3,4-Methylenedioxymethamphetamine (MDMA) abuse is a serious health problem yet little is known about its effects on developing brain. We established that neonatal rats administered MDMA (a model of 3rd trimester exposure) causes long-term path integration and spatial learning and memory impairments after P11-20 (but not P1-10) exposure, while sparing cued and working memory. New data show that exposed offspring have altered expression of CAPON, PSD95, nNOS, and NMDA-NR1 (all members of the NMDA receptor complex). This treatment also causes large reductions in 5-HT and sustained release of corticosterone (CORT). P11-20 overlaps the stress hyporesponseive period (SHRP, P4-15). We hypothesize that MDMA treatment that begins during the SHRP triggers a unique cascade of events beginning with overactivation of the stress response pathway (release of CRF, ACTH, CORT) but in which normal feedback mechanisms fail to operate correctly. The resulting prolonged CORT release alone or combined with the concomitant 5-HT reductions lead to changes in CNS organization and long-term cognitive deficits.
Specific aims to test this hypothesis are: (1a) Determine the critical period for MDMA-induced long-term cognitive and NMDA receptor complex effects using treatment intervals before, during and after the SHRP and for changes in response to stress. (1b) Compare the critical period from Aim 1a with a non-critical period for short-term effects on the HPA axis and brain 5-HT. (2) Test the role of HPA axis changes in the long-term effects using a new technique we developed involving adrenalectomy combined with adrenal alloengraftment to temporarily interrupt HPA responses with later restoration of basal CORT function. (3) Test 5-HT involvement by blocking MDMA-induced 5-HT reduction using SSRI pretreatment and test for prevention of cognitive deficits. (4) Determine changes .in nNOS, NMDA-NR1, PSD-95 and CAPON and related proteins in animals not tested behaviorally to ensure that these changes are not experience-dependent. The present model of developmental MDMA exposure is the first to establish induction of cognitve deficits and is the first step in our long range objective to ultimately test the effects of MDMA after exposure during other (earlier) stages of brain development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021394-05
Application #
7805428
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Purohit, Vishnudutt
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$282,620
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Vorhees, Charles V; Graham, Devon L; Braun, Amanda A et al. (2015) Prenatal immune challenge in rats: effects of polyinosinic-polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine. Neurotoxicol Teratol 47:54-65
Vorhees, Charles V; Williams, Michael T (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-32
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
Amos-Kroohs, Robyn M; Williams, Michael T; Braun, Amanda A et al. (2013) Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke. Neurotoxicol Teratol 35:34-45
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
Braun, Amanda A; Graham, Devon L; Schaefer, Tori L et al. (2012) Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats. Neurobiol Learn Mem 97:402-8
Vorhees, Charles V; Graham, Devon L; Braun, Amanda A et al. (2012) Prenatal immune challenge in rats: altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC. Synapse 66:725-37
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
Skelton, Matthew R; Graham, Devon L; Schaefer, Tori L et al. (2012) Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats. Int J Neuropsychopharmacol 15:811-24
Braun, Amanda A; Skelton, Matthew R; Vorhees, Charles V et al. (2011) Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: effects of anxiolytic and anxiogenic agents. Pharmacol Biochem Behav 97:406-15

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