BRAIN AROMATASE AVAILABILITY IN STEROID USERS: PET STUDIES WITH [11C]VOROZOLE
Biegon Anat
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 1R21DA032858-01 from National Institute On Drug Abuse
Abstract: Anabolic Androgenic Steroid (AAS) use affects about 1-3% of the population and is an issue of great social, academic, and medical interest. AAS use is associated with increased rates of violent death (homicide/suicide) and earlier age of death than other illicit drug-using populations, and exhibits a significant rate of dependency among users. Medical consequences may include increased risk for cardiac events, liver toxicity, skeletal changes, and hypothyroidism, and overall higher mortality and morbidity. Currently, there are no treatments for AAS dependence or intoxication. As a first step, characterizing the neurobiological changes associated with AAS intoxication will be essential to the development of novel and effective therapeutics designed to treat AAS dependence and limit the psychiatric consequences to AAS use. The proposed study aims to identify some of the key neurobiological processes responsible for AAS intoxication in a group of active and experienced AAS- using men. By studying AAS intoxication in relation to aromatase availability, we will be able to understand functional relationships between AAS metabolism and the core psychological and behavioral changes that reinforce AAS use. Although AASs are taken primarily for their ability to change appearance or increase athletic performance, the AAS intoxication syndrome can be defined by the desirable psychological and behavioral effects of AAS use that include increases in social dominance, sex drive, aggression, goal directed behavior, and self-esteem, which all share a common increase in behavioral disinhibition. The study aims to examine two novel hypotheses 1) AAS users will have higher levels of brain aromatase than controls, and will have further elevated levels when taking AASs; 2) Regional brain aromatase availability will be positively correlated with behavioral and self-report measures of impulsivity, aggression, and sensitivity to pleasure. Two specific aims were developed to test these hypotheses A) To evaluate the effect of AAS use on regional brain aromatase availability in relation to circulating gonadal hormone levels; B) To test for a correlation between change in regional brain aromatase availability and behavioral measures of the AAS intoxication syndrome (aggression, sexual activity, impulsivity, and sensation seeking) in AAS users. These aims will be tested in a controlled longitudinal study of male AAS users (n=8) and healthy exercising controls (n=8) matched on age, exercise, and education. The results of this study will be used as pilot data for a longitudinal study of AAS dependence in which we will examine the changes in aromatase as a function of repeated AAS use. This line of research will be aimed at developing biomarkers and investigating individual differences in AAS response among "real world" AAS users. The proposed study will also provide data to develop novel therapeutic targets to prevent and treat AAS addiction; specifically, aromatase inhibitors and estrogen antagonists may be used as pharmacological agents to treat AAS intoxication. These outcomes are in concordance with NIDA´s goals to directly inform prevention and treatment efforts in this population. Contrary to that of other drugs of abuse, the intoxication syndrome of anabolic-androgenic steroid (AAS) use is characterized by a significant increase in impulsivity and aggression coinciding with desired changes in muscularity and strength. The mechanisms behind these neurobiological changes have yet to be identified, however recent animal studies have found a strong link between elevated estrogen levels and aggression. Findings from the proposed study will be the first to propose a neurological and hormonal basis for an AAS intoxication syndrome marked by increased aggression and impulsivity, and will be the first study utilizing neuroimagery on AAS users
