Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.

1. In addition to inhibiting the dopamine transporter, cocaine affects a variety of other neurotransmitter systems. In the present study, the involvement of both dopaminergic and the nondopaminergic systems in the behavioral effects of cocaine was studied using an intravenous drug discrimination procedure. 2. One group (Group 1) of rats were trained to discriminate cocaine (1 mg/kg, i.v.) from saline, while a second group (Group 2) of rats were trained to discriminate the same dose of cocaine from both GBR-12909 (1 mg/kg i.v.), a dopamine-selective uptake inhibitor, and saline. 3. Following training, substitution tests with different doses of cocaine and several drugs pharmacologically related to cocaine were conducted. When cocaine dose was varied, there was a dose-dependent generalization to the cocaine-training stimulus in both groups of rats. Conversely, GBR-12909 and GBR-12935, another dopamine-selective uptake inhibitor, generalized to the cocaine-training stimulus in Group 1, but there was minimal or no generalization in Group 2 4. The norepinephrine-selective uptake inhibitors, desipramine and nisoxetine, and the serotonin-selective uptake inhibitor, zimeldine, produced little or no generalization to the cocaine-training stimulus in either group of rats. The sodium channel blocker, dimethocaine which has a relatively high affinity for the dopamine transporter fully generalized to the cocaine stimulus in both groups of rats, while procaine which has a low affinity for the dopamine transporters only partially generalized to the cocaine-training stimulus in both groups of rats 5. Finally, lidocaine, which has negligible affinity for the dopamine transporter, did not generalize to the cocaine-training stimulus in either group of rats. The findings suggest similarities as well as subtle, but important, differences between the discriminative stimulus effects of cocaine and the dopamine uptake inhibitors, GBR-12909 and GBR12935.