Striatal dopamine integrates cost, benefit, and motivation.

Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels.

An association between prediction errors and risk-seeking: Theory and behavioral evidence.

Reward prediction errors (RPEs) and risk preferences have two things in common: both can shape decision making behavior, and both are commonly associated with dopamine. RPEs drive value learning and are thought to be represented in the phasic release of striatal dopamine. Risk preferences bias choices towards or away from uncertainty; they can be manipulated with drugs that target the dopaminergic system. Based on the common neural substrate, we hypothesize that RPEs and risk preferences are linked on the level of behavior as well. Here, we develop this hypothesis theoretically and test it empirically. First, we apply a recent theory of learning in the basal ganglia to predict how RPEs influence risk preferences. We find that positive RPEs should cause increased risk-seeking, while negative RPEs should cause risk-aversion. We then test our behavioral predictions using a novel bandit task in which value and risk vary independently across options. Critically, conditions are included where options vary in risk but are matched for value. We find that our prediction was correct: participants become more risk-seeking if choices are preceded by positive RPEs, and more risk-averse if choices are preceded by negative RPEs. These findings cannot be explained by other known effects, such as nonlinear utility curves or dynamic learning rates.

The Striatum's Role in Executing Rational and Irrational Economic Behaviors.

The striatum is a critical component of the brain that controls motor, reward, and executive function. This ancient and phylogenetically conserved structure forms a central hub where rapid instinctive, reflexive movements and behaviors in response to sensory stimulation or the retrieval of emotional memory intersect with slower planned motor movements and rational behaviors. This review emphasizes two distinct pathways that begin in the thalamus and converge in the striatum to differentially affect movements, behaviors, and decision making. The convergence of excitatory glutamatergic activity from the thalamus and cortex, along with dopamine release in response to novel stimulation, provide the basis for motor learning, reward seeking, and habit formation. We outline how the rules derived through research on neural pathways may enhance the predictability of reflexive actions and rational responses studied in behavioral economics.

The power of price compels you: Behavioral economic insights into dopamine-based valuation of rewarding and aversively motivated behavior.

The mesocorticolimbic dopamine pathway is generally considered to be a reward pathway. While shortsighted, there is a strong basis for this view of dopamine function. Here, we first describe the role of phasic dopamine release events in reward seeking. We then explain why these release events are being reconsidered as value signals and how we applied behavioral economics to confirm they play a causal role in the valuation of reward. Just because dopamine release can function as a dopamine reward value signal however, does not imply that dopamine is solely a reward molecule. Rather, mesocorticolimbic dopamine appears to mediate many adaptive behaviors, including: reward seeking, avoidance, escape and fear-associated conditioned freezing. While more studies are needed before a consensus is reached on when, where and how dopamine mediates aversively-motivated behavior, its involvement is almost irrefutable. Thus, we next describe the role dopamine plays in these ethologically-relevant defensive behaviors. We conclude by describing our recent behavioral economics results that reveal a causal role for dopamine in the valuation of avoidance.

The costs and benefits of brain dopamine for cognitive control.

Cognitive control helps us attain our goals by resisting distraction and temptations. Dopaminergic drugs are well known to enhance cognitive control. However, there is great variability in the effects of dopaminergic drugs across different contexts, with beneficial effects on some tasks but detrimental effects on other tasks. The mechanisms underlying this variability across cognitive task demands remain unclear. I aim to elucidate this across-task variability in dopaminergic drug efficacy by going beyond classic models that emphasize the importance of dopamine in the prefrontal cortex for cognitive control and working memory. To this end, I build on recent advances in cognitive neuroscience that highlight a role for dopamine in cost-benefit decision making. Specifically, I reconceptualize cognitive control as involving not just prefrontal dopamine but also modulation of cost-benefit decision making by striatal dopamine. This approach will help us understand why we sometimes fail to (choose to) exert cognitive control while also identifying mechanistic factors that predict dopaminergic drug effects on cognitive control. WIREs Cogn Sci 2016, 7:317-329. doi: 10.1002/wcs.1401 For further resources related to this article, please visit the WIREs website.

Mesolimbic Dopamine and the Regulation of Motivated Behavior.

