Substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') are synthetic drugs which are widely abused as psychostimulants. In recent years, there is a growing epidemic of METH and MDMA abuse not only in urban areas, but also in many rural parts of the US that were previously unexposed to psychostimulant abuse. Repeated use of METH and MDMA causes the development of severe addiction, aggression, violent and psychotic behavior, memory loss, and potential dopaminergic and serotonergic neurotoxicity. Currently, there are no pharmacotherapies against substituted amphetamines addiction and neurotoxicity. The long term goal of this project is to identify potential pharmacotherapies against amphetamines addiction. Our recent studies suggest that besides the role of dopamine in the action of psychostimulants, nitric oxide (NO) may play a pivotal role in mediating the effects of these drugs. In brain, NO is produced by the neuronal, inducible and endothelial nitric oxide synthase isoforms (nNOS, iNOS, eNOS) and has been implicated in neural transmission, plasticity and neurotoxicity. We hypothesize that nNOS has a major role in 1) the psychomotor stimulating effects, 2) the reinforcing properties and 3) the dopaminergic neurotoxicity produced by substituted amphetamines. Accordingly, the specific goals of this proposal are: 1) To investigate the effects of selective NOS inhibitors on the development of behavioral sensitization to substituted amphetamines, and the effects of the latter on nNOS and iNOS knockout (KO) mice. Potential alteration in the expression of the NOS protein levels in correlation with behavioral sensitization will be investigated. 2) To examine the role of NOS isoforms in the rewarding effects of amphetamines. The effect of NOS inhibitors on amphetamines-induced conditioned place preference (CPP) will be investigated, and the effects of the amphetamines on the acquisition of reward in NOS KO mice will be determined. 3) To investigate the role of nNOS and iNOS in dopaminergic and serotonergic neurotoxicity elicited by various amphetamine analogs, and whether alteration in the expression of NOS proteins is associated with neurotoxicity. The proposed studies will utilize pharmacologic, genetic, and molecular techniques to investigate the role of NO in amphetamine-induced behavioral sensitization, reward, and neurotoxicity. The combined behavioral, neurochemical and molecular approaches designed will lead to better understanding of the mechanisms underlying the effects of substituted amphetamines and the development of new therapeutics for the management of amphetamine addiction and toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012867-05
Application #
6865499
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Frankenheim, Jerry
Project Start
2001-03-15
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$303,000
Indirect Cost
Name
University of Miami School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Tsvetanova, Nikoleta G; Irannejad, Roshanak; von Zastrow, Mark (2015) G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins from endosomes. J Biol Chem 290:6689-96
Achat-Mendes, Cindy; Anderson, Karen L; Itzhak, Yossef (2007) Impairment in consolidation of learned place preference following dopaminergic neurotoxicity in mice is ameliorated by N-acetylcysteine but not D1 and D2 dopamine receptor agonists. Neuropsychopharmacology 32:531-41
Itzhak, Yossef; Anderson, Karen L (2007) Memory reconsolidation of cocaine-associated context requires nitric oxide signaling. Synapse 61:1002-5
Kelley, Jonathan B; Anderson, Karen L; Itzhak, Yossef (2007) Long-term memory of cocaine-associated context: disruption and reinstatement. Neuroreport 18:777-80
Itzhak, Yossef; Ali, Syed F (2006) Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs. Pharmacol Ther 109:246-62
Balda, Mara A; Anderson, Karen L; Itzhak, Yossef (2006) Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: role of neuronal nitric oxide synthase (nNOS) gene. Neuropharmacology 51:341-9
Anderson, Karen L; Itzhak, Yossef (2006) Methamphetamine-induced selective dopaminergic neurotoxicity is accompanied by an increase in striatal nitrate in the mouse. Ann N Y Acad Sci 1074:225-33
Achat-Mendes, Cindy; Ali, Syed F; Itzhak, Yossef (2005) Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice. Neuropsychopharmacology 30:1128-37
Itzhak, Yossef; Anderson, Karen L; Ali, Syed F (2004) Differential response of nNOS knockout mice to MDMA (""ecstasy"")- and methamphetamine-induced psychomotor sensitization and neurotoxicity. Ann N Y Acad Sci 1025:119-28
Itzhak, Yossef; Achat-Mendes, Cindy (2004) Methamphetamine and MDMA (ecstasy) neurotoxicity: 'of mice and men'. IUBMB Life 56:249-55

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