, Volume 116, Issue 2, pp 135–142 | Cite as

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

  • Belinda J. Cole
  • Graham H. Jones
  • Jonathan D. Turner


A series of experiments examined the effects of 5-HT1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT1A receptors influences short term spatial working memory in the rat.

Key words

Short term memory Delayed matching to position 5-HT 5-HT1A receptor 8-OH DPAT Ipsapirone Rat 


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  1. Ahlers ST, Weissman BA, Barrett JE (1992) Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons. J Pharmacol Exp Ther 260: 474–481Google Scholar
  2. Aigner TG, Mishkin M (1986) The effects of physostigmine and scopolamine on recognition memory in primates. Behav Neural Biol 45: 81–87Google Scholar
  3. Amaral DG, Insausti R, Cowan WM (1987) The entorhinal cortex of the monkey: 1. Cytoarchitechtonic organization. J Comp Neurol 264: 326–355Google Scholar
  4. Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM, Tyers MB (1990) The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primate. Pharmacol Biochem Behav 35: 955–962Google Scholar
  5. Bartus RT, Johnson HR (1976) Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine. Pharmacol Biochem Behav 5: 39–46Google Scholar
  6. Beatty WM, Butters N, Janowsky DS (1986) Patterns of memory failure after scopolamine treatment: Implications for cholinergic hypotheses of dementia. Behav Neural Biol 45: 196–211Google Scholar
  7. Bianchi C, Siniscalchi A, Beani L (1990) 5-HT1A agonists increase and 5-HT3 agonists decrease acetylcholine efflux from the cerebral cortex of freely-moving guinea-pigs. Br J Pharmacol 101: 448–452Google Scholar
  8. Bockaert J, Dumois A, Bouhelal R, Sebben M, Cory RN (1987) Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons. Naunyn-Schmiedeberg's Arch Pharmacol 335: 588–592Google Scholar
  9. Bowen DM, Francis PT, Pangalos MN, Stephens PH, Procter AW (1992a) Treatment strategies for Alzheimer's disease. Lancet 339: 132–133Google Scholar
  10. Bowen DM, Francis PT, Pangalos MN, Stephens PH, Procter AW, Chessell IP (1992b) “Traditional” pharmacotherapy may succeed in Alzheimer's disease. Trends Neurosci 15: 84–85Google Scholar
  11. Broks P, Preston GC, Traub M, Poppleton P, Ward C, Stahl SM (1988) Modelling dementia: effects of scopolamine on memory and attention. Neuropsychology 26: 685–700Google Scholar
  12. Carli M, Lazarova M, Tatarczynska E, Samanin R (1992a) Stimulation of 5-HT1a receptors in the dorsal hippocampus impairs acquisition and performance of a spatial task in a water maze. Brain Res 595: 50–56Google Scholar
  13. Carli M, Samanin R (1992) 8-Hydroxy-2-(di-n-propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5-HT1a receptors. Br J Pharmacol 105:720–726Google Scholar
  14. Carli M, Tranchina S, Samanin R (1992b) 8-Hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1a receptor agonist, impairs performance in a passive avoidance task. Eur J Pharmacol 211: 227–234Google Scholar
  15. Claustre Y, Rouquier L, Serrano A, Benavides J, Scatton B (1991) Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission. Eur J Pharmacol 204: 71–77Google Scholar
  16. Cole BJ, Hillmann M (1994) Bi-directional effects of benzodiazepine receptor ligands on the performance of delayed matching to sample. Psychopharmacology (in press)Google Scholar
  17. Cole BJ, Jones GH, Stephens DN (1993) Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats. Psychopharmacology 111: 465–471Google Scholar
  18. Dawson GR, Bentley G, Draper F, Rycroft W, Iversen SD, Pagella PG (1991) The behavioral effects of heptyl physostigmine, a new cholinesterase inhibitor, in tests of long-term and working memory in the rat. Pharmacol Biochem Behav 39: 865–871Google Scholar
  19. Deutsch JA (1971) The cholinergic synapse and the site of memory. Science 174: 788–794Google Scholar
