An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze
- 410 Downloads
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.
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.
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).
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.
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.
KeywordsBenzodiazepine Memory Learning and memory GABA receptor Cognition
- Argyropoulos SV, Nutt DJ (1999) The use of benzodiazepines in anxiety and other disorders. Eur Neuropsychopharmacol 9(Suppl 6):S391–S392Google Scholar
- 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
- 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
- Cobain MR (1999) The localization and function of the alpha5 subunit containing GABAA receptors in the rat. PhD thesis, Downing College, CambridgeGoogle Scholar
- 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
- 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
- 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
- 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
- Sarter M, Stephens DN (1988) β-carbolines as tools in memory research: animal data and speculations. Psychopharmacol Ser 6:230–245Google Scholar
- 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
- 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