It has been known for some time that nucleus accumbens dopamine (DA) is involved in aspects of motivation , but theoretical approaches to understanding the functions of DA have continued to evolve based upon emerging data and novel concepts. Although it has become traditional to label DA neurons as "reward" neurons, the actual findings are more complicated than that, because they indicate that DA neurons can respond to a variety of motivationally significant stimuli. Moreover, it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. Studies that involve nucleus accumbens DA antagonism or depletion indicate that accumbens DA does not mediate primary food motivation or appetite. Nevertheless, DA is involved in appetitive and aversive motivational processes including behavioral activation , exertion of effort, sustained task engagement, and Pavlovian-to-instrumental transfer. Interference with accumbens DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task and also shifts effort-related choice behavior, biasing animals toward low-effort alternatives. Dysfunctions of mesolimbic DA may contribute to motivational symptoms seen in various psychopathologies, including depression , schizophrenia, parkinsonism, and other disorders.

Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats.

RATIONALE: Previous research suggests both genetic and environmental influences on substance abuse vulnerability. OBJECTIVES: The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. METHODS: Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). RESULTS: "Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats. CONCLUSIONS: The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene × environment effects in amphetamine self-administration.

Pharmacological assessment of methamphetamine-induced behavioral hyperactivity mediated by dopaminergic transmission in planarian Dugesia japonica.

The freshwater planarian Dugesia japonica has a simple central nervous system (CNS) and can regenerate complete organs, even a functional brain. Recent studies demonstrated that there is a great variety of neuronal-related genes, specifically expressed in several domains of the planarian brain. We identified a planarian dat gene, named it D. japonica dopamine transporter (Djdat), and analyzed its expression and function. Both in situ hybridization and immunofluorescence revealed that localization of Djdat mRNA and protein was the same as that of D. japonica tyrosine hydroxylase (DjTH). Although, dopamine (DA) content in Djdat(RNAi) planarians was not altered, Djdat(RNAi) planarians showed increased spontaneous locomotion. The hyperactivity in the Djdat(RNAi) planarians was significantly suppressed by SCH23390 or sulpiride pretreatment, which are D1 or D2 receptor antagonists, respectively. These results suggest that planarians have a Djdat ortholog and the ability to regulate dopaminergic neurotransmission and association with spontaneous locomotion.

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 DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA 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 COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) 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.

Navigating complex decision spaces: Problems and paradigms in sequential choice.

To behave adaptively, we must learn from the consequences of our actions. Doing so is difficult when the consequences of an action follow a delay. This introduces the problem of temporal credit assignment. When feedback follows a sequence of decisions, how should the individual assign credit to the intermediate actions that comprise the sequence? Research in reinforcement learning provides 2 general solutions to this problem: model-free reinforcement learning and model-based reinforcement learning. In this review, we examine connections between stimulus-response and cognitive learning theories, habitual and goal-directed control, and model-free and model-based reinforcement learning. We then consider a range of problems related to temporal credit assignment. These include second-order conditioning and secondary reinforcers, latent learning and detour behavior, partially observable Markov decision processes, actions with distributed outcomes, and hierarchical learning. We ask whether humans and animals, when faced with these problems, behave in a manner consistent with reinforcement learning techniques. Throughout, we seek to identify neural substrates of model-free and model-based reinforcement learning. The former class of techniques is understood in terms of the neurotransmitter dopamine and its effects in the basal ganglia. The latter is understood in terms of a distributed network of regions including the prefrontal cortex, medial temporal lobes, cerebellum, and basal ganglia. Not only do reinforcement learning techniques have a natural interpretation in terms of human and animal behavior but they also provide a useful framework for understanding neural reward valuation and action selection.

Valoración de los efectos fisiológicos y neuroquímicos de altas concentraciones de tetrahidrocannabinol en modelos biológicos / Assessment physiological and neurochemical effects of high concentrations of tetrahydrocannabinol in biological models

El objetivo de esta investigación fue evaluar los efectos fisiológicos y neuroquímicos en 60 ratones machos cepas Naval Medical Research Institute (NMRI) en edad adulto-joven con pesos promedios de 25,45 ± 3,05 g, sometidos durante seis semanas a dosis del principio psicoactivo de la marihuana el Δ-9-tetrahidrocannabinol en concentraciones entre 4 - 20%. Se realizaron tomas de sangre retroorbital para evaluar parámetros hematológicos y bioquímicos antes, durante y post experiencia. Se monitorearon medidas tales como: peso, ingesta de agua, alimentos, actividad locomotora horizontal y vertical, entre otros. Al final de la experiencia se realizo autopsia y toma de muestras de regiones cerebrales, para medir niveles de neurotransmisores aminoacidicos y dopamina. Estos resultados permiten concluir que altas concentraciones del principio psicoactivo de la marihuana hacen más dependiente al consumidor con los consecuentes daños fisiológicos y neurológicos. Esto lleva a que cada vez se necesite más droga para producir el mismo efecto.

The objective of this research was to evaluate the physiological and neurochemical effects in 60 (Naval Medical Research Institute) NMRI male mice strains in young adult - age average weight 25.45 ± 3.05 g, underwent six weeks at doses of the psychoactive ingredient in marijuana the Δ -9-tetrahydrocannabinol in concentrations between 4-20 %. Retroorbital blood shots were conducted to evaluate hematological and biochemical parameters before, during and post experience. Weight, water intake, food, horizontal and vertical locomotors activity include: measures such as monitored. At the end of the experience autopsy was conducted and sampling of brain regions to measure levels of amino acid neurotransmitters and dopamine. These results suggest that high concentrations of the psychoactive ingredient in marijuana consumers become more dependent with consequent physiological and neurological damage. This leads to more and more drugs is needed to produce the same effect.

Biogenic amines are associated with worker task but not patriline in the leaf-cutting ant Acromyrmex echinatior.

Division of labor among eusocial insect workers is a hallmark of advanced social organization, but its underlying neural mechanisms are not well understood. We investigated whether differences in whole-brain levels of the biogenic amines dopamine (DA), serotonin (5HT), and octopamine (OA) are associated with task specialization and genotype in similarly sized and aged workers of the leaf-cutting ant Acromyrmex echinatior, a polyandrous species in which genotype correlates with worker task specialization. We compared amine levels of foragers and waste management workers to test for an association with worker task, and young in-nest workers across patrilines to test for a genetic influence on brain amine levels. Foragers had higher levels of DA and OA and a higher OA:5HT ratio than waste management workers. Patrilines did not significantly differ in amine levels or their ratios, although patriline affected worker body size, which correlated with amine levels despite the small size range sampled. Levels of all three amines were correlated within individuals in both studies. Among patrilines, mean levels of DA and OA, and OA and 5HT were also correlated. Our results suggest that differences in biogenic amines could regulate worker task specialization, but may be not be significantly affected by genotype.

Relative response cost determines the sensitivity of instrumental reward seeking to dopamine receptor blockade.

Dopamine is a critical mediator of instrumental reward seeking behavior and appears to have a particularly important role in motivating actions that require considerable effort. As with rewards, response costs can be evaluated in both absolute and relative terms. The current study investigated whether the extent to which instrumental performance is dependent on dopamine transmission is influenced by relative or absolute response cost. Three groups of rats were rewarded for lever pressing on different fixed ratio (FR) schedules that required 1 (FR-1), 10 (FR-10), or 20 (FR-20) presses for each food reward. Rats were then injected systemically with flupentixol, a dopamine receptor antagonist, or vehicle before testing all groups on an intermediate-cost (FR-10) schedule, such that only the relative cost of responding differed across groups. Rats experiencing an upshift in cost (group FR-1/FR-10) showed greater response suppression following flupentixol administration than rats experiencing no shift in cost (group FR-10/FR-10), whereas flupentixol treatment had no effect on rats experiencing a downshift in cost (group FR-20/FR-10). A second round of flupentixol tests was conducted using the rats' maintenance schedules, such that only absolute response costs differed across groups. Here, the pattern was reversed among the groups, in line with previous reports. Specifically, flupentixol had a stronger suppressive effect in group FR-20/FR-20 than in group FR-10/FR-10, and had no detectable effect in group FR-1/FR-1. These findings suggest that response costs are evaluated in both absolute and relative terms and that dopamine has a role in overcoming both kinds of cost.

Acute stress induces selective alterations in cost/benefit decision-making.