  20. De Vivo M, Maayani T (1986) Characterization of the 5-hydroxytryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampus. J Pharmacol Exp Ther 238: 248–253Google Scholar
  21. De Vry J, Glaser T, Schuurman T, Schreiber R, Traber J (1991) 5-HT1A receptors in anxiety. In: Briley M, File SE (eds) New concepts in anxiety. Macmillan, London, pp 94–129Google Scholar
  22. Domeney AM, Costall B, Gerrard PA, Jones DNC, Naylor RJ, Tyers MB (1991) The effect of ondansetron on cognitive performance in the marmoset. Pharmacol Biochem Behav 38: 169–175Google Scholar
  23. Dourish CT, Hutson PH, Curson G (1985) Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT) elicit feeding in the rat. Pyschopharmacology 86: 197–204Google Scholar
  24. Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology 96: 174–180Google Scholar
  25. Dunnett SB, Martel FL (1990) Proactive interference effects on short-term memory in rats: 1. Basic parameters and drug effects. Behav Neurosci 104: 655–665Google Scholar
  26. Fletcher PJ (1987) 8-OH-DPAT elicits gnawing and eating of solid but not liquid foods. Psychopharmacology 92: 192–196Google Scholar
  27. Fletcher PJ, Zack MH, Coscina DV (1991) Influence of taste and food texture on the feeding responses induced by 8-OH-DPAT and gepirone. Psychopharmacology 104: 302–306Google Scholar
  28. Fletcher A, Bill DJ, Bill SJ, Cliffe IA, Dover GM, Forster EA, Haskins JT, Jones D, Mansell HL, Reilly Y (1993) WAY100135: a novel, selective antagonist at presynaptic and postsynaptic 5-HT1A receptors. Eur J Pharmacol 237: 283–291Google Scholar
  29. Flicker C, Serby M, Ferris SH (1990) Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed. Psychopharmacology 100: 243–250Google Scholar
  30. Fuller RW, Snoddy HD (1987) Influence of route of administrtion on potency of the selective 5HT-1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin, in rats. Res Commun Chem Pathol Pharmacol 58: 409–412Google Scholar
  31. Gilbert F, Dourish CT (1987) Effects of the novel anxiolytics gepirone, buspirone and ipsapirone on free feeding and on feeding induced by 8-OH DPAT. Psychopharmacology 93: 349–352Google Scholar
  32. Glennon RA, Naiman NA, Pierson ME, Titeler M, Lyon RA, Weisberg E (1988) NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur J Pharmacol 154: 339–341Google Scholar
  33. Glennon RA, Naiman NA, Pierson ME, Titeler M, Lyon RA, Herndon JL, Misenheimer B (1989) Stimulus properties of arylpiperazines: NAN-190, a potential 5-HT1A serotonin antagonist. Drug Dev Res 16: 335–343Google Scholar
  34. Gower AJ, Tricklebank MD (1988) Alpha2-adrenoceptor antagonist activity may account for the effects of buspirone in an anticonflict test in the rat. Eur J Pharmacol 155: 129–137Google Scholar
  35. Greuel JM, Glaser T (1992) The putative 5-HT1A receptor antagonists NAN-190 and BMY 7378 are partial agonists in the rat dorsal raphe nucleus in vitro. Eur J Pharmacol 211: 211–219Google Scholar
  36. Hjorth S, Magnusson T (1988) The 5-HT1A receptor agonist, 8-OH-DPAT, preferentially activates cell body 5-HT autoreceptors in rat brain in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 338: 463–471Google Scholar
  37. Hjorth S, Sharp T (1990) Mixed agonist/antagonist properties of NAN-190 at 5HT1A receptors: behavioural and in vivo brain microdialysis studies. Life Sci 46: 955–963Google Scholar
  38. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225: 1168–1170Google Scholar
  39. Insausti R, Amaral DG, Cowan WM (1987) The entorhinal cortex of the monkey: II. Cortical afferents. J Comp Neurol 264: 356–395Google Scholar
  40. Lejeune F, Rivet J-M, Gobert A, Canton H, Millan MJ (1993) WAY 100,135 and (-)-tertatolol act as antagonists at both 5-HT1A autoreceptors and post-synaptic 5-HT1A receptors in vivo. Eur J Pharmacol 240: 307–310Google Scholar
