Since chemical dependency is an important mental health concern, there is a need to study pathophysiology of addiction. These studies could lead to development of more effective therapeutic strategies. Based on the data acquired in laboratory animals, it was suggested that the mesolimbic dopamine system is involved in the processing of different aspects of addictive behavior. The neural mechanism by which dopamine induces drug-seeking behavior. Is not known but a number of models have been proposed to explain the mechanism. The hedonic homeostatic model suggests that repeated use of an addictive substance elevates dopaminergic activity and establishes a higher set point of hedonic homeostasis in the brain. It assumes that the drug-seeking behavior is an attempt to achieve the new set point. An alternate model suggests that addiction is a disorder of pathologically subverted dopamine-dependent processing of the memory of association between a drug and the context of its use. The subverted processing imparts motivational status to the memory and induces addictive behavior. Since both models suggest that dopamine neurotransmission is dysregulated in addicts, these assumptions could be complementary. Thus, if dysregulated dopamine neurotransmission disrupts the processing of reward and associative memory, it would alter hedonic homeostasis (which is dependent on the reward) and pathologically subvert processing of associative memory. In this study we propose to examine validity of this hypothesis by detecting, mapping and measuring dopamine released during processing of the reward and associative memory in non-addict and addict volunteers. If the hypothesis is validated, it will allow development of an integrated biological model of addiction. The study will use a newly developed dynamic molecular imaging technique to study dopamine release during task performance. The technique exploits the competition between dopamine and its ligand for occupancy of dopamine receptors. Because of this competition, the ligand is displaced from receptor sites by dopamine. Since the rate of ligand displacement depends on the amount of endogenously released dopamine;it is possible to detect, map and measure dopamine released during task performance (phasic release) by estimating displacement rate of a radiolabeled ligand using a positron emission tomography (PET) camera. Additionally, dopamine release at baseline (tonic release) will also be measured in addict and non-addict volunteers to examine the validity of hedonic homeostasis model, which predicts higher baseline level of dopamine in addicts. Comparison of the data acquired in the two groups of volunteer will reveal the nature of dysregulated phasic and tonic release of dopamine in addicts. Additionally, it will examine validity of assumptions of two important models of addiction (hedonic homeostasis and associative memory). The study will provide human data that will define the nature of dysregulated dopamine neurotransmission in addiction and will help us understand the role of dopamine in establishment and maintenance of addictive behavior. The proposed experiments will reveal the pattern of dysregulated dopamine neurotransmission in addicts. This pattern could lead to identification of novel therapeutic targets and development of novel strategies for treatment of addiction. It could also be used to formulate criteria for identification of susceptibe individuals.

Public Health Relevance

Chemical dependency is a major mental health problem in veterans. It is estimated that about 19% of veterans of current conflicts are addicted to illicit drugs. The percentage is much higher in Vietnam veterans. Since there is a need to develop more effective therapeutic strategies for treatment of addiction, it is important to understand the brain mechanisms that are responsible for development of drug seeking behavior. The proposed study will use a novel technique to study these mechanisms. The results will define the nature of dysregulated dopamine neurotransmission in addicts and examine the validity of two important models of addiction. The study could lead to development of novel therapeutic strategies based on empirical data. Additionally, the results will allow formulation of objective criteria for identification of suscepible individuals.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology A (NURA)
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VA Western New York Healthcare System
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