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Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests

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Abstract

Rationale

Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF1 receptor antagonists are being developed as potential novel anxiolytics, but while CRF1 receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF1 receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF1 receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.

Objective

The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF1 receptor antagonists in these tests.

Results

The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF1 receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects.

Conclusions

The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF1 receptor antagonists seem to have a wider therapeutic index than benzodiazepines.

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References

  • Arolfo MP, Brioni JD (1991) Diazepam impairs place learning in the Morris water maze. Behav Neural Biol 55:131–136

    CAS  PubMed  Google Scholar 

  • Bakshi VP, Smith-Roe S, Newman SM, Grigoriadis DE, Kalin NH (2002) Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum or CRH1 receptors in amygdala. J Neurosci 22:2926–2935

    CAS  PubMed  Google Scholar 

  • Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N, De Souza EB (1995) Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer’s disease. Nature 378:284–287

    Article  CAS  PubMed  Google Scholar 

  • Blank T, Nijholt I, Eckart K, Spiess J (2002) Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J Neurosci 22:3788–3794

    CAS  PubMed  Google Scholar 

  • Blank T, Nijholt I, Vollstaedt S, Spiess J (2003) The corticotropin-releasing factor receptor 1 antagonist CP-154,526 reverses stress-induced learning deficits in mice. Behav Brain Res 138:207–213

    Article  CAS  PubMed  Google Scholar 

  • Buffett-Jerrott SE, Stewart SH (2002) Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des 8:45–58

    CAS  PubMed  Google Scholar 

  • Contarino A, Dellu F, Koob GF, Smith GW, Lee KF, Vale W, Gold LH (1999) Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res 835:1–9

    Article  CAS  PubMed  Google Scholar 

  • Conti LH, Maciver CR, Ferkany JW, Abreu ME (1990) Footshock-induced freezing behavior in rats as a model for assessing anxiolytics. Psychopharmacology 102:492–497

    CAS  PubMed  Google Scholar 

  • Curran HV (1991) Benzodiazepines, memory and mood: a review. Psychopharmacology 105:1–8

    CAS  PubMed  Google Scholar 

  • Curran HV, Birch B (1991) Differentiating the sedative, psychomotor and amnesic effects of benzodiazepines: a study with midazolam and the benzodiazepine antagonist, flumazenil. Psychopharmacology 103:519–523

    CAS  PubMed  Google Scholar 

  • Curran HV, Schifano F, Lader M (1991) Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory, psychomotor performance and mood. Psychopharmacology 103:83–90

    CAS  PubMed  Google Scholar 

  • Curran HV, Bond A, O’Sullivan G, Bruce M, Marks I, Lelliot P, Shine P, Lader M (1994) Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Psychol Med 24:969–976

    CAS  PubMed  Google Scholar 

  • Curran HV, Pooviboonsuk P, Dalton JA, Lader MH (1998) Differentiating the effects of centrally acting drugs on arousal and memory: an event-related potential study of scopolamine, lorazepam and diphenhydramine. Psychopharmacology 135:27–36

    Article  CAS  PubMed  Google Scholar 

  • Davis KL, Mohs RC, Marin DB, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V (1999) Neuropeptide abnormalities in patients with early Alzheimer disease. Arch Gen Psychiatry 56:981–987

    Article  CAS  PubMed  Google Scholar 

  • De Souza EB, Whitehouse PJ, Kuhar MJ, Price DL, Vale WW (1986) Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer’s disease. Nature 319:593–595

    PubMed  Google Scholar 

  • Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF, Licinio J, Wong ML, Chrousos GP, Webster E, Gold PW (1999) The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress. Endocrinology 140:79–86

    Article  CAS  PubMed  Google Scholar 

  • Fanselow MS, Helmstetter FJ (1988) Conditional analgesia, defensive freezing, and benzodiazepines. Behav Neurosci 102:233–243

    Article  CAS  PubMed  Google Scholar 

  • Gallagher M, Burwell R, Burchinal M (1993) Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behav Neurosci 107:618–626

    Article  CAS  PubMed  Google Scholar 

  • Gilligan PJ, Baldauf C, Cocuzza A, Chidester D, Zaczek R, Fitzgerald LW, McElroy J, Smith MA, Shen HS, Saye JA, Christ D, Trainor G, Robertson DW, Hartig P (2000) The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine: a corticotropin-releasing factor (hCRF1) antagonist. Bioorg Med Chem 8:181–189

    Article  CAS  PubMed  Google Scholar 

  • Golombok S, Moodley P, Lader M (1988) Cognitive impairment in long-term benzodiazepine users. Psychol Med 18:365–374

