Elevated environmental temperatures can induce hyperthermia during d-fenfluramine exposure and enhance 5-hydroxytryptamine (5-HT) depletion in the brain.
d-Fenfluramine (d-Fen) has been demonstrated to alter body temperature (BT), decrease 5-hydroxytryptamine (5-HT) and decrease 5-HT plasma membrane transporters (PMT) in rats. Therefore, experiments were designed to test whether a correlation existed between elevated BT and brain 5-HT depletions. It was hypothesized that d-Fen would induce hyperthermia if the environmental temperature was elevated. Experiments were conducted to determine 1) the dose-response of d-Fen on BT in a 28 degrees C environment, 2) the acute effect of d-Fen on long-term depletion of 5-HT and 5-HT PMT in a 4 degrees C, 22 degrees C or 28 degrees C environment and 3) the effect of a 22 degrees C environment vs. a 28 degrees C environment on the plasma levels of d-Fen and d-norfenfluramine. d-Fen produced a dose-dependent elevation of BT in the 28 degrees C environment, decreased BT in the 4 degrees C environment and had no effect on BT in the 22 degrees C environment. Exposure to d-Fen in the 4 degrees C or 22 degrees C environment reduced 5-HT and 5-HT PMT concentrations compared with control. However, greater reductions of 5-HT and 5-HT PMT concentrations occurred in the 28 degrees C environment. Conversely, the plasma levels of d-Fen and d-norfenfluramine were not altered. Thus these experiments demonstrate that increased BT during d-Fen exposure occurs at elevated environmental temperatures without altering the plasma concentrations of the drug and results in an enhanced long-term depletion of brain 5-HT and 5-HT PMT.
Stewart
C W
CW
University of Arkansas for Medical Sciences, Department of Pharmacology and Toxicology, Little Rock, Arkansas, USA.
Bowyer
J F
JF
Slikker
W
W
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D002352:Carrier Proteins / Q000032:analysis; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D002352:Carrier Proteins; D005277:Fenfluramine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat