Caudate Volume in Offspring at Ultra High Risk for Alcohol Dependence: COMT Val158Met, DRD2, Externalizing Disorders, and Working Memory*

Abstract

Background: There is emerging evidence that the increased susceptibility to developing alcohol and substance use dis - orders in those with a family history of Alcohol Dependence (AD) may be related to structural differences in brain cir cuits that influence the salience of rewards or modify the efficiency of information processing. Externalizing disorders of childhood including Attention Deficit Hyperactivity Disorder, Conduct and Oppositional Disorders are a prominent feature of those with a positive family history. The caudate nuclei have been implicated in both the salience of rewards and in the pathophysiology of alcohol dependence and these often antecedent childhood disorders. Methods: Adoles cent/young adult high and low-risk for AD offspring (N = 130) were studied using magnetic resonance imaging. Vol umes of the caudate nucleus were obtained using manual tracing with BRAINS2 software and neuropsychological func tioning determined. Childhood disorders were assessed as part of a long-term longitudinal follow-up that includes young adult assessment. Dopaminergic variation was assessed using genotypic variation in the catechol-O-methyl transferase (COMT) and DRD2 genes. Results: High-risk subjects showed poorer Working Memory functioning. Cau date volume did not differ between high and low-risk subjects, but those with externalizing disorders of childhood showed reduced caudate volume. Variation in COMT and DRD2 genes was associated with Working Memory per formance and caudate volume. Conclusions: Caudate volume is reduced in association with externalizing disorders of childhood/adolescence. Working Memory deficits appear in familial high-risk offspring and those with externalizing disorders of childhood. The dopaminergic system appears to be involved in both working memory performance and externalizing disorders of childhood.