The abuse of psychostimulants among adolescents is continuously rising, but little is known about the long-term consequences of this practice. One of the major concerns is that early drug exposure may cause long-lasting adaptations which render the organism more susceptible to drug abuse and relapse later in life. Research on animal models of drug abuse has traditionally centered on adult subjects, with a paucity of studies on adolescent animal models. Studies in adult animals have indicated that repeated exposure to cocaine and amphetamine derivatives causes long-term susceptibility to the psychomotor stimulating and rewarding effects of these drugs. In a series of studies we have demonstrated that the nitrergic system (neuronal nitric oxide synthase; nNOS) has a major role in dopamine-mediated effects of psychostimulants in adult mice. In preliminary studies we found that in contrary to adult mice deficient in the nNOS gene (nNOS KO mice) which are resistant to psychomotor sensitization, adolescent nNOS KO mice developed psychomotor sensitization following repeated administration of methamphetamine. However both adolescent and adult wild-type (WT) mice were equally sensitive to the drug. Our working hypothesis is that although adolescents and adults develop sensitization to psychostimulants, there is an ontogeny-dependent difference in the mechanism that underlies this process in each age cohort, and that the expression of the nNOS gene in adolescence is essential for the persistence of long-term susceptibility to psychostimulants in adulthood. The overall aim of this project is to investigate the role of nNOS in ontogeny- and gender-dependent variations in the responsiveness to psychomotor stimulation and drug-seeking behavior, and the extent to which structural adaptations of nNOS-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons in mesolimbic and corticostriatal circuits correlate with the behavioral phenomena. The effects of cocaine, MDMA (ecstasy) and methylphenidate (Ritalin) on a) locomotor activation, b) conditioned place preference and c) the immunohistochemistry of nNOS- and TH-positive neurons will be investigated in WT and nNOS KO mice. Results of these studies would provide new information on mechanisms that underlie the development of hypersensitivity to these drugs from adolescence through adulthood.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019107-03
Application #
7111814
Study Section
Special Emphasis Panel (ZDA1-MXS-M (11))
Program Officer
Lin, Yu
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$258,895
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
Liddie, Shervin; Balda, Mara A; Itzhak, Yossef (2013) Nitric oxide (NO) signaling as a potential therapeutic modality against psychostimulants. Curr Pharm Des 19:7092-102
Itzhak, Yossef; Roger-Sánchez, Concepción; Kelley, Jonathan B et al. (2010) Discrimination between cocaine-associated context and cue in a modified conditioned place preference paradigm: role of the nNOS gene in cue conditioning. Int J Neuropsychopharmacol 13:171-80
Kelley, Jonathan B; Balda, Mara A; Anderson, Karen L et al. (2009) Impairments in fear conditioning in mice lacking the nNOS gene. Learn Mem 16:371-8
Balda, Mara A; Anderson, Karen L; Itzhak, Yossef (2009) Development and persistence of long-lasting behavioral sensitization to cocaine in female mice: role of the nNOS gene. Neuropharmacology 56:709-15
Itzhak, Yossef; Roger-Sánchez, Concepción; Anderson, Karen L (2009) Role of the nNOS gene in ethanol-induced conditioned place preference in mice. Alcohol 43:285-91
Balda, Mara A; Anderson, Karen L; Itzhak, Yossef (2009) The neuronal nitric oxide synthase (nNOS) gene contributes to the regulation of tyrosine hydroxylase (TH) by cocaine. Neurosci Lett 457:120-4
Itzhak, Yossef; Anderson, Karen L (2008) Ethanol-induced behavioral sensitization in adolescent and adult mice: role of the nNOS gene. Alcohol Clin Exp Res 32:1839-48
Itzhak, Yossef (2008) Role of the NMDA receptor and nitric oxide in memory reconsolidation of cocaine-induced conditioned place preference in mice. Ann N Y Acad Sci 1139:350-7
Balda, Mara A; Anderson, Karen L; Itzhak, Yossef (2008) Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice. Psychopharmacology (Berl) 200:509-19
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

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