Chronic cocaine use causes brain abnormalities and cognitive dysfunction, which may both impair a drug user's ability to resist further drug use and decrease the efficacy of treatment interventions. The severity of cocaine associated brain dysfunction is less in women than in men. Further, cocaine abuse treatment appears to benefit women more than men. These sex differences have important therapeutic implications, because they suggest a protective role for estrogen. Thus, estrogen (or a related compound) might be of therapeutic use to protect against brain vascular dysfunction. ? ? Cocaine's ability to reduce cerebral blood flow is likely to play a critical role in the development of brain dysfunction. Estrogen has been shown to acutely improve, while progesterone and testosterone acutely degrade vascular function. Consequently, vascular effects of hormones may account for sex differences in cocaine's brain effects. We seek to determine whether estrogen, progesterone, and testosterone alter cocaine pharmacokinetics and cocaine's acute cerebral vasoconstrictive effects. ? ? We will measure cocaine and hormone pharmacokinetics, and characterize cardiovascular responses after combined intravenous cocaine (0.4 mg/kg) and estrogen (men), or progesterone or testosterone (women) treatments. Subsequently, we will evaluate whether these hormones alter cocaine's acute cerebrovascular effects, using a noninvasive functional MRI technique called Dynamic Susceptibility Contrast MRI (DSC MRI). DSC MRI measures cerebral blood volume (CBV) and blood flow (CBF). Study subjects will include healthy men and women with histories of occasional cocaine use, who will each participate in a randomized, placebo-controlled, double-blind study. ? ? The pharmaceutical industry is actively developing novel steroid receptor agents with greater receptor selectivity than the natural hormones, which may improve the ability to selectively modulate vascular responses to cocaine. Thus, if our hypotheses regarding hormonal effects on cocaine-induced vasoconstriction are validated, the potential for identifying effective therapeutics for investigation in chronic treatment trials will be enhanced.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Grant, Steven J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mc Lean Hospital (Belmont, MA)
United States
Zip Code
Janes, Amy C; Smoller, Jordan W; David, Sean P et al. (2012) Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women. Drug Alcohol Depend 120:7-13
Mashhoon, Yasmin; Janes, Amy C; Jensen, J Eric et al. (2011) Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome. Prog Neuropsychopharmacol Biol Psychiatry 35:1709-13
Janes, Amy C; Pizzagalli, Diego A; Richardt, Sarah et al. (2010) Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry 67:722-9
Kaufman, Marc J; Prescot, Andrew P; Ongur, Dost et al. (2009) Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study. Psychiatry Res 173:143-9
Janes, Amy C; Frederick, Blaise deB; Richardt, Sarah et al. (2009) Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence. Exp Clin Psychopharmacol 17:365-73
Sim, Minyoung E; Lyoo, In Kyoon; Streeter, Chris C et al. (2007) Cerebellar gray matter volume correlates with duration of cocaine use in cocaine-dependent subjects. Neuropsychopharmacology 32:2229-37
Anderson, Carl M; Maas, Luis C; Frederick, Blaise deB et al. (2006) Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology 31:1318-26
Anderson, Carl M; Lowen, Steven B; Renshaw, Perry F (2006) Emotional task-dependent low-frequency fluctuations and methylphenidate: Wavelet scaling analysis of 1/f-type fluctuations in fMRI of the cerebellar vermis. J Neurosci Methods 151:52-61
Anderson, C M; Kaufman, M J; Lowen, S B et al. (2005) Brain T2 relaxation times correlate with regional cerebral blood volume. MAGMA 18:3-6
Silveri, Marisa M; Anderson, Carl M; McNeil, Jane F et al. (2004) Oral methylphenidate challenge selectively decreases putaminal T2 in healthy subjects. Drug Alcohol Depend 76:173-80

Showing the most recent 10 out of 11 publications