Title : Lateralization and Gender Differences in the Dopaminergic Response to Unpredictable Reward in the Human Ventral Striatum Running title : Lateralized Dopamine Response to Reward

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine's actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [11C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [11C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [11C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a 'slot-machine' task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP(ND) ) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP(ND) reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males. Title: Lateralization and Gender Differences in the Dopaminergic Response to Unpredictable Reward in the Human Ventral Striatum Running title: Lateralized Dopamine Response to Reward Chantal Martin-Soelch, PhD, 1, Joanna Szczepanik, MA, 2, Allison Nugent, PhD, 2, Krystle Barhaghi, BA, 2, Denise Rallis, PhD, 2, Peter Herscovitch, MD, 3, Richard E. Carson, PhD, 4, Wayne C. Drevets, MD, 2, 5 1. Department of Psychiatry and Psychotherapy, University Hospital Zurich, Zurich, Switzerland 2. Section on Neuroimaging in Mood and Anxiety Disorders, NIMH, NIH, Bethesda, MD, USA 3. PET Department, NIH Clinical Center, Bethesda, MD, USA 4. PET Center, Yale University School of Medicine, New Haven, CT, USA 5. Department of Psychiatry, Oklahoma University College of Medicine, Laureate Institute for Brain Research, Tulsa, OK, 74136 Address from which the work originated: Section on Neuroimaging in Mood and Anxiety Disorders, NIMH, NIH, Bethesda, MD, USA Corresponding author: Chantal Martin-Soelch, Department of Psychiatry and Psychotherapy, University Hospital Zurich, Culmannstrasse 8, CH-8091 Zurich, Switzerland, Phone: +41 (0)44 255 96 68; FAX: +41 (0)44 255 44 08, E-mail: chantal.martinsoelch@usz.ch Word count: whole manuscript: ,abstract: 248; Introduction: 491 Number of pages: 29, Tables: 3, figures: 6, equation: 1, supplemental material: 1