Methamphetamine (MIETH) is a highly addictive drug of abuse that has also raised concern since in laboratory animals it is neurotoxic to dopamine (DA) terminals. Moreover, recent imaging and postmortem studies in MIETH abusers have documented marked reductions in DA transporters (DAT), which serve as markers of DA terminals. However, the extent to which the DAT reductions in METH abusers are associated with abnormal DA cell function, the extent to which these changes may recover with detoxification and the extent to which they contribute to the addictive process have not been evaluated. In this competitive renewal we propose to assess whether the DAT losses in METH abusers are associated with disrupted DA cell function and to assess if they recover with detoxification. We will use positron emission tomography (PET) to measure DAT using 'C]cocaine (DAT radioligand) and to assess DA cell function by comparing the binding of raclopride (DA D2 radioligand whose binding to D2 receptors is sensitive to competition by endogenous DA) with and without pretreatment with methyiphenidate (drug that increases DA by blocking DAT). We propose to test METH abusers (n = 40) during early withdrawal (greater than 2 weeks and less than 3 months), and retest them 6-9 months later after a drug free period (we expect 10 abusers to return for testing). Normal controls (n = 20) will be tested in parallel and 10 of them will be retested 6-9 months later to assess reproducibility. Our working hypotheses are: ? ? (1) MIETH abusers will have decreased function of DA cells in addition to the loss of DAT (2) Detoxification will result in increase in DA cell function and in DAT levels. ? ? It is important to assess if there is disrupted DA cell function in METH abusers since it could perpetuate METH use as a means to temporarily compensate for this dysfunction. It is also of relevance to determine if it recovers with detoxification in order to understand the long-term consequences of DAT losses in the METH abusers vis a vis their vulnerability to neurodegenerative diseases (i.e Parkinson's disease). Such knowledge should help guide the management of the METH abuser and the development of medications that may help ameliorate the DA deficits.
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