ALCOHOL AND DRUG ABUSE RESEARCH CENTER
Clinical Research Laboratory
The Clinical Research Laboratory studies the biological and behavioral aspects of substance abuse in men and women who abuse or are dependent upon drugs, including nicotine, cocaine, opioids and alcohol. Multidisciplinary studies of substance abuse problems in women and the analysis of gender differences is one major focus of the ADARC clinical research program. The behavioral, neuroendocrine, cardiovascular and immunological effects of abused drugs are examined under controlled conditions in volunteers who provide informed consent, and who are not seeking treatment for drug abuse-related problems. The Clinical Research Laboratory consists of three component research programs: (1) a Neuroendocrinology Program; (2) a Brain Imaging Program and (3) a Policy Research Program.
Hormones, Drugs and Behavior
Several lines of evidence suggest that the hormonal milieu may influence behavioral responses to cocaine and other stimulant drugs. Increased levels of extracellular dopamine are an essential aspect of the reinforcing effects of cocaine, and the ovarian steroid hormone, estradiol, also stimulates dopamine synthesis and release. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis influences the reinforcing and locomotor activating effects of cocaine in preclinical studies. In clinical studies, the temporal concordance between reports of subjective high and peak levels of plasma cocaine and the anterior pituitary hormone, ACTH, are consistent with the hypothesis that perturbation of the HPA axis may contribute to cocaine's abuse-related effects. The covariance between plasma levels of cocaine and nicotine and rapid drug-induced changes in subjective, hormonal, cardiovascular effects are being examined in men and in women during the follicular and mid-luteal phases of the menstrual cycle.
Many drugs produce different biological and behavioral effects in men and women. The contribution of anterior pituitary and gonadal steroid hormones to these gender differences are poorly understood, and this question is a continuing focus of ADARC's clinical research program. Examination of the ways in which drugs modulate and are modulated by the neuroendocrine system may improve understanding of the neurobiology of drug reinforcement, as well as suggesting new medication-based approaches to treatment. Several examples of gender differences in drug effects are described below.
Cocaine and Gender Differences
In collaborative studies with the McLean Brain Imaging Center, we discovered one significant gender difference in our brain imaging SPECT studies of cocaine abusers. We found that women had fewer cocaine-related cerebral perfusion defects than men, even though women had used cocaine for longer than men. Subsequent studies using MRI procedures found that cocaine had greater vasoconstrictive effects in men than in follicular-phase women. Moreover, the vasoconstrictive effects of cocaine were greater in women during the luteal phase of the menstrual cycle then during the follicular phase when the effects of estradiol are not opposed by high levels of progesterone. These findings suggested that estradiol, an ovarian steroid hormone, may protect women from cocaine-associated cerebral vasospasm.Men also appear to be more sensitive to the stimulatory effects of cocaine on luteinizing hormone (LH) than women. A low dose of cocaine significantly increased LH in men but not in women during the follicular or the luteal phase of the menstrual cycle, whereas a high dose of cocaine increased LH in both men and women. One possible explanation for this apparent gender difference could be differences in the rate of cocaine metabolism in men and women. However, there were no gender differences in the pharmacokinetics of cocaine, administered intravenously to men and women who were matched for body mass index. In addition, no gender differences in subjective or cardiovascular responses to cocaine were detected. These findings are consistent with the notion that the hormonal differences between men and women may be one important contributor to gender differences in response to drugs.
Nicotine and Cocaine Comparisons
We have recently extended our clinical studies of cocaine to cigarette smoking and compared the behavioral and neuroendocrine effects of these drugs. Intravenous cocaine and smoking a high nicotine cigarette each produced a rapid and significant increase in LH and subjective "high" in men. The increases in LH were significantly correlated with increases in plasma levels of cocaine and nicotine. Placebo cocaine and low nicotine cigarette smoking did not alter LH or subjective reports. Although the behavioral significance of cocaine and nicotine-induced increases in LH is unclear, previous clinical studies have reported that cocaine increases sexual feelings and energy, and that there was a significant correlation between increases in LH and reports of sexual arousal and penile tumescence in young men viewing an erotic film.
