Methamphetamine is a potent psychomotor stimulant drug with high potential for abuse, and recent surveys indicate that its popularity is increasing. In animals, methamphetamine is a documented dopamine (DA) and serotonin (5-HT) neurotoxin. In baboons, doses on the order of those abused by human have recently been found to damage brain DA and 5-HT neurons. The overall goal of the present studies is to determine whether humans with a history of methamphetamine abuse show evidence of brain DA or 5-HT neural injury. To achieve this goal, the specific aims of the project will be: (1) To use PET imaging with [11C] WIN-35,428 to determine if humans with a history of methamphetamine abuse show evidence of a lasting decrease in striatal DA transporter sites; 2) To use PET imaging with [11C]DTBZ to ascertain if humans with a history of methamphetamine exposure evidence of a lasting reduction in striatal VMAT2 sites; 3) To determine if humans with a history of extensive methamphetamine use are more sensitive to the effects of the catecholamine-depleting agent a-methyparatyrosine exposure show evidence of a lasting reduction in striatal VMAT2 sites; 3) To determine if humans with a history of extensive ethamphetamine use are more sensitive to the effects of the catecholamine-depleting agent a-methylparatyrosine (a-MPT) 4) To use PET imaging with the 5-HT transporter ligand [11C] McN5652 to determine if humans with a history of methamphetamine abuse show evidence of a lasting decrement in 5-HT transporter sites. By pursuing these specific aims, this research will test the hypothesis that prior exposure to repeated doses of methamphetamine produces a lasting reduction of brain DA and 5-HT axonal markers in humans. In these studies, abstinent methamphetamine abusers will be compared to individuals who have abused drugs other than methamphetamine and to control subjects without a history of drug abuse or dependence. In addition, a positive control group consisting of subjects with Parkinson's disease will be studied. The long-term goals of the project are to detect subclinical DA and 5-HT neural injury in abstinent methamphetamine users (if such injury occurs), and to better delineate the neurobiologic and public health consequences of abuse of methamphetamine and related drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009487-05
Application #
2897949
Study Section
Special Emphasis Panel (ZDA1-MXS-M (08))
Program Officer
Frascella, Joseph
Project Start
1994-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
McCann, Una D; Szabo, Zsolt; Vranesic, Melin et al. (2008) Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine (""ecstasy"") users: relationship to cognitive performance. Psychopharmacology (Berl) 200:439-50
McCann, Una D; Kuwabara, Hiroto; Kumar, Anil et al. (2008) Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse 62:91-100
Ricaurte, George A; McCann, Una D (2005) Recognition and management of complications of new recreational drug use. Lancet 365:2137-45
McCann, Una D; Ricaurte, George A (2004) Amphetamine neurotoxicity: accomplishments and remaining challenges. Neurosci Biobehav Rev 27:821-6
Xie, Tao; Tong, Liqiong; McCann, Una D et al. (2004) Identification and characterization of metallothionein-1 and -2 gene expression in the context of (+/-)3,4-methylenedioxymethamphetamine-induced toxicity to brain dopaminergic neurons. J Neurosci 24:7043-50
Yuan, Jie; Cord, Branden J; McCann, Una D et al. (2002) Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity. J Neurochem 80:960-9
Reneman, Liesbeth; Booij, Jan; Habraken, Jan B A et al. (2002) Validity of [123I]beta-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity. Synapse 46:199-205
Hatzidimitriou, George; Tsai, Elizabeth H; McCann, Una D et al. (2002) Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine. Synapse 44:51-7
Ricaurte, George A; Yuan, Jie; Hatzidimitriou, George et al. (2002) Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (""ecstasy""). Science 297:2260-3
Xie, Tao; Tong, Liqiong; Barrett, Tanya et al. (2002) Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity. J Neurosci 22:274-83

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