The prevalence of obesity and related disorders such as diabetes has skyrocketed worldwide despite efforts to therapeutically target homeostatic mechanisms that regulate appetite, energy expenditure, and weight gain. The failure of these efforts points to the existence of additional, nonhomeostatic mechanisms that mediate feeding behavior (Palmiter, 2007). Indeed, redundancy in these systems makes obesity therapy difficult as further evidenced by the failure of newer drugs targeting distinct aspects of these systems. Thus, the epidemic of obesity begs for novel concepts and therapeutic targets that ideally treat ‘food-use’ disorders and related comorbidities such as drug addiction and neuropsychiatric disorders.

Nonhomeostatic or ‘reward’ circuits originating in dopamine-rich brain structures, which provide motivation and reward stimuli for feeding, are increasingly understood at the cellular and molecular levels (Palmiter, 2007). Long recognized as an important mediator of feeding behavior, dopamine signaling is increasingly of interest in obesity with findings that dopamine D2 receptor binding is reduced in a BMI-dependent manner (Wang et al, 2001). Building on this observation, current models of obesity pathogenesis posit that dopaminergic dysfunction, referred to as hypodopaminergic reward deficiency syndrome (HRDS), has a predisposing and/or causative role (Wang et al, 2001). HRDS shares features of impaired striatal dopamine neurotransmission with substance use disorders (Wang et al, 2001).

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