Psychopharmacology

, Volume 188, Issue 4, pp 619–628

An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze

  • N. Collinson
  • J. R. Atack
  • P. Laughton
  • G. R. Dawson
  • D. N. Stephens
Original Investigation

Abstract

Rationale

Compounds selective for the GABAA receptors containing an α5 subunit have been reported to enhance performance in the hippocampally mediated delayed-matching-to-position version of the Morris water maze, in which reduction in the time required to find a hidden platform relative to an initial trial is used as an index of learning and memory.

Objective

In the present study, we have used one such compound, α5IA-II, to examine whether these effects occur during the encoding, consolidation or recall phases of this paradigm.

Methods

α5IA-II was administered in the absence or presence of the benzodiazepine site antagonist flumazenil, so as to limit its action to periods associated with encoding, consolidation and recall. Drug doses and timings of administrations were defined using occupancy data derived from an in vivo [3H]flumazenil binding assay. Similar experiments were carried out to study the memory-disruptive properties of chlordiazepoxide (CDP).

Results

The trial 1 to trial 2 difference was increased when α5IA-II was given before either trial 1 or trial 2, indicating an effect on the encoding and recall phases, respectively, of learning and memory. Conversely, α5IA-II had no effect on performance when given immediately after trial 1, suggesting that it had no effect on the consolidation phase. In contrast to the facilitation of performance produced by the α5-selective inverse agonist α5IA-II given during the encoding and recall but not the consolidation phase, the non-selective agonist CDP impaired performance when given during the encoding and recall phases, whilst having no effect on the consolidation phase.

Conclusions

These data further highlight the cognition-enhancing properties of GABAA α5-selective inverse agonists and define the functional specificity of these effects in terms of encoding and recall processes in the Morris water maze.

