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The Journal of Neuroscience, October 29, 2008, 28(44):11354-11359; doi:10.1523/JNEUROSCI.2391-08.2008

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Brief Communications
Monoamine Oxidase A Genotype Predicts Human Serotonin 1A Receptor Availability In Vivo

Brian J. Mickey,^1,2 Francesca Ducci,³ Colin A. Hodgkinson,³ Scott A. Langenecker,^1,2 David Goldman,³ and Jon-Kar Zubieta^1,2

¹Molecular and Behavioral Neuroscience Institute and ²Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109-0720, and ³Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20892

Correspondence should be addressed to Jon-Kar Zubieta, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720. Email: zubieta{at}umich.edu

The serotonergic system, including the serotonin 1A (5-HT_1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT_1A receptor expression. We used positron emission tomography and [¹¹C]WAY-100635 to quantify 5-HT_1A receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT_1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT_1A receptor availability in women, but not in men. Genotype predicted a substantial 42–74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT_1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.

Key words: sex difference; polymorphism; positron emission tomography; serotonin; serotonergic 1A receptor; monoamine oxidase; imaging; genetics; human; depression

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Received May 23, 2008; revised Sept. 11, 2008; accepted Sept. 12, 2008.

Correspondence should be addressed to Jon-Kar Zubieta, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720. Email: zubieta{at}umich.edu

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