5-HT3 agonist 2-methylserotonin as a training drug in discrimination studies

Using a standard two-lever operant procedure, rats were trained to discriminate 5 mg/kg of the 5-HT3 agonist 2-methylserotonin (2-Me 5-HT; ED50 = 2.6 mg/kg) from saline using a VI 15-s schedule of reinforcement. The 2-Me 5-HT stimulus did not generalize to the 5-HT1/5-HT2 agonist 5-methoxy-N,N-dimethyltryptamine, but did generalize to the new 5-HT3 agonist 1-(m-chlorophenyl)biguanide (ED50 = 1.6 mg kg). The 5-HT3 antagonist ICS 205-930 potently antagonized the 2-Me 5-HT stimulus (ID50 = 0.001 mg/kg), whereas its quaternary amine analog, which does not readily penetrate the blood-brain barrier, failed to completely antagonize the 2-Me 5-HT stimulus at a 10,000-fold higher dose. The results of the present investigation show that 2-Me 5-HT serves as a discriminative stimulus in rats when paired with saline and suggest that its stimulus properties are likely mediated via a central 5-HT3 mechanism. As such, this is the first demonstration that a 5-HT3 agonist can be used as a training drug in drug discrimination studies.