669 [Frontiers in Bioscience, Landmark, 22, 669-691, January 1, 2017] 1. ABSTRACT Reward deficiency syndrome (RDS) was first proposed by Kenneth Blum in 1995 to provide a clinically relevant and predictive term for conditions involving deficits in mesocorticolimbic dopamine function. Genetic, molecular, and neuronal alterations in key components of this circuitry contribute to a reward deficit state that can drive drug-seeking, consumption, and relapse. Among the dysfunctions observed in RDS are dysregulated resting state networks, which recently have been assessed in detail in chronic drug users by, positron emission tomography, functional magnetic resonance imaging, and functional connectivity analysis. A growing number of studies are helping to determine the putative roles of dopamine and glutamatergic neurotransmission in the regulation of activity in resting state networks, particularly in brain reward circuitry affected in drug use disorders. Indeed, we hypothesize in the present review that loss of homeostasis of these systems may lead to ‘unbalanced’ functional networks that might be both cause and outcome of disrupted synaptic communication between cortical and subcortical systems essential for controlling reward, emotional control, sensation seeking, and chronic drug use. Dopamine homeostasis: brain functional connectivity in reward deficiency syndrome Marcelo Febo 1 , Kenneth Blum 1-4,8 , Rajendra D. Badgaiyan 5 , David Baron 6 , Panayotis K. Thanos 7 , Luis M. Colon-Perez 1 , Zsolt Demotrovics 8 , Mark S. Gold 1,6,9 1 Department of Psychiatry, McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, USA, 2 Division of Neuroscience based-Therapy, Summit Estate Recovery Center, Los Gatos, CA, USA, 3 Dominion Diagnostics, LLC, North Kingstown, RI, USA, 4 Division of Neuroscience Research and Addiction Therapy, Shores Treatment and Recovery Center, Port Saint Lucie, FL, USA, 5 Department of Psychiatry and Neuroimaging, University of Minnesota, Minneapolis, MN, USA, 6 Departments of Psychiatry & Behavioral Sciences , Keck School of Medicine of University of Southern California, Los Angeles, CA, USA, 7 Research Institute of Addictions, University at Buffalo, Buffalo, NY, USA, 8 Institute of Psychology, Eotvos Lorand University Budapest, Hungary, 9 Department of Psychiatry, Washington University School of Medicine. St. Louis, Mo., USA TABLE OF CONTENTS 1. Abstract 2. Introduction 3. “Dopamine homeostasis”: Bringing functional balance to the dopamine reward pathway 4. Understanding resting state brain functional connectivity 4.1. Functional connectivity and addiction: Neurobiological underpinnings 4.2. Are glutaminergic and dopaminergic pathways therapeutic targets for reward homeostasis? 4.3. Dopamine and brain functional connectivity: Psychiatric genetic links 5. Summary and perspectives 6. Conclusion 7. Acknowledgments 8. References 2. INTRODUCTION Drug use disorders continue to represent a major health and socioeconomic challenge affecting the lives of many in the U.S. and worldwide. In 2013, in the U.S. alone 24.6. million individuals aged 12 years or older reported illicit drug use, and among these, 1.5. million reported using the psychostimulant cocaine (1). An astounding 21.6. million adults 18 or older were reported that same year as having a substance use disorder, with 4.2. million showing abuse of dependence on marijuana, 1.9. million on pain relievers, 855,000 cocaine, and 517,000 heroin (1). These staggering numbers warrant more preclinical research, especially in novel directions that could ultimately help diagnose drug use disorders (through genetic testing) and offer effective treatments. Reward Deficiency Syndrome (RDS) was first defined by K. Blum in 1995 as a putative predictor of impulsive and addictive behaviors related in large part to mesolimbic dopamine (DA) system dysfunction (see Table 1) (2-6). Binding of the neurotransmitter dopamine (DA) to the D2 DA receptor (DRD2), for example, has been linked to a variety of behaviors reflecting reward seeking (7-9), and the DRD2 has been referred to as a reward gene (10-14). The TaqI A1 allele of the DRD2