  41. Levisohn LF, Isacson O (1991) Excitotoxic lesions of the rat entorhinal cortex. Effects of selective neuronal damage on acquisition and retention of a non-spatial reference memory task. Brain Res 564: 230–244Google Scholar
  42. Montgomery AMJ, Willner P, Muscat R (1988) Behavioural specificity of 8-OH-DPAT-induced feeding. Psychopharmacology 94: 110–114Google Scholar
  43. Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. 1. Serotonin-1 receptors. Brain Res 346: 205–230Google Scholar
  44. Peroutka SJ (1993) 5-Hydroxytryptamine receptors. J Neurochem 60: 408–416Google Scholar
  45. Pompeiano M, Palacios JM, Mengod G (1992) Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 12: 440–453Google Scholar
  46. Rawlins JNP (1985) Associations across time: the hippocampus as a temporary memory store. Behav Brain Sci 8: 479–496Google Scholar
  47. Richter-Levin G, Segal M (1989) Spatial performance is severely impaired in rats with combined reductions of serotonergic and cholinergic transmission. Brain Res 477: 404–407Google Scholar
  48. Riekkinen P Jr, Jakala P, Sirvio J, Riekkinen P (1991a) The effects of increased serotonergic and decreased cholinergic activities on spatial navigation performance in rats. Pharmacol Biochem Behav 39: 25–29Google Scholar
  49. Riekkinen P Jr, Sirvio J, Valjakka A, Riekkinen P (1991b) Pharmacological consequences of cholinergic plus serotonergic manipulations. Brain Res 552: 23–26Google Scholar
  50. Saghal A (1987) Contrasting effects of vasopressin, desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats. Psychopharmacology 93: 243–249Google Scholar
  51. Sakurai Y, Wenk GL (1990) The interaction of acetylcholinergic and serotonergic neural systems on performance in a continuous non-matching to sample task. Brain Res 519: 118–121Google Scholar
  52. Selden NRW, Cole BJ, Everitt BJ, Robbins TW (1990) Damage to ceruleo-cortical noradrenergic projections impairs locally cued but enhances spatially cued water maze acquisition. Behav Brain Res 39: 29–51Google Scholar
  53. Spencer DG, Emmett-Oglesby MW (1985) Parallel processing strategies in the application of microcomputers to the behavioral laboratory. Behav Res Methods Instrum Comput 17: 294–300Google Scholar
  54. Sprouse JS, Aghajanian GK (1988) Response of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonist: a comparative study with dorsal raphe neurons. Neuropharmacology 7: 707–715Google Scholar
  55. Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys and humans. Psychol Rev 99: 195–231Google Scholar
  56. Stevens R (1981) Scopolamine impairs spatial maze performance in rats. Physiol Behav 27: 385–386Google Scholar
  57. Van Hest A, Stroet J, Van Haaren F, Feenstra M (1990) Scopolamine differentially disrupts the behavior of male and female Wistar rats in a delayed nonmatching to position procedure. Pharmacol Biochem Behav 35: 903–909Google Scholar
  58. Van Wijngaarden I, Tulp MTM, Soudijn W (1990) The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 133: 47–56Google Scholar
  59. Williams AR, Dourish (1992) Effects of the putative 5-HT1A receptor antagonist NAN-190 on free feeding and on feeding induced by the 5-HT1A receptor agonist in the rat. Eur J Pharmacol 219: 105–112Google Scholar
  60. Winter JC, Petti DT (1987) The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory. Pharmacol Biochem Behav 27: 625–628Google Scholar
  61. Zola-Morgan S, Squire LR, Amaral DG (1986) Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 6: 2950–2967Google Scholar
  62. Zola-Morgan S, Squire LR, Amaral DG, Suzuki WA (1989) Lesions of perirhinal and parahippocampal cortex that spare the amygdala and hippocampal formation produce severe memory impairments. J Neurosci 9: 4355–4370Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Belinda J. Cole
    • 1
  • Graham H. Jones
    • 1
  • Jonathan D. Turner
    • 1
  1. 1.Department of NeuropsychopharmacologyResearch Laboratories of Schering AGBerlinGermany

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