Keywords: addiction; Adult; Affect; Age; Aggressive behavior; Amygdaloid structure; Anabolic steroids; Androgens; Androstenedione; Animals; Anti-Anxiety Agents; Appearance; Aromatase; Aromatase Inhibitors; Athletic; base; Behavior; behavior measurement; Behavioral; Binding (Molecular Function); biomarker; Brain; Brain region; Cardiac; Cessation of life; Clinical; Complex; Cytochrome P450; Data; Dependency (Psychology); design; Development; discounting; Disinhibition; Dopamine; Drug Addiction; drug of abuse; Drug usage; DSM-IV; Educational aspects; Enzymes; Esthesia; Estradiol; Estrogen Antagonists; Estrogens; Estrone; Ethnicity aspects; Euphoria; Event; Exercise; Exhibits; experience; Family; field study; Goals; Gonadal Hormones; Grant; Hepatotoxicity; Homicide; Hormonal; Human; hypothalamic pituitary gonadal axis; Hypothyroidism; Illicit Drugs; Impulsive Behavior; Impulsivity; Individual Differences; interest; Intoxication; Kinetics; Knock-out; Laboratories; Length; Libido; Link; Longitudinal Studies; male; malignant breast neoplasm; Measures; Medial; Mediating; Medical; meetings; member; men; Morbidity - disease rate; Mortality Vital Statistics; Nandrolone Decanoate; Neurobiology; Neurocognitive; Neuroendocrinology; Neurologic; new therapeutic target; novel; Outcome; Patient Self-Report; Performance; Pharmaceutical Preparations; Play; pleasure; Population; Positron-Emission Tomography; Prefrontal Cortex; Preoptic Areas; prevent; Prevention; Process; psychologic; Race; receptor; Receptor Activation; Regulation; Relative (related person); Research; response; Risk; Risk-Taking; Rodent; Role; Scanning; self esteem; Severities; Sex Behavior; skeletal; social; Social Dominance; steroid dependence; steroid metabolism; Steroids; Structure of terminal stria nuclei of preoptic region; Suicide; Syndrome; Testing; Testosterone; Thalamic structure; Therapeutic; Time; time interval; Tracer; uptake; Validation; Variant; Ventral Tegmental Area; Violence; Vorozole
Relevance: Contrary to that of other drugs of abuse, the intoxication syndrome of anabolic-androgenic steroid (AAS) use is characterized by a significant increase in impulsivity and aggression coinciding with desired changes in muscularity and strength. The mechanisms behind these neurobiological changes have yet to be identified, however recent animal studies have found a strong link between elevated estrogen levels and aggression. Findings from the proposed study will be the first to propose a neurological and hormonal basis for an AAS intoxication syndrome marked by increased aggression and impulsivity, and will be the first study utilizing neuroimagery on AAS users
Project start date: 2012-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
1R21DA032858-01 (2012): $303285
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Biegon Anat
NMDA RECEPTOR DYNAMICS AFTER BRAIN INJURY
Biegon Anat, Sr. Scientist
Brookhaven Science Assoc-brookhaven Labcity: Upton country: United States (us)
Grant 5R01NS050285-05 from National Institute Of Neurological Disorders And Stroke
Abstract: Brain injury is a leading cause of moratlity and morbidity among young people in the industrialized world. Attempts to treat accidental brain injuries with glutamate NMDA receptor (NMDAR) antagonists have failed to.produce any improvement in outcome in several major clinical trials. These trials were predicated on the hypothesis that neurological deficits after head injury are, at least in part, the result of hyperactivation of NMDAR and "excitotoxicity". The working hypothesis behind the proposed studies is three fold 1. Hyperactivation of NMDAR after head injury is short lived and gives way to prolonged hypofunction; 2. The cognitive deficits after brain injury are a results of underactivation, rather than overactivation, of NMDA receptors. 3. Delayed activation of NMDAR may accelerate recovery of function after brain injury. A secondary hypothesis postulates that some brain regions; such as the hippocampus; are inherently more vulnerable to brain injury than others. We propose to test these hypotheses in mice with closed head injury; an animal model of blunt head trauma. Regional changes in NMDAR availablility and functional (activational) state will be measured at times ranging from 5 min to 60 days after injury using quantitative autoradiography of the use-dependent ligand MK801. Physiological correlates of NMDAR hyepr-activation and hypo-activation will be measured using electrophysiology (Long term potentiation). Cognitive deficits will be tested 14 and 60 days after the injury using two different tasks; the object recognition test and the Morris water maze in animals administered with the full agonist NMDA , the partial NMDAR agonist d-Cycloserine or the antagonist MK801 at various time points and frequencies after the injury. Finally the contribution of several likely mechanisms to the dynamic changes in NMDAR after brain injury will be investigated by 1. Dose response and kinetic studies of the relationship between dose and duration of NMDAR activation and functional respone 2. Manipulating assay conditions 3. immuno-histochemical staining for the obligatory NR1 unit and the NR2 subunits of NMDAR. The proposed research focuses on the fate of NMDAR, a molecule believed to play a key role in the pathology of brain injury. Brain injury is a major public health problem since it is associated with death and long-term disability in a significant proportion of victims, who are mostly young adults. The results may explain the failure of NMDAR antagonists in clinical trials and suggest novel strategies for treatment of brain injury
