Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment

Dmitry V. Zaretsky, Maria V. Zaretskaia, Pamela J. Durant, Daniel E. Rusyniak

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The central mechanisms through which 3,4-methylenedioxymethamphetamine (MDMA) mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; additionally, either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32°C and microinjected with either control or the gamma-aminobutyric acid (GABA) agonist muscimol (80 pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg−1). To prevent undue suffering, a core temperature of 41°C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA-evoked hyperthermia.

Original languageEnglish (US)
Article numbere00031
JournalPharmacology Research and Perspectives
Volume2
Issue number2
DOIs
StatePublished - Apr 2014

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Brown Adipose Tissue
Hypothalamus
Fever
Locomotion
Mortality
Tail
Temperature
Thermogenesis
Vasoconstriction
Skin
Arteries
Hot Temperature
GABA Agonists
Muscimol
Brain
Body Temperature
Psychological Stress
Intravenous Injections
Blood Vessels

Keywords

  • Ambient temperature
  • MDMA
  • cutaneous blood flow
  • dorsomedial hypothalamus
  • hyperthermia
  • interscapular brown adipose tissue
  • locomotion
  • medullary raphe pallidus
  • thermoregulation

ASJC Scopus subject areas

  • Neurology
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment",
abstract = "The central mechanisms through which 3,4-methylenedioxymethamphetamine (MDMA) mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; additionally, either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32°C and microinjected with either control or the gamma-aminobutyric acid (GABA) agonist muscimol (80 pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg−1). To prevent undue suffering, a core temperature of 41°C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA-evoked hyperthermia.",
keywords = "Ambient temperature, MDMA, cutaneous blood flow, dorsomedial hypothalamus, hyperthermia, interscapular brown adipose tissue, locomotion, medullary raphe pallidus, thermoregulation",
author = "Zaretsky, {Dmitry V.} and Zaretskaia, {Maria V.} and Durant, {Pamela J.} and Rusyniak, {Daniel E.}",
year = "2014",
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T1 - Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment

AU - Zaretsky, Dmitry V.

AU - Zaretskaia, Maria V.

AU - Durant, Pamela J.

AU - Rusyniak, Daniel E.

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N2 - The central mechanisms through which 3,4-methylenedioxymethamphetamine (MDMA) mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; additionally, either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32°C and microinjected with either control or the gamma-aminobutyric acid (GABA) agonist muscimol (80 pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg−1). To prevent undue suffering, a core temperature of 41°C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA-evoked hyperthermia.

AB - The central mechanisms through which 3,4-methylenedioxymethamphetamine (MDMA) mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; additionally, either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32°C and microinjected with either control or the gamma-aminobutyric acid (GABA) agonist muscimol (80 pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg−1). To prevent undue suffering, a core temperature of 41°C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA-evoked hyperthermia.

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KW - cutaneous blood flow

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KW - hyperthermia

KW - interscapular brown adipose tissue

KW - locomotion

KW - medullary raphe pallidus

KW - thermoregulation

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