Dexmedetomidine increases the cocaine seizure threshold in rats.
BACKGROUND
Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats.


METHODS
Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group.


RESULTS
Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold.


CONCLUSIONS
These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.
Whittington
Robert A
RA
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. raw9@columbia.edu
Virag
Laszlo
L
Vulliemoz
Yvonne
Y
Cooper
Thomas B
TB
Morishima
Hisayo O
HO
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020927:Dexmedetomidine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*
D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D003042:Cocaine; D004298:Dopamine