Pharmacological validation of ritanserin and risperidone in the drug discrimination test procedure in the rat

The results presented here indicate that 0.16 mg/kg LSD, 2.50 mg/kg 8‐OHDPAT, 1.25 mg/kg d‐amphetamine, 10.00 mg/kg cocaine, 40.00 mg/kg chlordiazepoxide, 2.50 mg/kg xylazine, and 0.04 mg/kg fentanyl can be used as discriminative stimuli in a two‐lever drug discrimination test procedure in the rat. The central 5‐HT2 antagonist ritanserin and the 5‐HT2 and catecholamine (CA)‐antagonist risperidone were tested for stimulus generalization with, and possible antagonism of, the discriminative stimulus properties of the various training drugs. With both drugs at all doses tested, no stimulus generalization was observed with any of the training drugs. Ritanserin completely blocked the discriminative stimulus properties of LSD at 40.00 mg/kg but was, at doses up to 40.00 mg/kg, unable to block the discriminative stimulus properties of any of the other training drugs. Risperidone completely antagonized the stimulus properties of LSD and d‐amphetamine, partially blocked cocaine, and possessed minor effects on 8‐OHDPAT and fentanyl. Whereas ritanserin was almost without any effects or response rate, risperidone mostly reduced response rate at doses starting between 0.16 and 0.63 mg/kg. However, the complete antagonism of the LSD and d‐amphetamine was observed without effects on response rate. Globally, these results confirm ritanserin to be a selective 5‐HT2 antagonist without any effects on conditioned behaviour. Risperidone was found to be a potent 5‐HT2 and DA antagonist, affecting conditioned behaviour by interfering with response rate and with the response‐reinforcement contingency.