As part of a previously NIDA funded K grant (K02DA00354) my research group has developed an animal model in Swiss Webster (SW) mice to explore mechanisms underlying long-lasting structural and functional consequences of gestational cocaine exposure. Utilizing this model we can isolate the independent effect of cocaine in contributing to altered behavioral outcomes of clinical relevance, including the liability for subsequent addiction in exposed offspring. Specifically, my laboratory has recently focused attention on studying the reinforcing efficacy of cocaine in adult animals exposed to cocaine in utero. We have pursued these studies utilizing a number of behavioral paradigms including cocaine self-administration, brain stimulation reward, and cocaine-induced locomotor sensitization. Our preliminary findings from all 3 methods suggest that mice prenatally exposed to cocaine demonstrate an augmented response to cocaine when tested as adults. As the clinical implications of these findings are profoundly important, we are proposing to further pursue our studies of cocaine-induced locomotor sensitization at a mechanistic level. The current request for a competing renewal of a NIDA Independent Scientist Award (K02) is to utilize the cocaine-induced locomotor sensitization paradigm that we have developed to identify molecular mechanisms that may underlie the augmented behavioral response to cocaine evident in adult animals exposed to cocaine in utero. We have discovered that when compared to controls, mice exposed to cocaine prenatally demonstrate a significant blunting of locomotor sensitization, and a significant augmentation of stereotypic behaviors when challenged 21 days after their last cocaine injection The goal of the research proposed in this K02 application is to confirm and extend these behavioral findings, and to identify aspects of the molecular basis of this phenomenon. By performing such experiments in a prenatal model of gestational cocaine exposure our goal will be to correlate specific patterns of molecular changes in the brain that contribute to differences in behavioral sensitization observed when comparing animals from different prenatal treatment groups. Such information will provide unique mechanistic insights regarding an enhanced vulnerability of prenatally cocaine-exposed mice to cocaine, which may lead to improved prevention of addiction in cocaine-exposed offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000354-09
Application #
7410089
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Wu, Da-Yu
Project Start
1998-01-15
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
9
Fiscal Year
2008
Total Cost
$125,388
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Kabir, Zeeba D; Kennedy, Bruce; Katzman, Aaron et al. (2014) Effects of prenatal cocaine exposure on social development in mice. Dev Neurosci 36:338-46
Akyuz, Nurunisa; Kekatpure, Minal V; Liu, Jie et al. (2014) Structural brain imaging in children and adolescents following prenatal cocaine exposure: preliminary longitudinal findings. Dev Neurosci 36:316-28
Liu, Jie; Lester, Barry M; Neyzi, Nurunisa et al. (2013) Regional brain morphometry and impulsivity in adolescents following prenatal exposure to cocaine and tobacco. JAMA Pediatr 167:348-54
Kabir, Zeeba D; Katzman, Aaron C; Kosofsky, Barry E (2013) Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero. PLoS One 8:e84165
Kabir, Zeeba D; Lourenco, Frederico; Byrne, Maureen E et al. (2012) Brain-derived neurotrophic factor genotype impacts the prenatal cocaine-induced mouse phenotype. Dev Neurosci 34:184-97
Riday, Thorfinn T; Kosofsky, Barry E; Malanga, C J (2012) The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice. Neuropharmacology 62:1858-66
Derauf, Chris; Lester, Barry M; Neyzi, Nurunisa et al. (2012) Subcortical and cortical structural central nervous system changes and attention processing deficits in preschool-aged children with prenatal methamphetamine and tobacco exposure. Dev Neurosci 34:327-41
Ren, Jia-Qian; Jiang, Yan; Wang, Zhihui et al. (2011) Prenatal L-DOPA exposure produces lasting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference. Neuropharmacology 60:295-302
Derauf, Chris; Kekatpure, Minal; Neyzi, Nurunisa et al. (2009) Neuroimaging of children following prenatal drug exposure. Semin Cell Dev Biol 20:441-54
Malanga, C J; Riday, Thorfinn T; Carlezon Jr, William A et al. (2008) Prenatal exposure to cocaine increases the rewarding potency of cocaine and selective dopaminergic agonists in adult mice. Biol Psychiatry 63:214-21

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