The first experience most people have with addictive drugs occurs during adolescence and addiction may develop more quickly during adolescence than later in life. The present proposal tests the hypothesis that maturational events in presynaptic dopamine mechanisms contribute to the altered biologic reactivity of adolescents to behavioral and pharmacological stimuli. It is based on preliminary data showing greater baseline dopamine uptake, enhanced dopamine responses to cocaine and enhanced behavioral responses to cocaine in adolescent (day 28) compared to young adult (60 day old) rats. We will test this hypothesis by evaluating dopamine terminal function and dopamine responses to behavioral stimuli and drugs through adolescence. We will evaluate dopamine uptake and release through adolescence in male and female rats using both fast scan cyclic voltammetry (FSCV) in awake, behaving animals, and using in vitro preparations. First, we will determine the contribution of synaptosomal and vesicular uptake to the enhanced uptake observed in vivo. Second, we will determine the kinetics of dopamine uptake and release at baseline and after cocaine and L-Dopa using FSCV in 28, 42, 60 and 90 day old intact behaving male and female rats. Third, we will determine dopamine responses to an environmental stimulus (voluntary exposure to a novel environment) using FSCV in awake behaving animals. These studies should provide insight into potential biologic mechanisms that influence the onset of drug taking during adolescence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019114-04
Application #
7282475
Study Section
Special Emphasis Panel (ZDA1-MXS-M (11))
Program Officer
Frankenheim, Jerry
Project Start
2004-09-25
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$255,535
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Arrant, Andrew E; Coburn, Elizabeth; Jacobsen, Jacob et al. (2013) Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats. Neuropharmacology 73:359-67
Arrant, Andrew E; Schramm-Sapyta, Nicole L; Kuhn, Cynthia M (2013) Use of the light/dark test for anxiety in adult and adolescent male rats. Behav Brain Res 256:119-27
Arrant, Andrew E; Jemal, Hikma; Kuhn, Cynthia M (2013) Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine. Neuropharmacology 65:213-22
Walker, Q David; Johnson, Misha L; Van Swearingen, Amanda E D et al. (2012) Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy. Neuropharmacology 62:2267-77
Kuhn, Cynthia; Johnson, Misha; Thomae, Alex et al. (2010) The emergence of gonadal hormone influences on dopaminergic function during puberty. Horm Behav 58:122-37
Walker, Q David; Morris, Sarah E; Arrant, Andrew E et al. (2010) Dopamine uptake inhibitors but not dopamine releasers induce greater increases in motor behavior and extracellular dopamine in adolescent rats than in adult male rats. J Pharmacol Exp Ther 335:124-32
Walker, Q David; Schramm-Sapyta, Nicole L; Caster, Joseph M et al. (2009) Novelty-induced locomotion is positively associated with cocaine ingestion in adolescent rats; anxiety is correlated in adults. Pharmacol Biochem Behav 91:398-408
Schramm-Sapyta, Nicole L; Walker, Q David; Caster, Joseph M et al. (2009) Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models. Psychopharmacology (Berl) 206:1-21
Caster, J M; Kuhn, C M (2009) Maturation of coordinated immediate early gene expression by cocaine during adolescence. Neuroscience 160:13-31
Schramm-Sapyta, Nicole L; Kingsley, Megan A; Rezvani, Amir H et al. (2008) Early ethanol consumption predicts relapse-like behavior in adolescent male rats. Alcohol Clin Exp Res 32:754-62

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