Use of the amphetamine MDMA (ecstasy, 3, 4-methylenedioxymethamphetamine) can result in life- threatening medical complications including fatal hyperthermia and cardiac arrhythmias. These complications result in part from simultaneous activation of the sympathetic nervous system, the hypothalamic-pituitary- adrenal axis (HPA) and somatic motor systems. It is the long-term objective of the principal investigator to identify the key brain regions and mechanisms through which MDMA activates these systems. The objective of this application is to determine the mechanism by which MDMA activates neurons in the dorsomedial hypothalamus (DMH) - a site involved in the responses evoked by MDMA - and to subsequently determine how this activation stimulates other brain regions involved in sympathetic, somatic motor and neuroendocrine responses. In the DMH, neuronal activity appears to depend on the balance between inhibitory and excitatory inputs from two key brain regions: inhibitory (GABAergic) projections from the medial preoptic area (mPOA) and excitatory (glutamatergic) projections from the lateral/dorsolateral periaqueductal gray (l/dlPAG). Once activated, neurons in the DMH then send excitatory signals to brain regions involved in activating the HPA axis (paraventricular nucleus, PVN) and sympathetic cardiovascular and temperature responses (medullary raphe pallidus, rPa). The activity of neurons within these areas (the DMH, mPOA, l/dlPAG, PVN and rPa) appears to be governed by glutamatergic and GABAergic neurotransmission.
The specific aims of this grant will define the roles that these brain regions play in MDMA-induced responses. These studies will be performed in freely moving conscious rats using the following three complimentary experimental techniques: (1) immunohistochemical techniques to identify the putative GABAergic and glutamatergic neurons projecting to and from the DMH that are involved in MDMA-evoked responses;(2) microinjection techniques to determine the effects of inhibiting or exciting the regions of interest on MDMA-evoked responses;and (3) microdialysis techniques to determine how inhibiting or exciting the regions of interest affect GABAergic and glutamatergic neurotransmission in the DMH. The proposed research is significant because understanding the central pathways and mechanisms responsible for toxicity associated with the use of substituted amphetamines provides the necessary framework for rational treatment and prevention strategies. In addition these results may lead to treatments for medical conditions that, like MDMA, involve pathophysiologic activation of sympathetic, somatic motor and neuroendocrine systems: serotonin syndrome;cocaine toxicity, neuroleptic malignant syndrome;dysautonomia from brain injury, and heat stroke.

Public Health Relevance

Abuse of the amphetamine 3,4-methylenedoxymethamphetamine (ecstasy, MDMA) can result in life-threatening medical complication including heart attacks, heart failure, muscle breakdown and severe elevations in body temperature. By identifying the brain areas and chemical receptors responsible for causing MDMA's toxicity, our research may lead to new and innovative treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026867-03
Application #
8263783
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$336,105
Indirect Cost
$117,855
Name
Indiana University-Purdue University at Indianapolis
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Molkov, Yaroslav I; Zaretskaia, Maria V; Zaretsky, Dmitry V (2014) Meth math: modeling temperature responses to methamphetamine. Am J Physiol Regul Integr Comp Physiol 306:R552-66
Zaretsky, Dmitry V; Zaretskaia, Maria V; Dimicco, Joseph A et al. (2013) Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA. Neurosci Lett 555:42-6
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