, Volume 176, Issue 2, pp 167–175 | Cite as

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice

  • T. Escher
  • G. MittlemanEmail author
Original Investigation



It has been suggested that GABAB receptors may be part of a neural substrate mediating some of the effects of ethanol.


The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABAB receptors.


Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice.


Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance.


Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABAB drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.


GABAB Ethanol Alcohol DMTP Working memory Mice 


  1. Allan AM, Harris RA (1989) A new alcohol antagonist: phaclofen. Life Sci 45:1771–1779PubMedGoogle Scholar
  2. Ambrose ML, Bowden SC, Whelan G (2001) Working memory impairments in alcohol-dependent participants without clinical amnesia. Alcohol Clin Exp Res 25:185–191PubMedGoogle Scholar
  3. Ammassari-Teule M, Hoffmann HJ, Rossi-Arnaud C (1993) Learning in inbred mice: strain-specific abilities across three radial maze problems. Behav Genet 23:405–412PubMedGoogle Scholar
  4. Ammassari-Teule M, Save E, de Marsanich B, Thinus-Blanc C (1998) Posterior parietal cortex lesions severely disrupt spatial learning in DBA mice characterized by a genetic hippocampal dysfunction. Behav Brain Res 95:85–90CrossRefPubMedGoogle Scholar
  5. Bimonte HA, Hyde LA, Hoplight BJ, Denenberg VH (2000) In two species, females exhibit superior working memory and inferior reference memory on the water radial-arm maze. Physiol Behav 70:311–317CrossRefPubMedGoogle Scholar
  6. Bowery N (1989) GABAB receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci Rev 10:401–407CrossRefGoogle Scholar
  7. Broadbent J, Harless WE (1999) Differential effects of GABAA and GABAB agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Psychopharmacology 141:197–205Google Scholar
  8. Brucato FH, Levin ED, Mott DD, Lewis DV, Wilson WA, Swartzwelder HS (1996) Hippocampal long-term potentiation and spatial learning in the rat: effects of GABAB receptor blockade. Neuroscience 74:331–339CrossRefPubMedGoogle Scholar
  9. Castellano C, McGaugh JL (1989) Retention enhancement with post-training picrotoxin: lack of state dependency. Behav Neural Biol 51:165–170PubMedGoogle Scholar
  10. Chester JA, Cunningham CL (1999) Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice. Pharmacol Biochem Behav 63:325–331PubMedGoogle Scholar
  11. Cott J, Carlsson A, Engel J, Lindqvist M (1976) Suppression of ethanol-induced locomotor stimulation by GABA-like drugs. Naunyn-Schmiedeberg’s Arch Pharmacol 295:203–209PubMedGoogle Scholar
  12. Crabbe JC (1983) Sensitivity to ethanol in inbred mice: genotypic correlations among several behavioral responses. Behav Neurosci 97:280–289PubMedGoogle Scholar
  13. Crabbe JC, Johnson NA, Gray DK, Kosobud A, Young ER (1982) Biphasic effects of ethanol on open-field activity: sensitivity and tolerance in C57BL/6N and DBA/2N mice. J Comp Physiol Psychol 96:440–451PubMedGoogle Scholar
  14. Crabbe JC, Phillips TJ, Cunningham CL, Belknap JK (1992) Genetic determinants of ethanol reinforcement. Ann N Y Acad Sci 654:302–310PubMedGoogle Scholar
  15. Crabbe JC, Belknap JK, Buck KJ, Metten P (1994) Use of recombinant inbred strains for studying genetic determinants of responses to alcohol. Alcohol Alcohol 2:67–71Google Scholar
  16. DeSousa NJ, Beninger RJ, Jhamandas K, Boegman RJ (1994) Stimulation of GABAB receptors in the basal forebrain selectively impairs working memory in rats in the double Y-maze. Brain Res 641:29–38PubMedGoogle Scholar
  17. Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology 87:357–363Google Scholar
  18. Dunnett SB (1993) The role and repair of forebrain cholinergic systems in short-term memory: studies using the delayed matching-to-position task in rats. Adv Neurol 59:53–65PubMedGoogle Scholar
  19. Dunnett SB, Martel FL (1990) Proactive interference effects on short-term memory in rats. I. Basic parameters and drug effects. Behav Neurosci 104:655–665PubMedGoogle Scholar
  20. Dunnett SB, Badman F, Rogers DC, Evenden JL, Iversen SD (1988) Cholinergic grafts of neocortex or hippocampus of aged rats: reduction of delay-dependent deficits in the delayed non-matching to position task. Exp Neurol 102:57–64PubMedGoogle Scholar
  21. Dunnett SB, Martel FL, Iversen SD (1990) Proactive interference effects on short-term memory in rats. II. Effects in young and aged rats. Behav Neurosci 104:666–670CrossRefPubMedGoogle Scholar
  22. Estape N, Steckler T (2001) Effects of cholinergic manipulation on operant delayed non-matching to position performance in two inbred strains of mice. Behav Brain Res 212:39–55CrossRefGoogle Scholar
  23. Froestl W, Mickel SJ, von Sprecher G, Diel PJ, Hall RG et al (1995) Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J Med Chem 38:3313–3331PubMedGoogle Scholar
  24. Girard TA, Xing HC, Ward GR, Wainwright PE (2000) Early postnatal ethanol exposure has long-term effects on the performance of male rats in a delayed matching-to-place task in the Morris water maze. Alcohol Clin Exp Res 24:300–306PubMedGoogle Scholar
