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.