, Volume 210, Issue 2, pp 231–240 | Cite as

The effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat

  • Hugo A. Tejeda
  • Vladimir I. Chefer
  • Agustin Zapata
  • Toni S. Shippenberg
Original Investigation



Kappa-opioid receptor (KOR) agonists produce dysphoria and psychotomimesis in humans. KORs are enriched in the prefrontal cortex and other brain regions that regulate mood and cognitive function. Dysregulation of the dynorphin/KOR system has been implicated in the pathogenesis of schizophrenia, depression, and bipolar disorder. Prepulse inhibition of the acoustic startle reflex (PPI), a sensorimotor gating process, is disrupted in many psychiatric disorders.


The present study determined whether KOR ligands alter PPI in rats.


Utilizing a range of doses of the synthetic KOR agonists (±) U50,488, (−) U50,488, and U69,593 and the naturally occurring KOR agonist, Salvinorin A, we demonstrate that KOR activation does not alter PPI or startle reactivity in rats. Similarly, selective KOR blockade using the long-acting antagonist nor-binaltorphimine (nor-BNI) was without effect. In contrast to KOR ligands, MK-801 and quinpirole produced deficits in PPI. Stress and corticotropin-releasing factor (CRF) decrease PPI levels. The dynorphin/KOR system has been suggested to be a key mediator of various behavioral effects produced by stress and CRF. We therefore examined the contribution of KORs to CRF-induced alterations in PPI. Intracerebroventricular infusion of CRF decreased PPI. Administration of nor-BNI failed to affect the CRF-evoked disruption in PPI.


Together, these results provide no evidence of a link between the dynorphin/KOR system and deficits in sensory gating processes. Additional studies, however, examining whether dysregulation of this opioid system contributes to cognitive deficits and other behavioral abnormalities associated with psychiatric disorders are warranted.


Prepulse inhibition Kappa-opioid receptors Corticotropin-releasing factor Rat 



This research was supported by the NIDA Intramural Research Program of NIH and a Ford Foundation Predoctoral Fellowship. We thank Dr. Thomas Prinzano, Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS, USA, for generously providing Salvinorin A for these studies. The authors would like to thank Sean Mansoory and Vicky Minny for their excellent technical assistance.


