PNU-99,194 explained

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]

See also

Notes and References

  1. Claytor R, Lile JA, Nader MA . The effects of eticlopride and the selective D3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys . Pharmacology Biochemistry and Behavior . 83 . 3 . 456–64 . March 2006 . 16631246 . 10.1016/j.pbb.2006.03.007 . 39482275 .
  2. Waters N, Svensson K, Haadsma-Svensson SR, Smith MW, Carlsson A . The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity . Journal of Neural Transmission. General Section . 94 . 1 . 11–9 . 1993 . 8129881 . 10.1007/bf01244979. 32918280 .
  3. Kling-Petersen T, Ljung E, Svensson K . Effects on locomotor activity after local application of D3 preferring compounds in discrete areas of the rat brain . Journal of Neural Transmission. General Section . 102 . 3 . 209–20 . 1995 . 8788069 . 10.1007/bf01281155. 10327706 .
  4. Audinot V, Newman-Tancredi A, Gobert A, etal . A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194 . The Journal of Pharmacology and Experimental Therapeutics . 287 . 1 . 187–97 . October 1998 . 9765337 .
  5. Kling-Petersen T, Ljung E, Wollter L, Svensson K . Effects of dopamine D3 preferring compounds on conditioned place preference and intracranial self-stimulation in the rat . Journal of Neural Transmission. General Section . 101 . 1–3 . 27–39 . 1995 . 8695055 . 10.1007/bf01271543. 30848393 .
  6. Francès H, Smirnova M, Leriche L, Sokoloff P . Dopamine D3 receptor ligands modulate the acquisition of morphine-conditioned place preference . Psychopharmacology . 175 . 2 . 127–33 . September 2004 . 15095031 . 10.1007/s00213-004-1807-9 . 2721240 .
  7. Khroyan TV, Baker DA, Neisewander JL . Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning . Psychopharmacology . 122 . 4 . 351–7 . December 1995 . 8657832 . 10.1007/BF02246265. 20542615 .
  8. Millan MJ, Seguin L, Gobert A, Cussac D, Brocco M . The role of dopamine D3 compared with D2 receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats . Psychopharmacology . 174 . 3 . 341–57 . July 2004 . 14985929 . 10.1007/s00213-003-1770-x . 1592299 .
  9. Gyertyán I, Sághy K . Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011 . Behavioural Pharmacology . 15 . 4 . 253–62 . July 2004 . 15252275 . 10.1097/01.fbp.0000137857.26150.ab. 41821358 .
  10. Rodríguez-Arias M, Felip CM, Broseta I, Miñarro J . The dopamine D3 antagonist U-99194A maleate increases social behaviors of isolation-induced aggressive male mice . Psychopharmacology . 144 . 1 . 90–4 . May 1999 . 10379629 . 10.1007/s002130050981 . 20953625 . 2010-04-30 . https://web.archive.org/web/20000712113422/http://link.springer.de/link/service/journals/00213/bibs/9144001/91440090.htm . 2000-07-12 . dead .
  11. Meyer ME . Mesolimbic 7-OH-DPAT affects locomotor activities in rats . Pharmacology Biochemistry and Behavior . 55 . 2 . 209–14 . October 1996 . 8951956 . 10.1016/S0091-3057(96)00066-4. 46728735 .
  12. Casarrubea M, Sorbera F, Crescimanno G . Effects of 7-OH-DPAT and U 99194 on the behavioral response to hot plate test, in rats . Physiology & Behavior . 89 . 4 . 552–62 . November 2006 . 16919688 . 10.1016/j.physbeh.2006.07.014 . 45464906 .
  13. Boulay D, Depoortere R, Rostene W, Perrault G, Sanger DJ . Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice . Neuropharmacology . 38 . 4 . 555–65 . April 1999 . 10221759 . 10.1016/S0028-3908(98)00213-5. 1004412 .
  14. Rogóz Z, Kłodzińska A, Maj J . Anxiolytic-like effect of nafadotride and PNU 99194A, dopamine D3 receptor antagonists in animal models . Polish Journal of Pharmacology . 52 . 6 . 459–62 . 2000 . 11334239 .
  15. Laszy J, Laszlovszky I, Gyertyán I . Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats . Psychopharmacology . 179 . 3 . 567–75 . May 2005 . 15619116 . 10.1007/s00213-004-2096-z . 24086632 .
  16. Hale MW, Crowe SF . The effects of selective dopamine agonists on a passive avoidance learning task in the day-old chick . Behavioural Pharmacology . 13 . 4 . 295–301 . July 2002 . 12218510 . 10.1097/00008877-200207000-00006. 24698131 .
  17. Hammad H, Wagner JJ . Dopamine-mediated disinhibition in the CA1 region of rat hippocampus via D3 receptor activation . The Journal of Pharmacology and Experimental Therapeutics . 316 . 1 . 113–20 . January 2006 . 16162819 . 10.1124/jpet.105.091579 . 10007327 .
  18. Carr KD, Yamamoto N, Omura M, Cabeza de Vaca S, Krahne L . Effects of the D(3) dopamine receptor antagonist, U99194A, on brain stimulation and d-amphetamine reward, motor activity, and c-fos expression in ad libitum fed and food-restricted rats . Psychopharmacology . 163 . 1 . 76–84 . August 2002 . 12185403 . 10.1007/s00213-002-1132-0 . 1840764 .
  19. Chiang YC, Chen PC, Chen JC . D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine . Brain Research . 972 . 1–2 . 159–67 . May 2003 . 12711089 . 10.1016/S0006-8993(03)02522-8. 40067321 .
  20. Gál K, Gyertyán I . Targeting the dopamine D3 receptor cannot influence continuous reinforcement cocaine self-administration in rats . Brain Research Bulletin . 61 . 6 . 595–601 . October 2003 . 14519456 . 10.1016/S0361-9230(03)00217-X. 12383682 .

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