The orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress

Abstract We recently discovered that inhibiting neurons in the dorsomedial hypothalamus (DMH) attenuated hyperthermia, tachycardia, hypertension, and hyperactivity evoked by the substituted amphetamine 3, 4-methylenedioxymethamphetamine (MDMA). Neurons that synthesize orexin are also found in the re...

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Bibliographic Details
Published in:Physiology & behavior 2012-12, Vol.107 (5), p.743-750
Main Authors: Rusyniak, Daniel E, Zaretsky, Dmitry V, Zaretskaia, Maria V, Durant, Pamela J, DiMicco, Joseph A
Format: Article
Language:English
Subjects:
amphetamine
Amphetamines
Animals
antagonists
Behavioral psychophysiology
Benzoxazoles - pharmacology
Biological and medical sciences
Blood Pressure - drug effects
Blood Pressure - physiology
Body Temperature - drug effects
Body Temperature - physiology
dose response
Dose-Response Relationship, Drug
fever
Fundamental and applied biological sciences. Psychology
GABA-A Receptor Agonists - pharmacology
heart rate
hypertension
hypothalamus
Male
Medical sciences
Methamphetamine - antagonists & inhibitors
Methamphetamine - pharmacology
monoamines
Muscimol - pharmacology
neurons
Neuropharmacology
Orexin
Orexin Receptors
pharmacology
Pharmacology. Drug treatments
Psychiatry
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychology. Psychophysiology
Psychopharmacology
Rats
Rats, Sprague-Dawley
receptors
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - physiology
Receptors, Neuropeptide - antagonists & inhibitors
Receptors, Neuropeptide - physiology
Stress
Stress, Psychological - drug therapy
Stress, Psychological - physiopathology
Sympathetic Nervous System - drug effects
Sympathetic Nervous System - physiology
Thermoregulation
Urea - analogs & derivatives
Urea - pharmacology
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Summary:Abstract We recently discovered that inhibiting neurons in the dorsomedial hypothalamus (DMH) attenuated hyperthermia, tachycardia, hypertension, and hyperactivity evoked by the substituted amphetamine 3, 4-methylenedioxymethamphetamine (MDMA). Neurons that synthesize orexin are also found in the region of the DMH. As orexin and its receptors are involved in the regulation of heart rate and temperature, they would seem to be logical candidates as mediators of the effects evoked by amphetamines. The goal of this study was to determine if blockade of orexin-1 receptors in conscious rats would suppress cardiovascular and thermogenic responses evoked by a range of methamphetamine (METH) doses. Male Sprague–Dawley rats (n = 6 per group) were implanted with telemetric transmitters measuring body temperature, heart rate, and mean arterial pressure. Animals were randomized to receive pretreatment with either the orexin-1 receptor antagonist SB-334867 (10 mg/kg) or an equal volume of vehicle. Thirty minutes later animals were given intraperitoneal (i.p.) injections of either saline, a low (1 mg/kg), moderate (5 mg/kg) or high (10 mg/kg) dose of METH. Pretreatment with SB-334867 significantly attenuated increases in body temperature and mean arterial pressure evoked by the moderate but not the low or high dose of METH. Furthermore, animals treated with SB-334867, compared to vehicle, had lower temperature and heart rate increases after the stress of an i.p. injection. In conclusion, temperature and cardiovascular responses to a moderate dose of METH and to stress appear to involve orexin-1 receptors. The failure to affect a low and a high dose of METH suggests a complex pharmacology dependent on dose. A better understanding of this may lead to the knowledge of how monoamines influence the orexin system and vice versa.
ISSN:0031-9384
1873-507X
DOI:10.1016/j.physbeh.2012.02.010