The 3,4-Methylene-dioxymethamphetamine (MDMA, 'Ecstasy'') is an illicit amphetamine analog that is increasing in popularity in the United States and abroad. In addition to its abuse potential, MDMA is well documented as a potent and selective serotonin neurotoxin in animals. A growing body of evidence indicates that human MDMA users are also susceptible to MDMA-induced serotonin neurotoxicity. Although functional sequelae of MDMA-induced serotonin neurotoxicity appear to be subtle, a number of laboratories have documented abnormalities in memory and other cognitive processes in MDMA users compared to matched control groups. Since it is known that neurons involved in cognitive processes decrease with aging (e.g., catecholaminergic and cholinergic neurons), there is concern that MDMA users may be at risk for developing clinically significant cognitive abnormalities as they age. The overall goal of this revised competing renewal application is to determine if pharmacological and physiological challenges that are intended to simulate selected features of aging (i.e., loss of catecholaminergic/cholinergic function and/or sleep continuity) can be used to better detect and characterize possible detrimental effects of MDMA neurotoxicity upon cognitive processes in humans. The hypothesis to be tested is that MDMA-induced brain serotonergic injury will render MDMA users more susceptible to cognitive deficits associated with disruption of catecholaminergic and cholinergic neurotransmission and sleep continuity.
The Specific Aims of the project are: 1) To determine whether or not MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPE), on cognitive processes; V To determine if MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the cholinergic antagonist, scopolamine, on cognitive processes; 3) To determine whether or not sleep deprivation, a naturalistic physiological challenge that is known to lead to deficits in cognition (and which is common in elderly populations), produces more profound effects on cognition in MDMA users compared to matched controls; and 4) To determine whether there is a relationship between cognitive deficits in MDMA users and the level of CSF 5-hydroxyindoleacetic acid, a validated measure of MDMA-induced brain serotonin neurotoxicity. The proposed studies hold promise for improving our understanding of the functional consequences of MDMA-induced serotonin neurotoxicity in humans, and should advance knowledge regarding the role of brain serotonin and other neurotransmitter systems in cognition.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005938-10
Application #
6622086
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Nemeth-Coslett, Rosemarie V
Project Start
1989-08-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
10
Fiscal Year
2003
Total Cost
$405,910
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Yuan, Jie; Darvas, Martin; Sotak, Bethany et al. (2010) Dopamine is not essential for the development of methamphetamine-induced neurotoxicity. J Neurochem 114:1135-42
McCann, Una D; Wilson, Michael J; Sgambati, Francis P et al. (2009) Sleep deprivation differentially impairs cognitive performance in abstinent methylenedioxymethamphetamine (""Ecstasy"") users. J Neurosci 29:14050-6
McCann, Una D; Sgambati, Francis P; Schwartz, Alan R et al. (2009) Sleep apnea in young abstinent recreational MDMA (""ecstasy"") consumers. Neurology 73:2011-7
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, U D; Ridenour, A; Shaham, Y et al. (1994) Serotonin neurotoxicity after (+/-)3,4-methylenedioxymethamphetamine (MDMA;""Ecstasy""): a controlled study in humans. Neuropsychopharmacology 10:129-38