PNU 99,194

PNU-99,194(A) (or U-99,194(A)) is a drug which acts as a moderately selective D₃ receptor antagonist with ~15-30-fold preference for D₃ over the D₂ subtype. Though it has substantially greater preference for D₃ over D₂, the latter receptor does still play some role in its effects, as evidenced by the fact that PNU-99,194 weakly stimulates both prolactin secretion and striatal dopamine synthesis, actions it does not share with the more selective (100-fold) D₃ receptor antagonists S-14,297 and GR-103,691.

In rodent studies, low doses of PNU-99,194 produce conditioned place preference (CPP) with no effect on intracranial self-stimulation (ICSS), whereas low doses of D₃ agonists like 7-OH-DPAT inhibit ICSS behavior and cause conditioned place aversion (CPA). In contrast, high doses of PNU-99,194 produce CPA and inhibit ICSS, while high doses of 7-OH-DPAT result in the opposite. Paralleling this, low doses of PNU-99,194 and 7-OH-DPAT induce hyperactivity and hypoactivity, respectively, whereas the inverse is seen at high doses with both agents. These data indicate that the D₃ receptor has biphasic effects on reward mechanisms and locomotor activity, likely due to opposing roles of autoreceptors versus postsynaptic receptors.

Other effects of PNU-99,194 at low doses in rodents include increased nociceptive responses, hypothermia, anxiolysis, and facilitation of learning and memory, as well as augmentation and inhibition, respectively, of amphetamine-induced reward and behavioral sensitization, and reversal of morphine-induced CPP. At high doses it inhibits the self-administration of cocaine in both rats and monkeys.