Pharmacological analysis of the apomorphine discriminative stimulus in rhesus monkeys

Four rhesus monkeys were trained to discriminate apomorphine (APO) from saline in a two lever, food-reinforced drug discrimination paradigm. After acquisition of the discrimination (average = 161 sessions), they were tested with a series of compounds selected to characterize the neuronal mechanism(s) of the discrimination and to determine whether the site of action was central or peripheral. APO produced a dose-related increase in the percentage of responses that occurred on the drug lever during test sessions. The D2 dopamine (DA) agonist piribedil substituted completely for APO and the D2 DA antagonist pimozide antagonized the APO discriminative stimulus in a manner consistent with a competitive antagonism. On the other hand, the D1 agonist SKF 38393 engendered principally saline lever responding in all monkeys, whereas the D1 DA antagonist SCH 23390 was ineffective as an APO antagonist. The APO effect was neither mimicked by DA nor blocked by the D2DA antagonist domperidone, both of which fail to cross the blood-brain barrier to any significant extent. In substitution tests the norepinephrine reuptake blocker nisoxetine, the serotonin agonist quipazine and the cholinesterase inhibitor physostigmine, as well as d-amphetamine, cocaine and morphine engendered principally saline lever responding up to doses that substantially reduced rate of responding. Taken together these results suggest that the APO discriminative stimulus is based principally upon an action at a D2 receptor in the central nervous system and that this preparation can be used for studying the functional properties of central nervous system D2 receptors.