Acute stress can exert beneficial or detrimental effects on different forms of cognition. In the present study, we assessed the effects of acute restraint stress on different forms of cost/benefit decision-making, and some of the hormonal and neurochemical mechanisms that may underlie these effects. Effort-based decision-making was assessed where rats chose between a low effort/reward (1 press=2 pellets) or high effort/reward option (4 pellets), with the effort requirement increasing over 4 blocks of trials (2, 5, 10, and 20 lever presses). Restraint stress for 1 h decreased preference for the more costly reward and induced longer choice latencies. Control experiments revealed that the effects on decision-making were not mediated by general reductions in motivation or preference for larger rewards. In contrast, acute stress did not affect delay-discounting, when rats chose between a small/immediate vs larger/delayed reward. The effects of stress on decision-making were not mimicked by treatment with physiological doses of corticosterone (1-3 mg/kg). Blockade of dopamine receptors with flupenthixol (0.25 mg/kg) before restraint did not attenuate stress-induced effects on effort-related choice, but abolished effects on choice latencies. These data suggest that acute stress interferes somewhat selectively with cost/benefit evaluations concerning effort costs. These effects do not appear to be mediated solely by enhanced glucocorticoid activity, whereas dopaminergic activation may contribute to increased deliberation times induced by stress. These findings may provide insight into impairments in decision-making and anergia associated with stress-related disorders, such as depression.

The grid-walking test: assessment of sensorimotor deficits after moderate or severe dopamine depletion by 6-hydroxydopamine lesions in the dorsal striatum and medial forebrain bundle.

The present study aims to evaluate the applicability of the grid-walking test in rats with moderate or severe dopamine-depletion incurred by unilateral nigro-striatal 6-hydroxydopamine (6-OHDA) lesions. Striatum samples were analyzed by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC) after behavioral testing. In Experiment 1, 2 weeks after the injection of 6-OHDA into the medial forebrain bundle, adult Wistar rats were divided into an l-3,4-dihydroxyphenylalanine (L-dopa) and a vehicle treatment group and their behaviors on the grid were compared. The severely lesioned animals (mean dopamine depletion of 92%) did not exhibit behavioral asymmetry in the number of contralateral foot-slips. However, L-dopa administration selectively reduced the number of foot-slips of the contralateral forelimb when compared with the vehicle group. In Experiment 2, 6-OHDA was injected into the dorsal striatum and foot-slips on the grid were analyzed 4, 9 and 13 days following the lesion. The rats with moderate dopamine-depletion (mean depletion of 54%) exhibited more contralateral forelimb-slips on all testing days. Compared with naive rats, hemiparkinsonian rats also showed more forelimb-slips. These results suggest that the grid-walking test should be a powerful and sensitive behavioral assay for sensory-motor deficits in rat models of nigro-striatal dopamine lesions.

Reliance on habits at the expense of goal-directed control following dopamine precursor depletion.

RATIONALE: Dopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus-response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not well understood. OBJECTIVES: We present the first investigation of the effect of reducing dopamine function in healthy volunteers on the balance between habitual and goal-directed action control. METHODS: The dietary intervention of acute dietary phenylalanine and tyrosine depletion (APTD) was adopted to study the effects of reduced global dopamine function on action control. Participants were randomly assigned to either the APTD or placebo group (ns = 14) to allow for a between-subjects comparison of performance on a novel three-stage experimental paradigm. In the initial learning phase, participants learned to respond to different stimuli in order to gain rewarding outcomes. Subsequently, an outcome-devaluation test and a slips-of-action test were conducted to assess whether participants were able to flexibly adjust their behaviour to changes in the desirability of the outcomes. RESULTS: APTD did not prevent stimulus-response learning, nor did we find evidence for impaired response-outcome learning in the subsequent outcome-devaluation test. However, when goal-directed and habitual systems competed for control in the slips-of-action test, APTD tipped the balance towards habitual control. These findings were restricted to female volunteers. CONCLUSIONS: We provide direct evidence that the balance between goal-directed and habitual control in humans is dopamine dependent. The results are discussed in light of gender differences in dopamine function and psychopathologies.

Electroretinographic assessment in major depressed patients receiving duloxetine: might differences between responders and non-responders indicate a differential biological background?

