Addiction is one of the more complex and challenging problems facing Americans today. In addition to substance-related addictions such as smoking, drinking and drug abuse, there is growing evidence in of an involvement of the brain reward pathways in overconsumption of high carbohydrate foods. There is also recent interest in research to understand the similarities and differences in mechanisms underlying substance-related and non-substance-related addictions. One common feature across these addictions is the persistent and compulsive engagement in unhealthy addictive behaviors despite serious adverse health, social and legal consequences. Stress which is known to play a key role in addiction also facilitates lapses in self control. Norepinephrine (NE) mediates many of the adaptive and maladaptive consequences of stress exposure. The human NE transporter (NET) rapidly clears NE from the synaptic cleft via efficient transport system attenuating signaling, and recycling 90% of synaptic NE. The selective norepinephrine transporter (NET) radioligand, (S,S)-[11C]methylreboxetine (MRB), permits in vivo assessment of central NET expression using positron emission tomography (PET). The hypothesized mechanism for addictive behavior is that stress disrupts frontal-cortical control over limbic-striatal circuits and augments the incentive properties of addictive substances. NE pathways contribute in an important manner to the activation of mesolimbic dopamine, thereby providing a mechanism by which stress facilitates addictive behaviors to achieve shortterm hedonic homeostasis. The result is that drug use becomes a self-regulatory strategy performed to maintain hedonic homeostasis in the face of a compromised, pathological disease state. In this study we propose to study 24 unmedicated abstinent alcohol dependent patients, 24 obese individuals and 24 individually matched healthy control subjects and determine NET expression in vivo using (S,S)-[11C]MRB and PET. This will provide novel insight into alterations in pre- and post-synaptic synaptic homeostasis in alcoholism and obese people with the goal to explain regulatory processes and their alterations in these disorders. A better understanding of brain mechanisms and contributory stress would have an enormous impact on the public's understanding of the vulnerabilities for these disorders, influence medical and legal response to these problems, could lead to a new understanding of these phenomena, and stimulate a better means of prevention and treatment.
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