2007 — 2011 |
Mello, Nancy K. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Drug Abuse Research Training Program
DESCRIPTION (provided by applicant): This is a competing continuation application for a NIDA Postdoctoral Research Training Program at the Alcohol and Drug Abuse Research Center, McLean Hospital and Harvard Medical School. The program goals are to train M.Ds and Ph.Ds in clinical and preclinical research on drug abuse, and to prepare trainees for an independent research career. Trainees can participate in interdisciplinary studies involving Behavioral Science, Brain Imaging, Endocrinology, Medicinal Chemistry, Neurobiology, Neuroscience and Pharmacology with mentors from a 13-member faculty. These disciplines are integrated across basic and clinical projects to study the influence of gender and neuroendocrine hormones on the abuse-related effects of drugs, and to evaluate novel biologic and pharmacologic drug abuse treatment medications. The program is individually tailored to meet each trainee's interests and career goals. Clinical fellows can be trained in translational research on drug abuse treatment, clinical laboratory evaluations of new treatment medications, neuroendocrine and brain imaging measures (fMRI) of the acute and chronic effects of abused drugs. Preclinical fellows can be trained in medicinal chemistry, brain imaging techniques and operant behavioral procedures designed to evaluate candidate treatment medications. Trainees can also study the interactions between abused drugs and the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonadal axis, and analyze the analgesic efficacy of novel opioids. Trainees initially participate in one or more ongoing research projects with their mentors. Then trainees design an independent research project, compatible with the overall research goals of the program, that could form the basis for a research application. Trainees are taught about ethical issues that affect research, and learn about IRB and IACUC procedures. Trainees take courses, participate in a journal club, attend lectures and present research findings at scientific meetings. Six postdoctoral fellows (levels 0, 2,4,7) will be trained for 2 or 3 years. Twenty-seven of our 30 recent trainees now have independent research careers. Drug abuse is a major public health problem that afflicts many individuals and their families. Training young scientists in interdisciplinary translational research is the best strategy for learning about the multiple determinants of this complex biobehavioral disorder, and for developing more effective approaches to treatment and prevention.
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0.907 |
2008 — 2011 |
Mello, Nancy K. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex/Gender Factors in Nicotine Addiction
DESCRIPTION (provided by applicant): This is a revised application entitled "Sex/Gender Factors in Nicotine Addiction" submitted in response to PA-07-329. Cigarette smoking is one of the most prevalent addictive disorders and is associated with a number of debilitating diseases (e.g., lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis) that result in an estimated 438,000 deaths each year. Sex and gender factors in nicotine addiction are poorly understood, and we hypothesize that the hormonal milieu is one critical influence on the abuse-related effects of smoking. We propose preclinical behavioral studies to determine how sex and menstrual cycle phase influence nicotine self-administration, and how acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) alters the reinforcing effects of nicotine. Nonhuman primates are excellent models of drug self-administration and neuroendocrine control of the macaque menstrual cycle is very similar to that of women. Nicotine self- administration will be maintained on a progressive-ratio schedule that requires an increasing number of responses for successive nicotine injections. The dependent variables will be the number of nicotine injections self-administered, the rate of operant responding, and the progressive ratio "break point", i.e., the ratio at which animals stop responding for nicotine. In studies designed to examine the influence of sex and the menstrual cycle on nicotine self- administration, progesterone and estradiol levels will be measured to objectively define phases of the menstrual cycle and to distinguish between ovulatory and anovulatory menstrual cycles. We hypothesize that females will self-administer more nicotine and reach higher break points on a progressive ratio schedule than males. Next, we will examine the effects of acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) on nicotine self-administration dose-effect curves in gonadectomized males and females where basal steroid hormone levels are low. We hypothesize that estradiol and testosterone will enhance the reinforcing effects of nicotine, and that progesterone will attenuate the reinforcing effects of nicotine in females to a greater extent than in males. Steroid hormone receptor antagonists will be used to determine the hormone specificity of behavioral effects observed. Finally, the reinforcing effects of gonadal steroid hormones alone will be compared in males and females before and after gonadectomy. The neuroactive steroid hormones provide a novel approach to the treatment of a number of psychiatric disorders as well as drug abuse. The proposed studies may translate into new and more effective approaches to the treatment of nicotine addiction and will advance our understanding of its basic neurobiology. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many debilitating and lethal disorders (lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis), yet effective treatments remain elusive. We propose to study how sex and neuroactive gonadal steroids influence the abuse-related effects of nicotine (the main addictive component of tobacco) in males and females. We hypothesize that the neuroactive gonadal steroid hormones may offer a novel biologic approach to the treatment of nicotine addiction, in part because these neuroactive hormones are being used to treat a number of psychiatric disorders, including depression and anxiety, and may have therapeutic applications in drug dependence.
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0.907 |
2009 — 2010 |
Mello, Nancy K. |
N01Activity Code Description: Undocumented code - click on the grant title for more information. |
Assessment of Potential Cocaine Pharmacotherapies in Monkeys
The primary objective of the proposed studies is to provide sensitive, efficient and standardized behavioral evaluations of test compounds that may be useful for the treatment of cocaine abuse and dependence. Studies will be carried out by means of well-established protocols in nonhuman primates. New procedures will be developed if requested by NIDA. Careful records of all compounds tested under both Tasks 1 and 2 will be maintained throughout the contract period as specified by NIDA, and regualr reports will be filed as required. Test compounds provided by NIDA will be tested for their ability to antagonize the discriminative stimulus effects of cocaine.