  1. Armario A, Escorihuela RM, Nadal R (2008) Long-term neuroendocrine and behavioural effects of a single exposure to stress in adult animals. Neurosci Biobehav Rev 32:1121–1135CrossRefPubMedGoogle Scholar
  2. Arnsten AF (2007) Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex 17:6–15CrossRefGoogle Scholar
  3. Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794PubMedGoogle Scholar
  4. Bortolato M, Solbrig MV (2007) The price of seizure control: dynorphins in interictal and postictal psychosis. Psychiatry Res 151:139–143CrossRefPubMedGoogle Scholar
  5. Bortolato M, Aru GN, Frau R, Orrù M, Fà M, Manunta M, Puddu M, Mereu G, Gessa GL (2005) Kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats. Biol Psychiatry 57:1550–1558CrossRefPubMedGoogle Scholar
  6. Bruchas MR, Land BB, Chavkin C (2009) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. doi: 10.1016/j.brainres.2009.08.062 PubMedGoogle Scholar
  7. Bubser M, Koch M (1994) Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex. Psychopharmacology (Berl) 113:487–492CrossRefGoogle Scholar
  8. Byrnes JJ, Hammer RP (2000) The disruptive effect of cocaine on prepulse inhibition is prevented by repeated administration in rats. Neuropsychopharmacology 22:551–554CrossRefPubMedGoogle Scholar
  9. Cahill CM, Green MJ, Jairam R, Malhi GS (2007) Do cognitive deficits in juvenile bipolar disorder persist into adulthood? J Nerv Ment Dis 195:891–896CrossRefPubMedGoogle Scholar
  10. Carey AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP (2009) Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory. J Neurosci 29:4293–4300CrossRefPubMedGoogle Scholar
  11. Carlezon WA Jr, Béguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, Rothman RB, Ma Z, Lee DY, Cohen BM (2006) Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 316(1):440–447Google Scholar
  12. Carlezon WA Jr, Béguin C, Knoll AT, Cohen BM (2009) Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther 123:334–343CrossRefPubMedGoogle Scholar
  13. Chefer VI, Shippenberg TS (2006) Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Eur J NeuroSci 23:229–238CrossRefPubMedGoogle Scholar
  14. Chefer VI, Czyzyk T, Bolan EA, Moron J, Pintar JE, Shippenberg TS (2005) Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. Neurosci 18:5029–5037Google Scholar
  15. Conti LH, Murry JD, Ruiz MA, Printz MP (2002) Effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in two rat strains. Psychopharmacology (Berl) 161:296–303CrossRefGoogle Scholar
  16. Conti LH, Costill JE, Flynn S, Tayler JE (2005) Effects of a typical and an atypical antipsychotic on the disruption of prepulse inhibition caused by corticotropin-releasing factor and by rat strain. Behav Neurosci 119:1052–1060CrossRefPubMedGoogle Scholar
  17. Daumas S, Betourne A, Halley H, Wolfer DP, Lipp HP, Lassalle JM, Francés B (2007) Transient activation of the CA3 Kappa opioid system in the dorsal hippocampus modulates complex memory processing in mice. Neurobiol Learn Mem 88:94–103CrossRefPubMedGoogle Scholar
  18. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278CrossRefPubMedGoogle Scholar
  19. Dirks A, Groenink L, Westphal KG, Olivier JD, Verdouw PM, van der Gugten J, Geyer MA, Olivier B (2003) Reversal of startle gating deficits in transgenic mice overexpressing corticotropin-releasing factor by antipsychotic drugs. Neuropsychopharmacology 28:1790–1798CrossRefPubMedGoogle Scholar
  20. Doherty JM, Masten VL, Powell SB, Ralph RJ, Klamer D, Low MJ, Geyer MA (2008) Contributions of dopamine D1, D2, and D3 receptor subtypes to the disruptive effects of cocaine on prepulse inhibition in mice. Neuropsychopharmacology 33:2648–2656CrossRefPubMedGoogle Scholar
  21. El-Rawas R, Saadé NE, Thiriet N, Atweh S, Jaber M, Al-Amin HA (2009) Developmental changes in the mRNA expression of neuropeptides and dopamine and glutamate receptors in neonates and adult rats after ventral hippocampal lesion. Schizophr Res 113:298–307CrossRefPubMedGoogle Scholar
  22. Endoh T, Matsuura H, Tanaka C, Nagase H (1992) Nor-binaltorphimine: a potent and selective kappa-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Ther 316:30–42PubMedGoogle Scholar
  23. Ermutlu MN, Karamürsel S, Ugur EH, Senturk L, Gokhan N (2005) Effects of cold stress on early and late stimulus gating. Psychiatry Res 136:201–209CrossRefPubMedGoogle Scholar
  24. Faraday MM (2002) Rat sex and strain differences in responses to stress. Physiol Behav 75:507–522CrossRefPubMedGoogle Scholar
  25. Geyer MA (2006) The family of sensorimotor gating disorders: comorbidities or diagnostic overlaps? Dialogues Clin Neurosci 8:9–16PubMedGoogle Scholar
  26. Geyer MA (2008) Developing translational animal models for symptoms of schizophrenia or bipolar mania. Neurotox Res 14:71–78CrossRefPubMedGoogle Scholar
  27. Goel N, Bale TL (2009) Examining the intersection of sex and stress in modelling neuropsychiatric disorders. J Neuroendocrinol 21:415–420CrossRefPubMedGoogle Scholar
