Ecstasy and the Dorsomedial Hypothalamus

Summary

Principal Investigator: D E Rusyniak
Affiliation: Indiana University
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] MDMA (ecstasy, 3, 4-methylenedioxymethamphetamine) is a popular drug of abuse with rising use being coupled with increasing reports of medical complications and emergency department visits. MDMA abuse has been linked with hyperthermia, cardiovascular collapse, renal failure and death. Previous studies have shown that MDMA's toxic effects are dependent on the activation of the hypothalamic-pituitary-thyroidadrenal axis and the sympathetic nervous system. Activation of these systems likewise occurs during stress where it appears to be dependent on the activation of neurons in the region of the dorsomedial hypothalamus (DMH). Many of the physiologic effects of MDMA can be replicated by chemical stimulation of neurons in the area of the DMH. These effects include increases in heart rate (HR), mean arterial pressure (MAP), temperature, plasma ACTH and locomotor activity. Along with physiologic similarities, the DMH is an anatomic area rich in norepinephrine and dopamine, both integral in mediating MDMA's effects. Based on these findings, it is our central hypothesis that MDMA causes acute increases in norepinephrine and dopamine release in the DMH activating key effector sites involved in the stimulation of the HPTA axis and the sympathetic nervous system. Ultimately activation of these systems causes hyperthermia, tachycardia, hypertension, and cutaneous vasoconstriction, effects which are amplified in a warm environment. Specific Aims: The specific aims of this grant will (1) Characterize the role of neurons in the DMH in mediating MDMA's activation of neuroendocrine and sympathetic nervous systems in both normal and elevated ambient temperatures, (2) Identify key brain regions whose activation by MDMA is mediated through the DMH (3) Characterize changes in catecholamines in the DMH resulting from administration of MDMA. These studies will be performed in freely moving conscious rats using techniques of; microinjection, biotelemetric physiologic monitoring, radioimmunoassay for the markers of neuroendocrine activation, HPLC analysis of serum and brain catecholamines, microdialysis and C-fos immunohistochemistry. Relevance: The research proposed in this application is significant because through the understanding of the central pathways responsible for MDMA's toxic effects we will come closer to the development of improved treatment strategies for persons abusing MDMA as well as others stimulants. Goals: Through a comprehensive training program including didactic course work and mentored research training it is the goal of the proposal to provide the necessary training and education for the applicant's development as an independent investigator. [unreadable] [unreadable] [unreadable] [unreadable]
Funding Period: 2006-04-15 - 2011-03-31
more information: NIH RePORT

Top Publications

  1. pmc Neurologic manifestations of chronic methamphetamine abuse
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, 1050 Wishard Boulevard, Room 2200, Indianapolis, IN 46202, USA
    Psychiatr Clin North Am 36:261-75. 2013
  2. pmc The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neurosci Lett 498:162-6. 2011
  3. pmc Stress-free microinjections in conscious rats
    Dmitry V Zaretsky
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Neurosci Methods 199:199-207. 2011
  4. pmc Neurologic manifestations of chronic methamphetamine abuse
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, 1050 Wishard Boulevard, Room 2200, Indianapolis, IN 46202, USA
    Neurol Clin 29:641-55. 2011
  5. ncbi 3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors
    Daniel E Rusyniak
    Departments of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    J Pharmacol Exp Ther 323:477-87. 2007
  6. pmc When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists
    D E Rusyniak
    Departments of Emergency Medicine and Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neuroscience 154:1619-26. 2008
  7. pmc Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 2859, USA
    Brain Res 1226:116-23. 2008

Scientific Experts

Detail Information

Publications7

  1. pmc Neurologic manifestations of chronic methamphetamine abuse
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, 1050 Wishard Boulevard, Room 2200, Indianapolis, IN 46202, USA
    Psychiatr Clin North Am 36:261-75. 2013
    ..Understanding the chronic neurologic manifestations of Meth abuse will better arm practitioners with the diagnostic and therapeutic tools needed to make the Meth epidemic one of historical interest only...
  2. pmc The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neurosci Lett 498:162-6. 2011
    ....
  3. pmc Stress-free microinjections in conscious rats
    Dmitry V Zaretsky
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Neurosci Methods 199:199-207. 2011
    ..In this report we describe the details of this technique in conscious rats and provide examples of the effects and the reproducibility of a 100 nL drug injection on cardiovascular function...
  4. pmc Neurologic manifestations of chronic methamphetamine abuse
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, 1050 Wishard Boulevard, Room 2200, Indianapolis, IN 46202, USA
    Neurol Clin 29:641-55. 2011
    ....
  5. ncbi 3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors
    Daniel E Rusyniak
    Departments of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    J Pharmacol Exp Ther 323:477-87. 2007
    ..These results demonstrate that although hypothermia mediated by both MDMA and DPAT shares a common dependence on the activation of 5-HT(1A) receptors, the location of these receptors is different for each drug...
  6. pmc When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists
    D E Rusyniak
    Departments of Emergency Medicine and Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neuroscience 154:1619-26. 2008
    ....
  7. pmc Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses
    Daniel E Rusyniak
    Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 2859, USA
    Brain Res 1226:116-23. 2008
    ..These results indicate that neuronal activity in the DMH is necessary for the sympathetic and behavioral responses evoked by MDMA...