Gender differences in response to psychostimulants have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to psychostimulants remain for the most part, unexplained. The common observation is that females are more sensitive to psychostimulants, such as cocaine. Our hypothesis is: Activational as well as organizational effects of gonadal hormones on dopaminergic systems provide the underlying basis for the gender differences in behavioral sensitization produced by repeated IV cocaine administration. First, we will determine whether pharmacokinetic differences between the sexes result in higher levels of cocaine in the female brain. We have successfully developed a technically simple, economical and practical non-tethered technique for repeatedly administering cocaine IV to freely moving, group-housed, rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking cocaine levels following IV dosing in rats, which is similar to that observed in humans, as opposed to SC, PO, or IP dosing. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of cocaine. Second, we will determine whether gonadal hormones regulate the expression of gender differences in response to cocaine in adulthood. We will test the ability of gonadal hormones to modulate dopamine receptor responsiveness to chronic cocaine administration. Third, we will determine whether the brain organizational effect of the perinatal hormonal milieu mediates the gender differences in cocaine responsiveness. We have pharmacologically characterized a recently discovered unique dopamine receptor subtype (D3) which is localized to the striatum/nucleus accumbens region of the brain. We hypothesize that alterations in dopaminergic systems, in particular the D3 receptor system, underlie the gender differences produced by repeated IV cocaine administration. Our long-term goal is to determine the role of the dopamine neurochemical system (emphasizing the dopamine D3 receptors) in gender differences following repeated IV cocaine administration. The ultimate goal of this research is to develop pharmacological interventions to assist in correcting the behavioral problems associated with chronic cocaine abuse in humans, and specifically to provide potential insight into effective treatment strategies for women drug abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011337-03
Application #
6174693
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Wetherington, Cora Lee
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$238,320
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Aksenov, Michael Y; Aksenova, M V; Mactutus, C F et al. (2012) D1/NMDA receptors and concurrent methamphetamine+ HIV-1 Tat neurotoxicity. J Neuroimmune Pharmacol 7:599-608
Aksenov, M Y; Aksenova, M V; Mactutus, C F et al. (2010) HIV-1 protein-mediated amyloidogenesis in rat hippocampal cell cultures. Neurosci Lett 475:174-8
Adams, Sheila M; Aksenova, Marina V; Aksenov, Michael Y et al. (2010) ER-? mediates 17?-estradiol attenuation of HIV-1 Tat-induced apoptotic signaling. Synapse 64:829-38
Aksenova, Marina V; Aksenov, Michael Y; Adams, Sheila M et al. (2009) Neuronal survival and resistance to HIV-1 Tat toxicity in the primary culture of rat fetal neurons. Exp Neurol 215:253-63
Aksenov, Michael Y; Aksenova, Marina V; Mactutus, Charles F et al. (2009) Attenuated neurotoxicity of the transactivation-defective HIV-1 Tat protein in hippocampal cell cultures. Exp Neurol 219:586-90
Harrod, Steven B; Booze, Rosemarie M; Mactutus, Charles F (2007) Sex differences in nicotine levels following repeated intravenous injection in rats are attenuated by gonadectomy. Pharmacol Biochem Behav 86:32-6
Aksenov, Michael Y; Aksenova, Marina V; Nath, Avindra et al. (2006) Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: the role of oxidative stress and D1 dopamine receptor. Neurotoxicology 27:217-28
Aksenova, Marina V; Silvers, Janelle M; Aksenov, Michael Y et al. (2006) HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: changes in dopamine transporter binding and immunoreactivity. Neurosci Lett 395:235-9
Harrod, Steven B; Mactutus, Charles F; Browning, Catherine E et al. (2005) Home cage observations following acute and repeated IV cocaine in intact and gonadectomized rats. Neurotoxicol Teratol 27:891-6
Harrod, Steven B; Booze, Rosemarie M; Welch, Marion et al. (2005) Acute and repeated intravenous cocaine-induced locomotor activity is altered as a function of sex and gonadectomy. Pharmacol Biochem Behav 82:170-81

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