Addiction is one of the more complex and challenging problems facing Americans today. In addition tosubstance-related addictions such as smoking, drinking and drug abuse, there is growing evidence in of aninvolvement of the brain reward pathways in overconsumption of high carbohydrate foods. There is alsorecent interest in research to understand the similarities and differences in mechanisms underlyingsubstance-related and non-substance-related addictions. One common feature across these addictions isthe 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 inself control. Norepinephrine (NE) mediates many of the adaptive and maladaptive consequences of stressexposure. The human NE transporter (NET) rapidly clears NE from the synaptic cleft via efficient transportsystem 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 expressionusing positron emission tomography (PET). The hypothesized mechanism for addictive behavior is thatstress disrupts frontal-cortical control over limbic-striatal circuits and augments the incentive properties ofaddictive substances. NE pathways contribute in an important manner to the activation of mesolimbicdopamine, thereby providing a mechanism by which stress facilitates addictive behaviors to achieve shorttermhedonic homeostasis. The result is that drug use becomes a self-regulatory strategy performed tomaintain hedonic homeostasis in the face of a compromised, pathological disease state. In this study wepropose to study 24 unmedicated abstinent alcohol dependent patients, 24 obese individuals and 24individually matched healthy control subjects and determine NET expression in vivo using (S,S)-[11C]MRBand PET. This will provide novel insight into alterations in pre- and post-synaptic synaptic homeostasis inalcoholism and obese people with the goal to explain regulatory processes and their alterations in thesedisorders. A better understanding of brain mechanisms and contributory stress would have an enormousimpact on the public's understanding of the vulnerabilities for these disorders, influence medical and legalresponse to these problems, could lead to a new understanding of these phenomena, and stimulate a bettermeans of prevention and treatment.
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