Ecstasy and the Dorsomedial Hypothalamus

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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-thyroid- adrenal 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.