    CAS  PubMed  Google Scholar 

  • Gorissen ME, Curran HV, Eling PA (1998) Proactive interference and temporal context encoding after diazepam intake. Psychopharmacology 138:334–343

    Article  CAS  PubMed  Google Scholar 

  • Griebel G, Perrault G, Sanger DJ (1998) Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents. Comparison with diazepam and buspirone. Psychopharmacology 138:55–66

    Article  CAS  PubMed  Google Scholar 

  • Griebel G, Simiand J, Steinberg R, Jung M, Gully D, Roger P, Geslin M, Scatton B, Maffrand JP, Soubrie P (2002) 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders. J Pharmacol Exp Ther 301:333–345

    Article  CAS  PubMed  Google Scholar 

  • He L, Gilligan PJ, Zaczek R, Fitzgerald LW, McElroy J, Shen HS, Saye JA, Kalin NH, Shelton S, Christ D, Trainor G, Hartig P (2000) 4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: a potent, orally bioavailable CRF(1) receptor antagonist. J Med Chem 43:449–456

    Article  CAS  PubMed  Google Scholar 

  • Heinrichs SC, Stenzel-Poore MP, Gold LH, Battenberg E, Bloom FE, Koob GF, Vale WW, Pich EM (1996) Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor. Neuroscience 74:303–311

    Article  CAS  PubMed  Google Scholar 

  • Hikichi T, Akiyoshi J, Yamamoto Y, Tsutsumi T, Isogawa K, Nagayama H (2000) Suppression of conditioned fear by administration of CRF receptor antagonist CP-154,526. Pharmacopsychiatry 33:189–193

    Article  CAS  PubMed  Google Scholar 

  • Ho SP, Takahashi LK, Livanov V, Spencer K, Lesher T, Maciag C, Smith MA, Rohrbach KW, Hartig PR, Arneric SP (2001) Attenuation of fear conditioning by antisense inhibition of brain corticotropin releasing factor-2 receptor. Brain Res Mol Brain Res 89:29–40

    Article  CAS  PubMed  Google Scholar 

  • Hommer D, Weingartner H, Breier A (1993) Dissociation of benzodiazepine-induced amnesia from sedation by flumazenil pretreatment. Psychopharmacology 112:455–460

    CAS  PubMed  Google Scholar 

  • Institute of Laboratory Animal Resources (1996) Guide for the care and use of laboratory animals. National Academy, Washington

    Google Scholar 

  • Kehne J, De Lombaert S (2002) Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Curr Drug Target CNS Neurol Disord 1:467–493

    CAS  Google Scholar 

  • Kikusui T, Takeuchi Y, Mori Y (2000) Involvement of corticotropin-releasing factor in the retrieval process of fear-conditioned ultrasonic vocalization in rats. Physiol Behav 71:323–328

    Article  CAS  PubMed  Google Scholar 

  • Koelega HS (1989) Benzodiazepines and vigilance performance: a review. Psychopharmacology 98:145–156

    CAS  PubMed  Google Scholar 

  • Lee EH, Sung YJ (1989) Differential influences of corticotropin-releasing factor on memory retention of aversive learning and appetitive learning in rats. Behav Neural Biol 52:285–294

    CAS  PubMed  Google Scholar 

  • Lelas S, Wong H, Li YW, Heman KL, Ward KA, Zeller KL, Sieracki KK, Polino JL, Godonis HE, Ren SX, Yan XX, Arneric SP, Robertson DW, Hartig PR, Grossman S, Trainor GL, Taub RA, Zaczek R, Gilligan PJ, McElroy JF (2004) Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats. J Pharmacol Exp Ther 309:293–302

    Article  CAS  PubMed  Google Scholar 

  • Lindner MD, Plone MA, Cain CK, Frydel B, Francis JM, Emerich DF, Sutton RL (1998) Dissociable long-term cognitive deficits after frontal versus sensorimotor cortical contusions. J Neurotrauma 15:199–216

    CAS  PubMed  Google Scholar 

  • Mansbach RS, Brooks EN, Chen YL (1997) Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol 323:21–26

    Article  CAS  PubMed  Google Scholar 

  • McElroy JF, Ward KA, Zeller KL, Jones KW, Gilligan PJ, He L, Lelas S (2002) The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats. Psychopharmacology 165:86–92

    Article  CAS  PubMed  Google Scholar 

  • McNamara RK, Skelton RW (1991) Diazepam impairs acquisition but not performance in the Morris water maze. Pharmacol Biochem Behav 38:651–658

    Article  CAS  PubMed  Google Scholar 

  • McNaughton N, Morris RG (1987) Chlordiazepoxide, an anxiolytic benzodiazepine, impairs place navigation in rats. Behav Brain Res 24:39–46

