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Background: Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both., Methods: In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age., Results: The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction., Conclusions: These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use.

Objective: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes., Method: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally., Results: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses., Conclusions: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.

Background: Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in reward sensitivity and response inhibition. The relative contribution of these frontostriatal mechanisms to ADHD symptoms and their genetic determinants is largely unexplored. Methods: Using functional magnetic resonance imaging and genetic analysis of the monoamine oxidase A (MAOA) gene, we investigated how striatal and inferior frontal activation patterns contribute to ADHD symptoms depending on MAOA genotype in a sample of adolescent boys (n = 190). Results: We demonstrate an association of ADHD symptoms with distinct blood oxygen level–dependent (BOLD) responses depending on MAOA genotype. In A hemizygotes of the expression single nucleotide polymorphism rs12843268, which express lower levels of MAOA, ADHD symptoms are associated with lower ventral striatal BOLD response during the monetary incentive delay task and lower inferior frontal gyrus BOLD response during the stop signal task. In G hemizygotes, ADHD symptoms are associated with increased inferior frontal gyrus BOLD response during the stop signal task in the presence of increased ventral striatal BOLD response during the monetary incentive delay task. Conclusions: Depending on MAOA genotype, ADHD symptoms in adolescent boys are associated with either reward deficiency or insufficient response inhibition. Apart from its mechanistic interest, our finding may aid in developing pharmacogenetic markers for ADHD. [Copyright &y& Elsevier]