There has been little study of biologic factors which influence drug addiction in women. Recent studies suggest that women may be more sensitive to some effects of locomotor stimulants like cocaine. The purpose of the present proposal is to investigate possible biologic factors which might lead to differential effects of stimulants in males and females. Our previous studies have documented a robust gender difference in the locomotor response to cocaine in rats that is accompanied by markedly enhanced dopamine release as assessed with fast-scan cyclic voltammetry (FSCV) in intact brain and brain slices. The goal of the present proposal is to test the hypothesis that the integration of rapid membrane effects of estrogen on dopamine release and slow effects on dopamine transporter synthesis mediate the greater response of female rats to the locomotor stimulant actions of cocaine and the enhanced dopamine release that females demonstrate relative to males. To test this hypothesis, we plan to compare the ability of estrogen (E), progesterone (P), E+P or testosterone (T) receptors to influence locomotor responses to cocaine and dopamine release in ovariectomized (OVX) or castrated (CAS) rats, using dose response, time course and pharmacologic specificity studies of hormone effects. Dopamine uptake and release will be assessed using in vivo and in vitro FSCV. The last specific aim will address the related hypothesis that these effects of E, P or T are indirect, and mediated through central actions of CRF and/or corticosterone. These studies should provide insight into basic mechanisms which mediate gender differences in dopaminergic function and the effects of locomotor stimulants which depend upon dopaminergic transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA009079-04
Application #
2619855
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Wetherington, Cora Lee
Project Start
1995-03-15
Project End
2002-01-31
Budget Start
1998-03-15
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
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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