Keywords: Ablation; Abscission; Acquired brain injury; Acute; adult youth; Agonist; Ammon Horn; Animal Model; Animal Models and Related Studies; Animals; Assay; Autoradiography; Bioassay; Biochemical; Biologic Assays; Biological Assay; Brain; brain damage; Brain Injuries; brain lesion (from injury); Brain region; brain tissue; Catheters; Cessation of life; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Closed head injuries; Cognitive deficits; Cornu Ammonis; Craniocerebral Trauma; Cycloserine; Death; desensitization; disability; Dose; Effects, Longterm; Electrophysiology; Electrophysiology (science); Encephalon; Encephalons; Event; Excision; excitotoxicity; Extirpation; failure; Failure (biologic function); FLR; Frequencies (time pattern); Frequency; functional loss; functional recovery; Gene Expression; Glutamates; Head Injuries; Head Injuries, Nonpenetrating; Head Trauma; Head Trauma, Closed; hippocampal; Hippocampus; Hippocampus (Brain); Human; Human, General; improved; injured; Injuries, Craniocerebral; Injury; Kinetic; Kinetics; L-Glutamate; Life; Ligands; Long-Term Effects; Long-Term Potentiation; long-term study; Longitudinal Studies; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mediating; Memory; Mice; MK 801; MK801; model organism; Modeling; Monitor; Morbidity; Morbidity - disease rate; Morphology; morris water maze; morris watermaze; Murine; Mus; N methyl D aspartate; N Methyl D aspartic Acid; N-Methyl-D-aspartate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurologic; Neurologic Dysfunctions; Neurological; neurological dysfunction; neuronal; Neurons; Neurophysiology / Electrophysiology; Neurosurgical Procedures; new approaches; NMDA; NMDA receptor antagonist; NMDA Receptor-Ionophore Complex; NMDA Receptors; novel approaches; novel strategies; novel strategy; NR1; NR1 gene; object recognition; Outcome; Pathology; Phase; Physiologic; Physiological; Play; Procedures; Public Health; public health medicine (field); Quantitative Autoradiography; R-4-Amino-3-isoxazolidi; Radioautography; receptor; Receptor Activation; receptor function; Receptor Gene; Receptor Protein; Receptors, N-Methylaspartate; Recovery of Function; Removal; Research; resection; response; Staining method; Stainings; Stains; Surgery, Neurological; Surgical Removal; Testing; Time; Trauma, Brain; traumatic brain damage; Traumatic Brain Injury; Traumatic encephalopathy; Work; young adult
Project start date: 2007-02-06
Project end date: 2011-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
5R01NS050285-05 (2011): $340291
[11C]VOROZOLE AS A PET TRACER FOR IN VIVO STUDIES OF HUMAN AROMATASE
Biegon Anat, Sr. Scientist
Brookhaven Science Assoc-brookhaven Labcity: Upton country: United States (us)
Grant 1R21EB012707-01 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: * Aromatase, the cyp19A gene product, is the enzyme responsible for estrogen synthesis. To date, there are no quantitative studies of the distribution and regulation of aromatase in living humans. Using a newly developed method of synthesis and purification, we propose to 1. Validate and characterize [11C]vorozole as a PET radiotracer for the non invasive assessment of aromatase in the brain and peripheral organs of living humans This aim will address the human dosimetry, pharmacological specificity and kinetic modeling of the radiopharmaceutical. 2. Examine the effects of age, sex and gonadal hormones on the kinetic parameters of [11C]vorozole. For this aim, PET studies will be performed in men and women, young and old, and young women will be studied at different phases of the menstrual cycle. Gonadal hormone plasma levels will be assayed in all subjects. 3. Examine the effects of cigarette smoking on aromatase availability in the brain and peripheral organs. Both smokers and non-smokers will be recruited to address this aim. The data gathered from these studies will serve as the basis for an IND application, opening the way for studies using aromatase as a biomarker for drug discovery and for pathophysiological studies of CNS disorders in various pathologies. Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer´s disease, endometriosis, liver cancer, ovarian cancer and brain injury; which affect millions in the US. The availability of a validated tracer which can be used to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors (AI) in different diseases, facilitate AI treatment monitoring and provide a tool for new AI drug development and evaluation. Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer´s disease, endometriosis, liver cancer and brain injury; which affect millions in the US and have a major impact on public health. The ability to use [11C]vorozole to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors, facilitate aromatase inhibitor treatment monitoring and provide a new tool for the development and evaluation of new aromatase inhibitors
