Comparison of the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine: asymmetric generalization

Evidence suggests that (+/-)3,4-methylenedioxymethamphetamine (MDMA) and psychostimulants produce similar but non-identical stimulus effects in animals. To examine this hypothesis, groups of rats were trained to discriminate either MDMA (1.5 mg/kg) or cocaine (8 mg/kg) from saline vehicle using a two-lever operant procedure under a variable interval (VI) 15 s schedule of reinforcement. Once the animals were trained, tests of stimulus generalization were conducted with (+/-)MDMA, cocaine, S(+)MDMA, and R(-)MDMA. As previously demonstrated, both S(+)MDMA and R(-)MDMA (ED50 0.8 and 1.2 mg/kg, respectively) substituted for ()MDMA. Stimulus generalization also occurred upon administration of cocaine (ED50 4.6 mg/kg) to the ()MDMA-trained animals. In the cocaine-trained animals, however, stimulus generalization did not occur to ()MDMA, S(+)MDMA nor R(-)MDMA. Receptor binding profiles for MDMA and cocaine were compared in an effort to identify any novel and common receptor-based mechanism(s) to explain stimulus generalization of MDMA-trained animals to the effects of cocaine, but only their actions on neurotransmitter transporters seem applicable. Taken together, the results indicate that stimulus substitution between MDMA and cocaine is asymmetric and suggest that although similarities exist between the stimulus actions of MDMA and cocaine, differences might be explained by their differential effects on increasing synaptic concentrations of serotonin (5-HT), dopamine (DA), and/or norepinephrine (NE). (C) 2004 Elsevier Ireland Ltd. All rights reserved.