Keywords

Benzodiazepine Memory Learning and memory GABA receptor Cognition 

References

  1. Abel T, Lattal KM (2001) Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 11:180–187PubMedCrossRefGoogle Scholar
  2. Argyropoulos SV, Nutt DJ (1999) The use of benzodiazepines in anxiety and other disorders. Eur Neuropsychopharmacol 9(Suppl 6):S391–S392Google Scholar
  3. Atack JR (2005) The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 14:601–618PubMedCrossRefGoogle Scholar
  4. Atack JR, Hutson PH, Collinson N, Marshall G, Bentley G, Moyes C, Cook SM, Collins I, Wafford K, McKernan RM, Dawson GR (2005) Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors. Br J Pharmacol 144:357–366PubMedCrossRefGoogle Scholar
  5. Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal S, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro J-L, Whiting P, Dawson GR, McKernan RM (2006) TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for α2- and α3-containing GABAA receptors, is a non-sedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316:410–422PubMedCrossRefGoogle Scholar
  6. Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA (2002) Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors. Br J Pharmacol 136:965–974PubMedCrossRefGoogle Scholar
  7. Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, Ferris P, Hobbs SC, O’Connor D, Marshall G, Rycroft W, Macleod AM (2004) An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA α5 receptors with cognition enhancing properties. J Med Chem 47:5829–5832PubMedCrossRefGoogle Scholar
  8. Cobain MR (1999) The localization and function of the alpha5 subunit containing GABAA receptors in the rat. PhD thesis, Downing College, CambridgeGoogle Scholar
  9. Collinson N, Kuenzi F, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PW, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor. J Neurosci 22:5572–5580PubMedGoogle Scholar
  10. Crestani F, Keist R, Fritschy J-M, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U (2002) Trace fear conditioning involves hippocampal α5 GABAA receptors. Proc Natl Acad Sci U S A 99:8980–8985PubMedCrossRefGoogle Scholar
  11. Davis HP, Squire LR (1984) Protein synthesis and memory: a review. Psychol Bull 96:518–559PubMedCrossRefGoogle Scholar
  12. Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (2006) An inverse agonist selective for α5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther 316:1335–1345PubMedCrossRefGoogle Scholar
  13. Dias R, Sheppard WFA, Fradley RL, Garrett EM, Stanley JL, Marshall GR, Goodacre S, Lincoln RJ, Tye SJ, Cook S, Conley R, Hallett D, Wafford KA, Street LJ, Castro JL, Whiting PJ, Rosahl TW, Atack JR, McKernan R, Dawson GR, Reynolds DS (2005) Anxiolytic properties of benzodiazepines are mediated through the GABAA α3 receptor subtype. J Neurosci 25:10682–10688PubMedCrossRefGoogle Scholar
  14. Dorow R, Horowsli R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG 7142, a β-carboline ligand for benzodiazepine receptors. Lancet 2:98–99PubMedCrossRefGoogle Scholar
  15. Duka T, Curran HV, Rusted JM, Weingartner HJ (1996a) Perspectives on cognitive psychopharmacology research. Behav Pharmacol 7:401–410PubMedGoogle Scholar
  16. Duka T, Ott H, Rohloff A, Voet B (1996b) The effects of a benzodiazepine receptor antagonist beta-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills. Psychopharmacology (Berl) 123:361–373CrossRefGoogle Scholar
  17. Fritschy JM, Möhler H (1995) GABAA receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol 359:154–194PubMedCrossRefGoogle Scholar
  18. Ghoneim MM, Mewaldt SP (1975) Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory. Psychopharmacologia 44:257–262PubMedCrossRefGoogle Scholar
  19. Ghoneim MM, Mewaldt SP (1990) Benzodiazepines and human memory: a review. Anesthesiology 72:926–938PubMedCrossRefGoogle Scholar
  20. Ghoneim MM, Hinrichs JV, Mewaldt SP (1984) Dose response analysis of the behavioral effects of diazepam: I. Learning and memory. Psychopharmacology (Berl) 82:291–295CrossRefGoogle Scholar
  21. Goelet P, Castellucci VF, Schacher S, Kandel ER (1986) The long and short of long-term memory—a molecular framework. Nature 322:419–422PubMedCrossRefGoogle Scholar
  22. Hinrichs JV, Ghoneim MM, Mewaldt SP (1984) Diazepam and memory: retrograde facilitation produced by interference reduction. Psychopharmacology (Berl) 84:158–162CrossRefGoogle Scholar
  23. Jensen LH, Stephens DN, Sarter M, Petersen EN (1987) Bidirectional effects of β-carbolines and benzodiazepines on cognitive processes. Brain Res Bull 19:359–364PubMedCrossRefGoogle Scholar
  24. Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy JM, Rülicke T, Bluethmann H, Möhler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134PubMedCrossRefGoogle Scholar
  25. Maubach K (2003) GABAA receptor subtype selective cognition enhancers. Curr Drug Target CNS Neurol Disord 2:233–239CrossRefGoogle Scholar
