Reversal effect of sulpiride on rotational behaviour of rats with unilateral frontal cortex ablation: an alternative explanation for the pharmacological mechanism of its antidepressant effect

The antidepressant effect of sulpiride has been generally explained as the result of its preferential blocking effect on self‐inhibitory presynaptic dopamine autoreceptors at low doses. Low dose haloperidol has the same blocking effect. In rats with unilateral ablation of the frontal cortex, methamphetamine administration induced mild contralateral rotation 10 days after the operation. We examined whether low dose sulpiride and haloperidol would have the same effect on this rotational model. High dose sulpiride (100 mg/kg) or low dose haloperidol (0.05 mg/kg) prevented this methamphetamine‐induced rotation. However, low dose (15 mg/kg) sulpiride clearly reversed the direction of rotation. This reversal effect of low dose sulpiride is not explained by the preferential blocking effect on dopamine autoreceptors. The results suggest that low dose sulpiride, unlike low dose haloperidol, has a prominent blocking effect on D2 receptors in the frontal cortex. This unique effect of sulpiride may be relevant to its clinical antidepressant and anxiolytic effects at low doses.