INTRODUCTION: Despite intense research efforts, still too little is known about the biological determinants of depression, thus soliciting diverse study approaches. Among others, the electroretinography (ERG) has been proposed even as a putative proxy (retinal) measurement of central dopaminergic activity for Major Depressive Disorder (MDD) both in drug-naïve patients and subjects receiving antidepressant treatments. Nonetheless, current evidences are merely preliminary, essentially considering just older classes of antidepressants, thus requiring confirmation studies even with newer agents as duloxetine. METHOD: Twenty MDD subjects and 20 matched controls received duloxetine 60 mg/day for 12 weeks, being monitored both by standard ERG recording and by administration of the Hamilton scales for Depression and Anxiety and the Young Mania Rating Scale at baseline and week 12 (end of the study). RESULTS: ERG mean rod b-wave amplitude significantly reduced from baseline to week 12 in those depressed subjects achieving final response (p=.024), decreasing from the highest rank values to the ones, substantially unmodified, seen among non-responders and controls. LIMITATIONS: Small sample size and lack of multiple assessments. CONCLUSIONS: At least some MDD patients responding to duloxetine might exhibit a peculiar ERG pattern, hypothetically indicating a specific biological background. If confirmed by larger-sampled studies, these results might shed further light in the understanding of the biological determinants of different subtypes of depression, ideally showing alternative patterns of response upon different treatment interventions.

Speed/accuracy trade-off between the habitual and the goal-directed processes.

Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time.

A multivariate assessment of individual differences in sensation seeking and impulsivity as predictors of amphetamine self-administration and prefrontal dopamine function in rats.

Drug abuse vulnerability has been linked to sensation seeking (behaviors likely to produce rewards) and impulsivity (behaviors occurring without foresight). Since previous preclinical work has been limited primarily to using single tasks as predictor variables, the present study determined if measuring multiple tasks of sensation seeking and impulsivity would be useful in predicting amphetamine self-administration in rats. Multiple tasks were also used as predictor variables of dopamine transporter function in the medial prefrontal and orbitofrontal cortexes, as these neural systems have been implicated in sensation seeking and impulsivity. Rats were tested on six behavioral tasks as predictor variables to evaluate sensation seeking (locomotor activity, novelty place preference, and sucrose reinforcement on a progressive ratio schedule) and impulsivity (delay discounting, cued go/no-go, and passive avoidance), followed by d-amphetamine self-administration (0.0056-0.1 mg/kg infusion) and kinetic analysis of dopamine transporter function as outcome variables. The combination of these predictor variables into a multivariate approach failed to yield any clear relationship among predictor and outcome measures. Using multivariate approaches to understand the relation between individual predictor and outcome variables in preclinical models may be hindered by alterations in behavior due to training and thus, the relation between various individual differences in behavior and drug self-administration may be better assessed using a univariate approach in which a only a single task is used as the predictor variable.

Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions.

Harsh corporal punishment (HCP) was defined as frequent parental administration of corporal punishment (CP) for discipline, with occasional use of objects such as straps, or paddles. CP is linked to increased risk for depression and substance abuse. We examine whether long-term exposure to HCP acts as sub-traumatic stressor that contributes to brain alterations, particularly in dopaminergic pathways, which may mediate their increased vulnerability to drug and alcohol abuse. Nineteen young adults who experienced early HCP but no other forms of maltreatment and twenty-three comparable controls were studied. T2 relaxation time (T2-RT) measurements were performed with an echo planar imaging TE stepping technique and T2 maps were calculated and analyzed voxel-by-voxel to locate regional T2-RT differences between groups. Previous studies indicated that T2-RT provides an indirect index of resting cerebral blood volume. Region of interest (ROI) analyses were also conducted in caudate, putamen, nucleus accumbens, anterior cingulate cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus and cerebellar hemispheres. Voxel-based relaxometry showed that HCP was associated with increased T2-RT in right caudate and putamen. ROI analyses also revealed increased T2-RT in dorsolateral prefrontal cortex, substantia nigra, thalamus and accumbens but not globus pallidus or cerebellum. There were significant associations between T2-RT measures in dopamine target regions and use of drugs and alcohol, and memory performance. Alteration in the paramagnetic or hemodynamic properties of dopaminergic cell body and projection regions were observed in subjects with HCP, and these findings may relate to their increased risk for drug and alcohol abuse.