Keywords: (17Beta)-17-hydroxyandrost-4-en-3-one; 17-beta-Hydroxy-4-Androsten-3-one; 1H-Benzotriazole, 6-((4-chlorophenyl)-1H-1, 2, 4-triazol-1-ylmethyl)-1-methyl-; 2-Pyrrolidi, 1-methyl-5-(3-pyridinyl)-, (S)-; 4, 4`-(1H-1, 2, 4-triazol-1-yl-methylene)-bis(benzonitrile); 6-((4-chlorophenyl)-(1H-1, 2, 4-triazol-1-yl)methyl)-1-methyl-1H-benzotriazole; Acquired brain injury; Address; Affect; age effect; aging effect; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Androgenic Agents; Androgenic Compounds; Androgens; Androst-4-en-17beta-ol-3-one; Androstenedione Aromatase; Androstenedione Aromatase Inhibitor; Aquadiol; Aromatase; Aromatase Cytochrome P450; Aromatase Inhibitors; Assay; base; Behavioral; Benzonitrile, 4, 4`-(1H-1, 2, 4-triazol-1-ylmethylene)bis-; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; biomarker; Blood Plasma; Brain; brain damage; Brain Injuries; brain lesion (from injury); Cancer of Breast; Cancer of the Ovary; Central Nervous System Diseases; Central Nervous System Disorders; cigarette smoking; CNS Diseases; CNS disorder; Cotinine; CYP 19; CYP19 Protein; CYPXIX; Cytochrome P-450 CYP19; Cytochrome P-450(AROM); Cytochrome P450 19; Cytochrome P450 19A1; Cytochrome P450, Family 19, Subfamily A, Polypeptide 1; Cytochrome P450, Subfamily XIX; Cytochrome P450, Subfamily XIX (Aromatization of Androgens); Data; Delta4-androsten-17beta-ol-3-one; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dimenformon; Diogyn; Diogynets; Disease; disease phenotype; disease/disorder; Disorder; Dose; dosimetry; drug development; drug discovery; Drug Evaluation; Encephalon; Encephalons; Endometriosis; endometriosis; Endometriosis, site unspecified; Enzymes; Estra-1, 3, 5(10)-triene-3, 17-diol (17beta)-; Estrace; Estradiol; Estradiol-17 beta; Estradiol-17beta; Estraldine; Estrogen Synthase; Estrogen Synthase Inhibitor; Estrogen Synthetase; Estrogen Synthetase Inhibitor; Estrogenic Agents; Estrogenic Compounds; Estrogens; Evaluation; Evaluation Studies, Drug; FDA approved; Femara; Future; gene product; Goals; Gonadal Hormones; Gonadal Steroid Hormones; gonadal steroids; Hepatic Cancer; Human; human disease; human subject; Human, General; in vivo; Kinetic; Kinetics; Letrozole; Life; liver cancer; malignant breast neoplasm; malignant liver tumor; Malignant neoplasm of breast; Malignant neoplasm of liver; Malignant neoplasm of ovary; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Breast; Malignant Tumor of the Ovary; Man (Taxonomy); Man, Modern; Measures; Medical Imaging, Positron Emission Tomography; men; men`s; Menstrual cycle; Methods; Modeling; Molecular Interaction; Monitor; Names; Nervous System, Brain; Nicotine; Non-smoker; non-smoking; nonsmoker; Novartis Brand of Letrozole; Organ; ovarian cancer; Ovocyclin; Ovocylin; P450AROM; Pathology; Patients; Peripheral; PET; PET imaging; PET Scan; PETSCAN; PETT; Phase; Plasma; Positron Emission Tomography Scan; Positron-Emission Tomography; primary degenerative dementia; Primary Senile Degenerative Dementia; Progynon; Proteins; Proton Magnetic Resonance Spectroscopic Imaging; Public Health; public health medicine (field); public health relevance; Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-; Rad.-PET; radioactive drugs; radiolabel; Radiopharmaceutical Compound; Radiopharmaceuticals; radiotracer; recruit; Recruitment Activity; Regulation; Reticuloendothelial System, Serum, Plasma; Role; Scotine; senile dementia of the Alzheimer type; Serum, Plasma; Sex Hormones; sex steroid; Sex Steroid Hormones; smoke cigarette; Smoker; social role; Specificity; Structure; Tag; Testosterone; Therapeutic Androgen; Therapeutic Estradiol; Therapeutic Estrogen; Therapeutic Testosterone; tool; tool development; Tracer; Trans-Testosterone; Vorozole; Woman
Relevance: Narrative Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer´s disease, endometriosis, liver cancer and brain injury; which affect millions in the US and have a major impact on public health. The ability to use [11C]vorozole to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors, facilitate aromatase inhibitor treatment monitoring and provide a new tool for the development and evaluation of new aromatase inhibitors
Project start date: 2011-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-023
1R21EB012707-01 (2011): $356948