    Article  CAS  PubMed  Google Scholar 

  • Mouradian MM, Farah JM Jr, Mohr E, Fabbrini G, O’Donohue TL, Chase TN (1986) Spinal fluid CRF reduction in Alzheimer’s disease. Neuropeptides 8:393–400

    Article  CAS  PubMed  Google Scholar 

  • Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Nakazato A, Kumagai T, Okubo T, Tomisawa K (1999) Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. J Pharmacol Exp Ther 289:926–935

    CAS  PubMed  Google Scholar 

  • Pomara N, Singh RR, Deptula D, LeWitt PA, Bissette G, Stanley M, Nemeroff CB (1989) CSF corticotropin-releasing factor (CRF) in Alzheimer’s disease: its relationship to severity of dementia and monoamine metabolites. Biol Psychiatry 26:500–504

    Article  CAS  PubMed  Google Scholar 

  • Radulovic J, Ruhmann A, Liepold T, Spiess J (1999) Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J Neurosci 19:5016–5025

    CAS  PubMed  Google Scholar 

  • Sahgal A, Wright C, Edwardson JA, Keith AB (1983) Corticotrophin releasing factor is more potent than some corticotrophin-related peptides in affecting passive avoidance behaviour in rats. Neurosci Lett 36:81–86

    Article  CAS  PubMed  Google Scholar 

  • SAS Institute Inc. (1989) SAS/STAT user’s guide, version 6, 4th edn. SAS Institute, Inc., Cary, N.C.

    Google Scholar 

  • Sauvage M, Steckler T (2001) Detection of corticotropin-releasing hormone receptor 1 immunoreactivity in cholinergic, dopaminergic and noradrenergic neurons of the murine basal forebrain and brainstem nuclei—potential implication for arousal and attention. Neuroscience 104:643–652

    Article  CAS  PubMed  Google Scholar 

  • Schultz DJ, Cahoon EB, Shanklin J, Craig R, Cox-Foster DL, Mumma RO, Medford JI (1996) Expression of a delta 9 14:0-acyl carrier protein fatty acid desaturase gene is necessary for the production of omega 5 anacardic acids found in pest-resistant geranium (Pelargonium xhortorum). Proc Natl Acad Sci USA 93:8771–8775

    Article  CAS  PubMed  Google Scholar 

  • Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102

    Article  CAS  PubMed  Google Scholar 

  • Sramek JJ, Zarotsky V, Cutler NR (2002) Generalised anxiety disorder: treatment options. Drugs 62:1635–1648

    CAS  PubMed  Google Scholar 

  • Steckler T, Holsboer F (2001) Interaction between the cholinergic system and CRH in the modulation of spatial discrimination learning in mice. Brain Res 906:46–59

    Article  CAS  PubMed  Google Scholar 

  • Takahashi LK (2001) Role of CRF(1) and CRF(2) receptors in fear and anxiety. Neurosci Biobehav Rev 25:627–636

    Article  CAS  PubMed  Google Scholar 

  • Veldhuis HD, De Wied D (1984) Differential behavioral actions of corticotropin-releasing factor (CRF). Pharmacol Biochem Behav 21:707–713

    CAS  PubMed  Google Scholar 

  • Whitehouse PJ, Vale WW, Zweig RM, Singer HS, Mayeux R, Kuhar MJ, Price DL, De Souza EB (1987) Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer’s disease, Parkinson’s disease, and progressive supranuclear palsy. Neurology 37:905–909

    CAS  PubMed  Google Scholar 

  • Zanotti A, Arban R, Perazzolo M, Giusti P (1994) Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze. Psychopharmacology 115:73–78

    CAS  PubMed  Google Scholar 

  • Zorrilla EP, Schulteis G, Ormsby A, Klaassen A, Ling N, McCarthy JR, Koob GF, De Souza EB (2002) Urocortin shares the memory modulating effects of corticotropin-releasing factor (CRF): mediation by CRF1 receptors. Brain Res 952:200–210

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neuroscience Drug Discovery, Bristol–Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT, 06492, USA

    John B. Hogan, Donald B. Hodges Jr, Snjezana Lelas, Paul J. Gilligan, John F. McElroy & Mark D. Lindner

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  1. John B. Hogan
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  2. Donald B. Hodges Jr
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  3. Snjezana Lelas
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  4. Paul J. Gilligan
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  6. Mark D. Lindner
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Correspondence to Mark D. Lindner.

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Hogan, J.B., Hodges, D.B., Lelas, S. et al. Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests. Psychopharmacology 178, 410–419 (2005). https://doi.org/10.1007/s00213-004-2028-y

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  • DOI: https://doi.org/10.1007/s00213-004-2028-y

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