  28. Grillon C, Morgan CA, Southwick SM, Davis M, Charney DS (1996) Baseline startle amplitude and prepulse inhibition in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 64:169–178CrossRefPubMedGoogle Scholar
  29. Groenink L, Dirks A, Verdouw PM, de Graaff M, Peeters BW, Millan MJ, Olivier B (2008) CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF. Biol Psychiatry 63:360–368CrossRefPubMedGoogle Scholar
  30. Heidbreder CA, Schenk S, Partridge B, Shippenberg TS (1998) Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist. Synapse 30:255–262CrossRefPubMedGoogle Scholar
  31. Heikkilä L, Rimón R, Terenius L (1990) Dynorphin A and substance P in the cerebrospinal fluid of schizophrenic patients. Psychiatry Res 34:229–236CrossRefPubMedGoogle Scholar
  32. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull 35:549–562CrossRefPubMedGoogle Scholar
  33. Hurd YL (1996) Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain. Neuroscience 72:767–783CrossRefPubMedGoogle Scholar
  34. Hurd YL (2002) Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Mol Psychiatry 7:75–81CrossRefPubMedGoogle Scholar
  35. Keefe RS, Fenton WS (2007) How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophr Bull 33:912–920CrossRefPubMedGoogle Scholar
  36. Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323:838–845CrossRefPubMedGoogle Scholar
  37. Koch M, Bubser M (1994) Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol. Eur J NeuroSci 6:1837–1845CrossRefPubMedGoogle Scholar
  38. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28:407–414CrossRefPubMedGoogle Scholar
  39. Leitner DS (1986) Alterations in other sensory modalities accompanying stress analgesia as measured by startle reflex modification. Ann N Y Acad Sci 467:82–92CrossRefPubMedGoogle Scholar
  40. Leitner DS (1989) Multisensory deficits in rats produced by acute exposure to cold swim stress. Behav Neurosci 103:151–157CrossRefPubMedGoogle Scholar
  41. Levin ED, Petro A, Caldwell DP (2005) Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade. Prog Neuropsychopharmacol Biol Psychiatry 29:581–586CrossRefPubMedGoogle Scholar
  42. Lipska BK, Swerdlow NR, Geyer MA, Jaskiw GE, Braff DL, Weinberger DR (1995) Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology (Berl) 122:35–43CrossRefGoogle Scholar
  43. Lipska BK, Lerman DN, Khaing ZZ, Weickert CS, Weinberger DR (2003) Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J NeuroSci 18:391–402CrossRefPubMedGoogle Scholar
  44. Ludewig K, Geyer MA, Vollenweider FX (2003) Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia. Biol Psychiatry 54:121–128CrossRefPubMedGoogle Scholar
  45. Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514CrossRefGoogle Scholar
  46. Mansour A, Burke S, Pavlic RJ, Akil H, Watson SJ (1996) Immunohistochemical localization of the cloned kappa 1 receptor in the rat CNS and pituitary. Neuroscience 71:671–690CrossRefPubMedGoogle Scholar
  47. Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL (2006) Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci USA 103:2938–2942CrossRefPubMedGoogle Scholar
  48. McDaniel KL, Mundy WR, Tilson HA (1990) Microinjection of dynorphin into the hippocampus impairs spatial learning in rats. Pharmacol Biochem Behav 35:429–435CrossRefPubMedGoogle Scholar
  49. McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C (2006) Prior activation of kappa opioid receptors by U50, 488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 31:787–794CrossRefPubMedGoogle Scholar
  50. Millan MJ, Schreiber R, Dekeyne A, Rivet JM, Bervoets K, Mavridis M, Sebban C, Maurel-Remy S, Newman-Tancredi A, Spedding M, Muller O, Lavielle G, Brocco M (1998) S 16924 ((R)-2-[1-[2-(2, 3-dihydro-benzo[1, 4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: II. Functional profile in comparison to clozapine and haloperidol. J Pharmacol Exp Ther 286:1356–1373PubMedGoogle Scholar
  51. Miyazato H, Skinner RD, Garcia-Rill E (2000) Locus coeruleus involvement in the effects of immobilization stress on the p13 midlatency auditory evoked potential in the rat. Prog Neuropsychopharmacol Biol Psychiatry 24:1177–1201CrossRefPubMedGoogle Scholar
  52. Nespor AA, Tizabi Y (2008) Effects of nicotine on quinpirole- and dizocilpine (MK-801)-induced sensorimotor gating impairments in rats. Psychopharmacology (Berl) 200:403–411CrossRefGoogle Scholar
  53. Ornitz EM, Pynoos RS (1989) Startle modulation in children with posttraumatic stress disorder. Am J Psychiatry 146:866–870PubMedGoogle Scholar
  54. Paulzen M, Gründer G (2008) Toxic psychosis after intake of the hallucinogen salvinorin A. J Clin Psychiatry 69:1501–1502CrossRefPubMedGoogle Scholar
  55. Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776CrossRefPubMedGoogle Scholar
  56. Plappert CF, Pilz PK (2002) Difference in anxiety and sensitization of the acoustic startle response between the two inbred mouse strains BALB/cAN and DBA/2 N. Genes Brain Behav 1:178–186CrossRefPubMedGoogle Scholar