Cocaine and nicotine both are associated with disruptions of the menstrual cycle and infertility in women. Ongoing studies are examining the effects of cigarette smoking on both HPA and HPG hormones in men and women who are daily smokers and are nicotine-dependent. One goal is to determine if hormone fluctuations across the menstrual cycle influence nicotine's biological and abuse-related effects. In addition, there is considerable evidence that cigarette smoking contributes to some reproductive disorders in women including infertility and early menopause. Clinical reports suggest that the nicotine has anti-estrogenic effects, but there have been no comprehensive studies of the effects of cigarette smoking on the HPG axis. A better understanding of the acute effects of nicotine in anterior pituitary, gonadal and adrenal hormones may suggest new strategies for the development of anti-nicotine medications.
Treatment Related Research
Another major focus of the ADARC Clinical Research Laboratory is the inpatient evaluation of the safety and efficacy of candidate drug abuse treatment medications. The ADARC Clinical Research Laboratory was recently awarded a contract by the National Institute on Drug Abuse to evaluate new treatment medications in Phase I and Phase II clinical trials. ADARC clinical researchers were among the first to investigate the use of a new opioid mixed agonist-antagonist, buprenorphine for the treatment of opioid dependence. There is now a general consensus that buprenorphine may be safer and more effective than methadone for the treatment of heroin dependence. In 2002, buprenorphine was approved by the Food and Drug Administration (FDA) for use as a treatment for heroin dependence. Importantly, buprenorphine can be used for outpatient treatment of heroin abuse by qualified physicians. Our studies indicate that buprenorphine may also be safe and effective for the treatment of persons with concurrent heroin and cocaine dependence. These clinical findings were validated in preclinical studies in the ADARC Behavioral Science Laboratory, where it was found that buprenorphine decreased both cocaine self-administration and cocaine + heroin (speedball) self-administration.
Parallel clinical and preclinical medication evaluations are often conducted in collaboration with the ADARC Behavioral Science Laboratory. For example, there is considerable evidence that activation of kappa opioid receptors may functionally antagonize some effects of cocaine, possibly by inhibiting dopamine release from the dopaminergic neurons. ADARC preclinical studies suggested that kappa selective opioid agonists were often effective in reducing cocaine self-administration. Moreover, kappa agonists with activity at mu opioid receptors were more effective in reducing cocaine self-administration than kappa selective agonists, and mixed mu/kappa compounds produced fewer side effects. The ADARC Medicinal Chemistry Laboratory has synthesized a series of mixed mu/kappa agonists for preclinical evaluation. Unfortunately, most of these candidate medications are not FDA approved for clinical trials in humans. However, we have identified one clinically available analgesic with both mu and kappa activity and are in the process of studying how it affects subjective, cardiovascular and endocrine responses to cocaine. These studies illustrate the productive interactions between the Clinical, Preclinical and Medicinal Chemistry Laboratories of the Alcohol and Drug Abuse Research Center.
In collaborative studies with the McLean Brain Imaging Center, we have found that it is possible to detect alcohol tolerance in the human brain with proton magnetic resonance spectroscopy procedures. Brain to blood ethanol ratios were determined using proton spectrospectric imaging to assess the putative effects of family history of alcoholism on the apparent detectability of brain alcohol. Two cohorts of men classified as light drinkers (< 10 drinks per week) with a positive (n = 8) or a negative family history (n = 8) background of alcoholism were given an alcohol dose of 0.8 g/kg body weight. No significant difference was found in the brain/blood ethanol ratios from the two groups. Subjective assessments of feeling the extreme effects of alcohol and the extent of intoxication ("how drunk"), however, were highly correlated with the family history of alcoholism. The family history negative (FHN) group reported a significantly more intense feeling of intoxication. We are currently exploring detection of alcohol tolerance in humans with procedures which involve in vitro alcohol detection in erythrocyte preparations. These studies may provide a new basis for determining the magnitude of alcohol abuse by persons who are engaged in safety sensitive positions within the transportation industry and the Department of Defense.
Representative Publications from the ADARC Clinical Research Laboratory
- Chiu T-M, Mendelson JH, Sholar MB, Mutschler N, Wines JD, Hessselbrock VM and Mello NK (2004) Brain alcohol detectability in human subjects with and without a paternal history of alcoholism. J. Stud. Alcohol 65:16-21.
- Ginsburg ES, Mello NK and Mendelson JH (2002) Alcohol abuse: Endocrine concomitants, in Hormones, Brain and Behavior (Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE and Rubin RT eds) pp 747-780, Academic Press, New York.
- Ginsburg ES, Mello NK, Mendelson JH, Barbieri RL, Teoh SK, Rothman M, Gao X and Sholar JW (1996) Effects of alcohol ingestion on estrogens in postmenopausal women. JAMA 276:1747-1751.
- Halpern JH, Sholar MB, Glowacki J, Mello NK, Mendelson JH and Siegel AJ (2003) Diminished interleukin-6 response to pro-inflammatory challenge in men and women after i.v. cocaine administration. J Clin Endo Metab. 88:1188-1193.
- Kaufman MJ, Chiu TM, Mendelson JH, Woods BT, Teoh SK, Eros-Sarnyai M, Mercer G and Mello NK (1996) Brain alcohol detectability increase with repeated administration in humans. A proton spectroscopy study. Magn Res Med 35:435-440.
- Kaufman MJ, Levin JM, Maas LC, Kukes TJ, Villafuerte RA, Dostal K, Lukas SE, Mendelson JH, Cohen BM and Renshaw PF (2001) Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biol. Psychiat. 49:774-781.
- Kaufman MJ, Levin JM, Maas LC, Rose SL, Lukas SE, Mendelson JH, Cohen BM and Renshaw PF (1998) Cocaine decreases relative cerebral blood volume in humans: A dynamic susceptibility contrast magnetic resonance imaging study. Psychopharmacology 138:76-81.
- Kaufman MJ, Levin JM, Ross MH, Lange N, Rose SL, Kukes TJ, Mendelson JH, Lukas SE, Cohen BM and Renshaw PF (1998) Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 279:376-380.
- Kaufman MJ, Pollack MH, Rose SL, Kukes TJ, Villafuerte RA, Mendelson JH, Lukas SE, Cohen BM and Renshaw PF (1999) Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance. Psychiatry Res: Neuroimag 90:143-152.
- Mello NK (1998) Cocaine abuse and reproductive function in women, in Drug Addiction Research and the Health of Women. National Institute on Drug Abuse (Wetherington CL and Roman AB eds) pp 131-149, U.S. Government Printing Office, NIH Publ. No. 98-4290, Washington, DC.
- Mendelson JH and Mello NK (1996) Drug Therapy: Management of cocaine abuse and dependence. N. Eng. J. Med. 334:965-972.
- Mendelson JH and Mello NK (2004) Cocaine and other commonly abused drugs, In: Harrison's Principles of Internal Medicine (Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL and Jameson JL eds.), 16th ed. The McGraw-Hill Co., New York, 2005.
- Mendelson JH, Mello NK, Sholar MB, Siegel AJ, Kaufman MJ, Levin JM, Renshaw PF and Cohen BM (1999) Cocaine pharmacokinetics in men and in women during the follicular and luteal phase of the menstrual cycle. Neuropsychopharmacology 21:294-303.
- Mendelson JH, Mello NK, Sholar MB, Siegel AJ, Mutschler N and Halpern J (2002) Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. Psychoneuroendocrinology. 27:71-82.
- Mendelson JH, Sholar M, Mello NK, Teoh SK and Sholar JW (1998) Cocaine tolerance: Behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology 18:263-271.
- Mendelson JH, Sholar M, Siegel AJ and Mello NK (2001) Effects of cocaine on luteinizing hormone in women during the follicular and luteal phases of the menstrual cycle and in men. J. Pharmacol. Exp. Ther. 296:972-979.
- Mendelson JH, Sholar MB, Mutschler NH, Jaszyna-Gasior M, Goletiani NV, Siegel AJ and Mello NK (2003) Effects of intravenous cocaine and cigarette smoking on luteinizing hormone, testosterone and prolactin in men. J. Pharmacol. Exp. Ther. 307:339-348.
- Sholar MB, Mendelson JH, Mello NK, Siegel AJ, Kaufman MJ, Levin JM, Renshaw PF and Cohen BM (1998) Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men. J. Clin. Endocrinol. Metab. 83:966-968.