and/or insensitivity to consequences, all of which occur in addiction (Evenden, 1999; (de Wit, 2009). Binge drinking models indicate chronic alcohol damages corticolimbic brain regions (Crews et al., 2000) causing reversal learning deficits indicative of loss of executive function (Obernier et al., 2002b). Genetics and adolescent age are risk factors for alcoholism that coincide with sensitivity to alcohol induced neurotoxicity. Cortical degeneration from alcohol abuse may increase impulsivity contributing to the development, persistence and severity of alcohol use disorders. Interestingly, abstinence results in bursts of neurogenesis and brain regrowth (Crews and Nixon, 2009). Treatments for alcoholism, including naltrexone pharmacotherapy and psychotherapy may work through improving executive functions. This review will examine the relationships between impulsivity and executive function behaviors to changes in cortical structure during alcohol dependence and recovery

From learned value to sustained bias: how reward conditioning changes attentional priority

IntroductionAttentional bias to reward-associated stimuli can occur even when it interferes with goal-driven behavior. One theory posits that dopaminergic signaling in the striatum during reward conditioning leads to changes in visual cortical and parietal representations of the stimulus used, and this, in turn, sustains attentional bias even when reward is discontinued. However, only a few studies have examined neural activity during both rewarded and unrewarded task phases.MethodsIn the current study, participants first completed a reward-conditioning phase, during which responses to certain stimuli were associated with monetary reward. These stimuli were then included as non-predictive cues in a spatial cueing task. Participants underwent functional brain imaging during both task phases.ResultsThe results show that striatal activity during the learning phase predicted increased visual cortical and parietal activity and decreased ventro-medial prefrontal cortex activity in response to conditioned stimuli during the test. Striatal activity was also associated with anterior cingulate cortex activation when the reward-conditioned stimulus directed attention away from the target.DiscussionOur findings suggest that striatal activity during reward conditioning predicts the degree to which reward history biases attention through learning-induced changes in visual and parietal activities

Targeting cognitive-affective risk mechanisms in stress-precipitated alcohol dependence: An integrated, biopsychosocial model of automaticity, allostasis, and addiction

This paper proposes a novel hypothetical model integrating formerly discrete theories of stress appraisal, neurobiological allostasis, automatic cognitive processing, and addictive behavior to elucidate how alcohol misuse and dependence are maintained and re-activated by stress. We outline a risk chain in which psychosocial stress initiates physiological arousal, perseverative cognition, and negative affect that, in turn, triggers automatized schema to compel alcohol consumption. This implicit cognitive process then leads to attentional biases toward alcohol, subjective experiences of craving, paradoxical increases in arousal and alcohol-related cognitions due to urge suppression, and palliative coping through drinking. When palliative coping relieves distress, it results in negative reinforcement conditioning that perpetuates the cycle by further sensitizing the system to future stressful encounters. This model has implications for development and implementation of innovative behavioral interventions (such as mindfulness training) that disrupt cognitive-affective mechanisms underpinning stress-precipitated dependence on alcohol

Genetic Polymorphisms Regulating Dopamine Signaling in the Frontal Cortex Interact to Affect Target Detection under High Working Memory Load

Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the DA D1-type receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n=97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits), and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT×DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMTValVal individuals, but impaired target detection in COMTMet carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMTValVal) but impairs target detection in those with putatively higher frontal DA levels (COMTMet carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory