Women comprise about one third of cocaine addicts. They start using cocaine earlier in life, are more sensitive to some cocaine effects and progress to dependence more rapidly. Rodents show some similarities to this pattern: cocaine elicits greater increases in cocaine-stimulated locomotion, females work harder for cocaine reinforcement and extracellular dopamine rises more than in male rats. Our preliminary findings suggest that developmental exposure to gonadal steroids contributes to sex differences in cocaine action. The purpose of this proposal is to investigate the basis for the organizational effect of gonadal steroids on forebrain dopamine systems and the behavioral response to psychomotor stimulants mediated by these systems. We will test the hypothesis that sex differences in cocaine effects reflect anatomical or functional differences in dopamine neurons established during ontogeny. To determine when steroid effects are exerted, male and female rats will be gonadectomized on postnatal day 2, prepubertally on day 25 or in adulthood, and cocaine-stimulated locomotion and electrically-stimulated dopamine overflow will be determined on postnatal day 70. To evaluate which steroid mediates these effects, rat pups will be treated with vehicle, testosterone or estrogen antagonist ICI82780 (females), an aromatase inhibitor or androgen antagonist flutamide (males) during the early postnatal window or during puberty and the same dependent measures will be assessed. Finally, to evaluate how organizational effects of steroids are manifested, the number of dopamine neurons, density of innervation, dopamine content and electrically-stimulated dopamine release in nucleus accumbens and caudate nucleus will be determined following the same treatments. These studies should provide insight into potential biologic mechanisms that influence gender differences in diseases related to dopamine neuronal function in humans including Parkinson's disease and psychostimulant addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009079-09
Application #
6661368
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Wetherington, Cora Lee
Project Start
1995-03-15
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
9
Fiscal Year
2003
Total Cost
$308,000
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Van Swearingen, Amanda E D; Sanchez, Cristina L; Frisbee, Suzanne M et al. (2013) Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha. Neuropharmacology 72:236-49
Van Swearingen, Amanda E D; Walker, Q David; Kuhn, Cynthia M (2013) Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice. Psychopharmacology (Berl) 225:707-18
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; 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
Johnson, M L; Day, A E; Ho, C C et al. (2010) Androgen decreases dopamine neurone survival in rat midbrain. J Neuroendocrinol 22:238-47
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
Naylor, Jennifer C; Li, Qiang; Kang-Park, Maeng-hee et al. (2010) Dopamine attenuates evoked inhibitory synaptic currents in central amygdala neurons. Eur J Neurosci 32:1836-42
Johnson, M L; Ho, C C; Day, A E et al. (2010) Oestrogen receptors enhance dopamine neurone survival in rat midbrain. J Neuroendocrinol 22:226-37
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

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