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| Routes of administration | Oral |
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| Formula | C17H27NO2 |
| Molar mass | 277.408 g·mol−1 |
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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. [1] [2] [3] 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. [4]
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). [5] [6] [7] In contrast, high doses of PNU-99,194 produce CPA and inhibit ICSS, while high doses of 7-OH-DPAT result in the opposite. [5] [6] [7] 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. [2] [3] [7] [8] [9] [10] 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. [8] [11]
Other effects of PNU-99,194 at low doses in rodents include increased nociceptive responses, [12] hypothermia, [4] [13] anxiolysis, [14] and facilitation of learning and memory, [12] [15] [16] [17] as well as augmentation and inhibition, respectively, of amphetamine-induced reward and behavioral sensitization, [18] [19] and reversal of morphine-induced CPP. [6] At high doses it inhibits the self-administration of cocaine in both rats and monkeys. [1] [20]