  57. Pulliam JV, Dawaghreh AM, Alema-Mensah E, Plotsky PM (2009) Social defeat stress produces prolonged alterations in acoustic startle and body weight gain in male Long Evans rats. J Psychiatr Res. doi: 10.1016/j.jpsychires.2009.05.005 PubMedGoogle Scholar
  58. Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21:305–313PubMedGoogle Scholar
  59. Ralph-Williams RJ, Paulus MP, Zhuang X, Hen R, Geyer MA (2003) Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system. Biol Psychiatry 53:352–359CrossRefPubMedGoogle Scholar
  60. Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology (Berl) 200:59–70CrossRefGoogle Scholar
  61. Risbrough VB, Hauger RL, Roberts AL, Vale WW, Geyer MA (2004) Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci 24:6545–6552CrossRefPubMedGoogle Scholar
  62. Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci USA 99:11934–11939CrossRefPubMedGoogle Scholar
  63. Sandin J, Nylander I, Georgieva J, Schött PA, Ogren SO, Terenius L (1998) Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect. Neuroscience 85:375–382CrossRefPubMedGoogle Scholar
  64. Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116:306–321CrossRefPubMedGoogle Scholar
  65. Shoemaker JM, Saint Marie RL, Bongiovanni MJ, Neary AC, Tochen LS, Swerdlow NR (2005) Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats. Neuroscience 135:385–394CrossRefPubMedGoogle Scholar
  66. Sipos ML, Bauman RA, Widholm JJ, Kant GJ (2000) Behavioral effects Of 8-OH-DPAT in chronically stressed male and female rats. Pharmacol Biochem Behav 66:403–411CrossRefPubMedGoogle Scholar
  67. Spanagel R, Herz A, Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89:2046–2050CrossRefPubMedGoogle Scholar
  68. Sutherland JE, Page ME, Conti LH (2008) The effect of corticotropin-releasing factor on prepulse inhibition is independent of serotonin in Brown Norway and Wistar-Kyoto rats. Pharmacol Biochem Behav 89:324–337CrossRefPubMedGoogle Scholar
  69. Svingos AL, Colago EE (2002) Kappa-opioid and NMDA glutamate receptors are differentially targeted within rat medial prefrontal cortex. Brain Res 946:262–271CrossRefPubMedGoogle Scholar
  70. Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology (Berl) 101:414–420CrossRefGoogle Scholar
  71. Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J Pharmacol Exp Ther 256:530–536PubMedGoogle Scholar
  72. Swerdlow NR, Braff DL, Geyer MA (1999) Cross-species studies of sensorimotor gating of the startle reflex. Ann N Y Acad Sci 877:202–216CrossRefPubMedGoogle Scholar
  73. Swerdlow NR, Martinez ZA, Hanlon FM, Platten A, Farid M, Auerbach P, Braff DL, Geyer MA (2000) Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists. J Neurosci 20:4325–4336PubMedGoogle Scholar
  74. Swerdlow NR, Shoemaker JM, Bongiovanni MJ, Neary AC, Tochen LS, Saint Marie RL (2007) Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration. Pharmacol Biochem Behav 87:1–10CrossRefPubMedGoogle Scholar
  75. Tejeda HA (2009) Modulation of extracellular dopamine in the prefrontal cortex by local and ventral tegmental area kappa-opioid receptors. 40th Ann. Soc for Neurosci Meeting, Chicago, IL, 56:751.7Google Scholar
  76. Thompson AC, Zapata A, Justice JB Jr, Vaughan RA, Sharpe LG, Shippenberg TS (2000) Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci 20:9333–9340PubMedGoogle Scholar
  77. Vinkers CH, Risbrough VB, Geyer MA, Caldwell S, Low MJ, Hauger RL (2007) Role of dopamine D1 and D2 receptors in CRF-induced disruption of sensorimotor gating. Pharmacol Biochem Behav 86:550–558CrossRefPubMedGoogle Scholar
  78. Wan FJ, Swerdlow NR (1993) Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats. Psychopharmacology (Berl) 113:103–109CrossRefGoogle Scholar
  79. Weber M, Chang WL, Breier M, Ko D, Swerdlow NR (2008) Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation. Behav Pharmacol 19:786–795CrossRefPubMedGoogle Scholar
  80. Wevers A, Schmidt P, Cserpan E, Cserpan I, Maderspach K, Staak M, Schröder H (1995) Cellular distribution of the mRNA for the kappa-opioid receptor in the human neocortex: a non-isotopic in situ hybridization study. Neurosci Lett 195:125–128CrossRefPubMedGoogle Scholar
  81. Yamashita M, Fukushima S, Shen HW, Hall FS, Uhl GR, Numachi Y, Kobayashi H, Sora I (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31:2132–2139PubMedGoogle Scholar

Copyright information

© US Government 2010

Authors and Affiliations

  • Hugo A. Tejeda
    • 1
    • 2
  • Vladimir I. Chefer
    • 1
  • Agustin Zapata
    • 1
  • Toni S. Shippenberg
    • 1
  1. 1.Integrative Neuroscience Section, Integrative Neuroscience Branch, National Institute on Drug AbuseNational Institutes of HealthBaltimoreUSA
  2. 2.Program in NeuroscienceUniversity of Maryland, BaltimoreBaltimoreUSA

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