The 5-HT3 receptor partial agonist MD-354 (meta-chlorophenylguanidine) enhances the discriminative stimulus actions of (+)amphetamine in rats

The effect of the 5-HT3 receptor partial agonist MD-354 (meta-chlorophenylguanidine) was examined on the discriminative stimulus produced by (+)amphetamine. Using male Sprague–Dawley rats trained to discriminate 1.0 mg/kg (i.p.) of (+)amphetamine from saline vehicle (VI 15-s schedule of reinforcement) in a two-lever operant procedure for appetitive reward, tests of stimulus generalization (substitution) and antagonism showed that MD-354 neither substituted for, nor antagonized, the amphetamine stimulus at the doses evaluated. Administration of (+)amphetamine doses in combination with a fixed (i.e., 1.0 mg/kg) dose of MD-354 shifted the (+)amphetamine dose–response curve to the left such that, following 0.3 mg/kg of (+)amphetamine, stimulus generalization occurred. Furthermore, MD-354 doses of 0.1, 0.3 and 1.0 mg/kg, but not doses of 0.01, 0.5, 1.5 or 3.0 mg/kg (i.p.), administered in combination with the ED50 dose (0.33 mg/kg) of (+)amphetamine resulted in stimulus generalization (i.e., > 80% drug-appropriate responding). It is concluded that even though MD-354 lacks amphetamine-like central stimulant actions of its own it can modulate the discriminative stimulus effects of (+)amphetamine in rats.