Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA.
Acute and chronic complications from the substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) are linked to activation of the hypothalamic-pituitary-adrenal (HPA) axis. How MDMA activates the HPA axis is not known. HPA responses to stress are known to be mediated through the paraventricular (PVH) hypothalamus and to involve serotonin-1a (5-HT1A) receptors. We sought to determine if the PVH and 5-HT1A receptors were also involved in mediating HPA responses to MDMA. Rats were pretreated with either saline or a 5-HT1A antagonist, WAY-100635 (WAY), followed by a systemic dose of MDMA (7.5mg/kg i.v.). Animals pretreated with WAY had significantly lower plasma ACTH concentrations after MDMA. To determine if neurons in the PVH were involved, and if their involvement was mediated by 5-HT1A receptors, rats implanted with guide cannulas targeting the PVH were microinjected with the GABAA receptor agonist muscimol, aCSF, or WAY followed by MDMA. Compared to aCSF, microinjections of muscimol significantly attenuated the MDMA-induced rise in plasma ACTH (126 vs. 588pg/ml, P=<0.01). WAY had no effect. Our data demonstrates that neurons in the PVH, independent of 5-HT1A receptors, mediate ACTH responses to MDMA.
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Dmitry V
DV
Zaretsky
Maria V
MV
Zaretskaia
Joseph A
JA
Dimicco
Pamela J
PJ
Durant
Christian T
CT
Ross
Daniel E
DE
Rusyniak
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D008297:Male; D008845:Microinjections; D009118:Muscimol / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*
D010879:Piperazines; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A; D009118:Muscimol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000324:Adrenocorticotropic Hormone; D018817:N-Methyl-3,4-methylenedioxyamphetamine
3,4-methylenedioxymethamphetamine; 5-HT1A; ACTH; Adrenocorticotropic hormone; Amphetamine; HPA; MDMA; PVH; Paraventricular hypothalamus; Serotonin 1a receptors; WAY; WAY-100635; aCSF; adrenocorticotropin releasing hormone; artificial cerebrospinal fluid; hypothalamic–pituitary–adrenal axis; paraventricular hypothalamus; serotonin-1a receptors