5-HT3 receptor antagonists inhibit morphine-induced stimulation of mesolimbic dopamine release and function in the rat.
The effects of three different 5HT3 receptor antagonists, granisetron, ICS 205-930 and ondansetron (0.01, 0.1 and 1 mg/kg, s.c.) were tested on changes in mesolimbic dopamine function produced by 1 mg/kg of morphine in the rat. Increases of in vivo dopamine release and stimulation of behavioural activity (grooming, locomotion, rearing and sniffing) were monitored. Morphine (0.5 and 1 mg/kg, s.c.) increased dose-dependently the concentration of dopamine in dialysates obtained from the nucleus accumbens. This action of morphine was inhibited by the opiate antagonist naloxone (1 mg/kg, s.c.). Morphine (0.5 and 1 mg/kg) stimulated behavioural activity, which in the early part of the time course corresponded closely with the increase of dopamine in the nucleus accumbens. Pretreatment with 1 mg/kg (s.c.) of granisetron resulted in moderate inhibition (28%) of the morphine-induced stimulation of the extracellular dopamine levels, while doses of 0.01 and 0.1 mg/kg (s.c.) had no effect. The highest dose of granisetron (1 mg/kg, s.c.) also significantly reduced the morphine-induced enhancement of behavioural activity. The fact that granisetron attenuated morphine-induced effects on mesolimbic DA only at the highest dose tested (1 mg/kg, s.c.) was also true for ICS 205-930 and ondansetron. It is concluded that 5HT3 receptor antagonists partially inhibit, with low potency, the morphine-induced stimulation of dopamine release in the nucleus accumbens and the corresponding behavioural activation.
Oxford University SmithKline Beecham Centre for Applied Neuropsychobiology, Department of Clinical Pharmacology, Radcliffe Infirmary, UK.
Q
Q
Pei
T
T
Zetterström
R A
RA
Leslie
D G
DG
Grahame-Smith
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D017829:Granisetron; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D000077526:Tropisetron
D004298:Dopamine; D017829:Granisetron; D007191:Indazoles; D007211:Indoles; D009020:Morphine; D017294:Ondansetron; D012702:Serotonin Antagonists; D000077526:Tropisetron