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0.907 |
2009 — 2012 |
Mello, Nancy K. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preclinical Evaluation of Medications to Treat Polydrug Addiction
DESCRIPTION (provided by applicant): This is a new application in response to NIDA Program Announcement PAS-08-186 for Medications Development for Polydrug Addiction Treatment. The concurrent use of cocaine + heroin and cocaine + nicotine are prevalent forms of polydrug abuse, and are associated with significant public health problems, including cancer, pulmonary and cardiovascular disease and HIV/AIDS. We developed the first preclinical model of cocaine + heroin (speedball) addiction, and now we propose to develop a new polydrug model of cocaine + nicotine abuse. These two models will be used to identify and evaluate medications for the treatment of dual addiction to cocaine in combination with heroin or nicotine. Polydrug abuse involving two or more drugs is a complex treatment challenge, and often the effectiveness of a medication is not predictable from its known pharmacology. To facilitate translation of the most effective treatment approaches into clinical practice, we propose to evaluate a pharmacologically diverse series of medications that are FDA approved for other indications. These medications include anxiolytics, antidepressants, nicotinic partial agonists, stimulants, and an opioid mixed agonist antagonist. Each medication has been shown to reduce the abuse-related effects of cocaine, heroin, or nicotine alone in clinical or preclinical studies. We hypothesize that medications that effectively reduce cocaine self-administration may also be effective in reducing the abuse-related effects of cocaine in combination with nicotine or heroin. Well-validated behavioral procedures are proposed to evaluate the effects of these medications on the abuse-related effects of cocaine and polydrug combinations of cocaine + heroin or nicotine. Drug discrimination procedures will be used to characterize the potency, time-course and stimulus characteristics of polydrug combinations, and candidate treatment medications. In drug self-administration studies, medications will be administered chronically to model clinical treatment programs. Chronic treatment is necessary to determine the stability of medication effects, the severity and duration of any adverse side effects, and to monitor possible medication withdrawal signs when treatment is discontinued. The selectivity of medication effects will be determined with a second-order schedule of drug- and food-maintained responding. The abuse liability of the most effective medications will also be examined. A progressive-ratio procedure will be used to compare the relative effectiveness of treatment medications as well as the extent to which the reinforcing efficacy of polydrug combinations is altered. These multi-disciplinary studies will facilitate translation of novel polydrug abuse medications into clinical treatment. PUBLIC HEALTH RELEVANCE: Polydrug addiction to cocaine in combination with heroin or nicotine is a significant public health problem associated with cancer, cardiovascular and pulmonary disorders and HIV/AIDS. We propose to evaluate the effectiveness of medications that are clinically available for other indications for treatment of addiction in preclinical models of polydrug abuse involving cocaine + heroin and cocaine + nicotine. This strategy will facilitate translation of the most effective treatment medications into clinical trials.
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0.907 |
2010 — 2013 |
Mello, Nancy K. Renshaw, Perry Franklin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex/Gender and Nicotine Addiction: Hormones, Behavior and Neuroimaging
DESCRIPTION (provided by applicant): This is a revised application (A2) for interdisciplinary behavioral, neuroendocrine and neuroimaging studies of sex differences in response to nicotine submitted in response to NIDA PA-07-329. Among the addictive disorders, nicotine addiction is one of the most pervasive, and is associated with a number of potentially lethal diseases (lung cancer, cardiovascular and respiratory disease) that result in an estimated 448,000 deaths each year. Improved treatments for nicotine addiction are urgently needed, and will be facilitated by advances in our understanding of the basic neurobiology of nicotine. We propose clinical studies to examine the covariance between the hormonal, behavioral and neuroimaging effects of nicotine in nicotine- dependent men and women to determine if there are significant sex differences. Women will be studied during the mid-follicular and the mid-luteal phase of the menstrual cycle to determine if the effects of nicotine are influenced by changes in the neuroactive gonadal steroid hormones that define phases of the menstrual cycle. Functional magnetic resonance imaging (fMRI) will be used to study regional changes in brain activity. The effects of IV nicotine and placebo nicotine on neuronal activity in brain areas with a high density of nicotinic receptors, and also in regions that may be important drug reward pathways will be measured over time, and correlated with subjective and hormonal responses. Nicotine (0, 1.0 or 2.0 mg/70 kg, IV) will be administered under double-blind conditions. Samples for analysis of hypothalamic-pituitary-adrenal and gonadal hormones will be collected every 2 min to examine the temporal covariance with neuroimaging activation patterns and reports of subjective effects. We hypothesize that neuronal and hormonal activation and positive subjective responses to IV nicotine administration will be greater in men than in women. We also hypothesize that women will have greater neuronal and hormonal activation and positive responses to nicotine during the follicular phase of the menstrual cycle (when neuroactive steroid hormone levels are low) than during the luteal phase of the menstrual cycle (when neuroactive steroid hormone levels are high). Because the neuroactive steroid hormones are being used to treat a number of psychiatric disorders including drug abuse, this could lead to novel treatments for nicotine addiction. The results of these translational studies will increase our understanding of the interaction between sex, hormones, and the abuse-related effects of nicotine. These interdisciplinary studies will integrate behavioral, hormonal and neuroimaging measures to provide a comprehensive analysis of how sex differences and phases of the menstrual cycle may affect the abuse- related effects of nicotine. Advances in understanding the basic neurobiology of nicotine will inform efforts to develop better pharmacologic interventions to treat nicotine addiction. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many potentially lethal disorders (lung cancer, cardiovascular and respiratory disease), yet effective treatments remain elusive. Sex differences in response to smoking and other abused drugs are important factors in disease progression and in relapse. We propose to study how sex and phase of the menstrual cycle may influence the hormonal, neuroimaging and abuse-related effects of nicotine (the main addictive component of tobacco) in nicotine- dependent men and women.
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0.907 |