Effects of granisetron, a 5-HT3 receptor antagonist, on morphine-induced potentiation of brain stimulation reward

Using the curve-shift method, we studied the effects of four doses (0.003, 0.03, 0.3 and 3 mg/kg, s.c.) of granisetron (endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1-H-indazole-3-carboxamide hydrochloride), a selective 5-hydroxytryptamine(3) (5-HT3) receptor antagonist, on the potentiation of brain stimulation reward by microinjection of 2.5 mu g/0.25 mu l of morphine sulphate (7,8-didehydro-4,5-epoxy-17-methylmorphinan sulphate) into the ventral tegmental area. As previously reported, morphine produced a significant reduction in reward threshold without altering maximal rates of responding. Granisetron attenuated the potentiating effect of morphine at the highest dose and failed to alter reward threshold or maximal rates of responding when given alone, except at the lowest dose where a small and statistically significant increase in threshold was found. These results provide additional evidence that 5-HT3 receptor antagonists may reduce the rewarding effect of opiates and do not impair the ability to produce operant responses. The weak attenuation observed with granisetron alone suggests that 5-HT3 receptors are unlikely to constitute an important influence on the directly stimulated reward-relevant pathway(s).