My immediate goals are to establish myself as an independent researcher, to gain an understanding for the interaction of methamphetamine (MA) and the hypothalamic-pituitary-adrenal (HPA) axis during development, and to increase my experience in methods related to learning and memory. For my long-term goals, I see myself in an academic position that allows for interaction among a variety of fields and interests with the possibility of collaborative work. I would like to be in a position to be promoted to a tenure track position and to gain tenure. My research pursuits will continue to be in the areas of drugs of abuse, development, learning and memory, neurotrophic factors, gene expression, and hormones. I feel that concurrent investigation of these areas will provide possible mechanisms for the development of cognitive deficits following drug exposure. Since very little research has incorporated all of these areas in a focused manner, this research will enable me to have a strong influence in developmental problems associated with early drug exposure, especially MA. MA use has reached epidemic proportions in a very short period of time. Very few data exist for the effects of MA during development in humans, therefore of particular concern is that women of childbearing age are among the growing number of users/abusers. Research in Dr. Charles V. Vorhees' laboratory, the mentor for the proposed application, has demonstrated that rats exposed to MA during a period of hippocampal development that correlates with third trimester human development, show cognitive impairments as adults, without apparent alterations to neurotransmitters or neurotoxicity during drug administration. Recently we have demonstrated that MA administration on P11-20 causes elevated corticosterone (CORT) and ACTH levels. The proposed studies will investigate the interaction of MA and the hormones of the HPA axis to determine if the elevation in these hormones mediates the cognitive deficits. Several converging lines of research will be used to determine these effects. Investigations will include assessing the dose-dependent response of the HPA axis to MA, the critical period of hormone release, the effect early MA exposure has on the development of the HPA axis and release of these hormones following exposure to an environmental challenge (either forced swim in a novel environment, or a novel environment alone). Further, experiments investigating the effect of CORT on cell proliferation, development, and receptors has been proposed. Investigation of gene expression changes will be undertaken. The use of different strains of rats prone to hyper- or hyposecretion of HPA axis hormones will be used, as will animals that are exposed to MA without the concurrent increase in CORT.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA014269-03
Application #
6732684
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Thadani, Pushpa
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$116,726
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Williams, Michael T; Skelton, Matthew R; Longacre, Ian D et al. (2014) Neuronal reorganization in adult rats neonatally exposed to (±)-3,4-methylenedioxymethamphetamine. Toxicol Rep 1:699-706
Schaefer, Tori L; Grace, Curtis E; Braun, Amanda A et al. (2013) Cognitive impairments from developmental exposure to serotonergic drugs: citalopram and MDMA. Int J Neuropsychopharmacol 16:1383-94
Hemmerle, Ann M; Dickerson, Jonathan W; Herring, Nicole R et al. (2012) (±)3,4-methylenedioxymethamphetamine (""ecstasy"") treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain. J Comp Neurol 520:2459-74
Vorhees, Charles V; Johnson, Holly L; Burns, Lindsey N et al. (2009) Developmental treatment with the dopamine D2/3 agonist quinpirole selectively impairs spatial learning in the Morris water maze. Neurotoxicol Teratol 31:1-10
Vorhees, Charles V; Schaefer, Tori L; Skelton, Matthew R et al. (2009) (+/-)3,4-Methylenedioxymethamphetamine (MDMA) dose-dependently impairs spatial learning in the morris water maze after exposure of rats to different five-day intervals from birth to postnatal day twenty. Dev Neurosci 31:107-20
Schaefer, T L; Vorhees, C V; Williams, M T (2009) Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness. Neuroscience 164:1431-43
Vorhees, Charles V; Skelton, Matthew R; Grace, Curtis E et al. (2009) Effects of (+)-methamphetamine on path integration and spatial learning, but not locomotor activity or acoustic startle, align with the stress hyporesponsive period in rats. Int J Dev Neurosci 27:289-98
Skelton, Matthew R; Williams, Michael T; Vorhees, Charles V (2008) Developmental effects of 3,4-methylenedioxymethamphetamine: a review. Behav Pharmacol 19:91-111
Skelton, Matthew R; Able, Jessica A; Grace, Curtis E et al. (2008) (+/-)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: a comparison of single vs once per week treatment for 5 weeks. Neuropharmacology 55:1121-30
Grace, Curtis E; Schaefer, Tori L; Herring, Nicole R et al. (2008) (+)-Methamphetamine increases corticosterone in plasma and BDNF in brain more than forced swim or isolation in neonatal rats. Synapse 62:110-21

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