  26. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garret L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci 3:587–592PubMedCrossRefGoogle Scholar
  27. McNamara RK, Skelton RW (1993) Effects of intracranial infusions of chlordiazepoxide on spatial learning in the Morris water maze. I. Neuroanatomical specificity. Behav Brain Res 59:175–191PubMedCrossRefGoogle Scholar
  28. McNaughton N, Morris RGM (1987) Chlordiazepoxide, an anxiolytic benzodiazepine impairs place navigation in rats. Behav Brain Res 24:39–46PubMedCrossRefGoogle Scholar
  29. Milner B, Squire LR, Kandel ER (1998) Cognitive neuroscience and the study of memory. Neuron 20:445–468PubMedCrossRefGoogle Scholar
  30. Minier F, Sigel E (2004) Techniques: use of concatenated subunits for the study of ligand-gated ion channels. Trends Pharmacol Sci 25:499–503PubMedCrossRefGoogle Scholar
  31. Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683PubMedCrossRefGoogle Scholar
  32. Nadel L, Land C (2000) Memory traces revisited. Nat Rev Neurosci 1:209–212PubMedCrossRefGoogle Scholar
  33. Nadel L, Moscovitch M (1997) Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 7:217–227PubMedCrossRefGoogle Scholar
  34. Nadel L, Moscovitch M (1998) Hippocampal contributions to cortical plasticity. Neuropharmacology 37:431–439PubMedCrossRefGoogle Scholar
  35. Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726PubMedCrossRefGoogle Scholar
  36. Petersen EN (1983) DMCM: a potent convulsive benzodiazepine receptor ligand. Eur J Pharmacol 94:117–124PubMedCrossRefGoogle Scholar
  37. Riedel G, Micheau J, Lam AG, Roloff E, Martin SJ, Bridge H, Hoz L, Poeschel B, McCulloch J, Morris RG (1999) Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 2:898–905PubMedCrossRefGoogle Scholar
  38. Rudolph U, Möhler H (2004) Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 44:475–498PubMedCrossRefGoogle Scholar
  39. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy J-M, Martin JR, Bluethmann H, Möhler H (1999) Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401:796–800PubMedCrossRefGoogle Scholar
  40. Sarter M, Stephens DN (1988) β-carbolines as tools in memory research: animal data and speculations. Psychopharmacol Ser 6:230–245Google Scholar
  41. Schafe GE, LeDoux JE (2000) Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20:RC96, 1–5PubMedGoogle Scholar
  42. Sieghart W (1995) Structure and pharmacology of γ-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:181–234PubMedGoogle Scholar
  43. Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2:795–816PubMedCrossRefGoogle Scholar
  44. Simon J, Wakimoto H, Fujita N, Lalande M, Barnard EA (2004) Analysis of the set of GABAA receptor genes in the human genome. J Biol Chem 279:41422–41435PubMedCrossRefGoogle Scholar
  45. Squire LR, Alvarez P (1995) Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 5:169–177PubMedCrossRefGoogle Scholar
  46. Stephens DN, Schneider HH, Kehr W, Jensen LH, Petersen E, Honore T (1987) Modulation of anxiety by beta-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy. Brain Res Bull 19:309–318PubMedCrossRefGoogle Scholar
  47. Stephens DN, Pistovkacova J, Worthing L, Atack JR, Dawson GR (2005) Role of GABAA α5-containing receptors in ethanol reward in the mouse: the effects of targeted gene deletion and a selective inverse agonist. Eur J Pharmacol 526:240–250PubMedCrossRefGoogle Scholar
  48. Sternfeld F, Carling RW, Jelley RA, Ladduwahetty T, Merchant KJ, Moore KW, Reeve AJ, Street LJ, O’Connor D, Sohal B, Atack JR, Cook S, Seabrook GR, Wafford KA, Tattersall FD, Collinson N, Dawson GR, Castro JL, MacLeod AM (2004) Selective, orally active γ-aminobutyric acidA α5 receptor inverse agonists as cognition enhancers. J Med Chem 47:2176–2179PubMedCrossRefGoogle Scholar
  49. Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM (2004) Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABAAα5 benzodiazepine binding site. J Med Chem 47:3642–3657PubMedCrossRefGoogle Scholar
  50. Sur C, Fresu L, Howell O, McKernan RM, Atack JR (1999) Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain. Brain Res 822:265–270PubMedCrossRefGoogle Scholar
  51. Venault P, Chapouthier G, de Carvalho LP, Simiand J, Morre M, Dodd RH, Rossier J (1986) Benzodiazepine impairs and beta-carboline enhances performance in learning and memory tasks. Nature 321:864–866PubMedCrossRefGoogle Scholar
  52. Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 12:1040–1062PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • N. Collinson
    • 1
    • 3
  • J. R. Atack
    • 1
  • P. Laughton
    • 1
  • G. R. Dawson
    • 1
  • D. N. Stephens
    • 2
  1. 1.Merck Sharp and Dohme Research LaboratoriesThe Neuroscience Research CentreHarlow,UK
  2. 2.Department of Psychology, JMS BuildingUniversity of SussexBrightonUK
  3. 3.c/o D. N. Stephens, Department of Psychology, JMS BuildingUniversity of SussexBrightonUK

Personalised recommendations