  25. Givens B (1995) Low doses of ethanol impair spatial working memory and reduce hippocampal theta activity. Alcohol Clin Exp Res 19:763–767PubMedGoogle Scholar
  26. Givens B, McMahon K (1997) Effects of ethanol on nonspatial working memory and attention in rats. Behav Neurosci 111:275–282CrossRefPubMedGoogle Scholar
  27. Hoffman SE, Matthews DB (2001) Ethanol-induced impairments in spatial working memory are not due to deficits in learning. Alcohol Clin Exp Res 25:856–861CrossRefPubMedGoogle Scholar
  28. Humeniuk RE, White JM, Ong J (1993) The role of GABAB receptors in mediating the stimulatory effects of ethanol in mice. Psychopharmacology 111:219–224Google Scholar
  29. Kiianmaa K, Hyytia P, Samson HH, Engel JA, Svensson L et al (2003) New neuronal networks involved in ethanol reinforcement. Alcohol Clin Exp Res 27:209–219CrossRefPubMedGoogle Scholar
  30. Lalley PM (1983) Biphasic effects of baclofen on phrenic motoneurons: possible involvement of two types of gamma-aminobutyric acid (GABA) receptors. J Pharmacol Exp Ther 226:616–624PubMedGoogle Scholar
  31. Lawson CJ, Homewood J, Taylor AJ (2002) The effects of l-glucose on memory in mice are modulated by peripherally acting cholinergic drugs. Neurobiol Learn Mem 77:17–28CrossRefPubMedGoogle Scholar
  32. Lewohl JM, Wilson WR, Mayfield RD, Brozowski SJ, Morrisett RA et al (1999) G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci 2:1084–1090CrossRefPubMedGoogle Scholar
  33. Lister RG, Gorenstein C, Risher-Flowers D, Weingartner HJ, Eckardt MJ (1991) Dissociation of the acute effects of alcohol on implicit and explicit memory processes. Neuropsychologia 29:1205–1212PubMedGoogle Scholar
  34. Martz A, Deitrich RA, Adron Harris R (1983) Behavioral evidence for the involvement of γ-aminobutryric acid in the actions of ethanol. Eur J Pharmacol 89:53–62PubMedGoogle Scholar
  35. Matthews DB, Morrow AL (2000) Effects of acute and chronic ethanol exposure on spatial cognitive processing and hippocampal function in the rat. Hippocampus 10:122–130CrossRefPubMedGoogle Scholar
  36. Mead AJ, Little HJ (1995) Do GABAB receptors have a role in causing behavioral hyperexcitability, both during ethanol withdrawal and in naive mice? Psychopharmacology 117:232–239Google Scholar
  37. Mehta AK, Ticku MK (1999) An update on the GABAA receptors. Brain Res Rev 29:196–217PubMedGoogle Scholar
  38. Melia KF, Koob GF, Ehlers CL (1990) Ethanol effects on delayed spatial matching as modeled by a negative exponential forgetting function. Psychopharmacology 102:391–398PubMedGoogle Scholar
  39. Mondadori C, Jaekel J, Preiswerk G (1993) CGP 36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys. Behav Neural Biol 60:62–68PubMedGoogle Scholar
  40. Mondadori C, Hengerer B, Ducret T, Borkowski J (1994) Delayed emergence of effects of memory-enhancing drugs: implications for the dynamics of long-term memory. Proc Natl Acad Sci USA 91:2041–2045PubMedGoogle Scholar
  41. Mondadori C, Mobius H, Borkowski J (1996) The GABAB receptor antagonist CGP 36,742 and the nootropic oxiracetam facilitate the formation of long-term memory. Behav Brain Res 77:223–225CrossRefPubMedGoogle Scholar
  42. Murray DM, Blitstein JL (2003) Methods to reduce the impact of intraclass correlation in group-randomized trials. Eval Rev J Appl Soc Res 27:79–103CrossRefGoogle Scholar
  43. Nakagawa Y, Takashima T (1997) The GABAB receptor antagonist CGP36742 attenuates the baclofen- and scopolamine-induced deficit in Morris water maze task in rats. Brain Res 766:101–106CrossRefPubMedGoogle Scholar
  44. Pache D, Sewell R, Spencer P (1999) Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task. J Pharmacol Toxicol Meth 41:135–141CrossRefPubMedGoogle Scholar
  45. Phillips TJ, Dickinson S, Burkhart-Kasch S (1994) Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice. Behav Neurosci 108:789–803PubMedGoogle Scholar
  46. Phillips TJ, Huson M, Gwiazdon C, Burkhart-Kasch S, Shen EH (1995) Effects of acute and repeated ethanol exposures on the locomotor activity of BXD recombinant inbred mice. Alcohol Clin Exp Res 19:269–278PubMedGoogle Scholar
  47. Pittaluga A, Feligioni M, Ghersi C, Gemignani A, Raiteri M (2001) Potentiation of NMDA receptor function through somatostatin release: a possible mechanism of the cognition-enhancing activity of GABAB receptor antagonists. Neuropharmacology 41:301–310CrossRefPubMedGoogle Scholar
  48. Pokk P, Vassiljev V, Vali M (2000) The effect of baclofen on the locomotor activity of control and small-platform-stressed mice. Pharmacol Res 42:235–237CrossRefPubMedGoogle Scholar
  49. Romanides AJ, Duffy P, Kalivas PW (1999) Glutamatergic and dopaminergic afferents to the prefrontal cortex regulate spatial working memory in rats. Neuroscience 92:97–106PubMedGoogle Scholar
  50. Rossetti Z, Carboni S, Stancampiano R, Sori P, Pepeu G et al (2002) Bidirectional modulation of spatial working memory by ethanol. Alcohol Clin Exp Res 26:181–185CrossRefPubMedGoogle Scholar
  51. Sahgal A (1987a) Contrasting effects of vasopressin, desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats. Psychopharmacology 93:243–249Google Scholar
  52. Sahgal A (1987b) Some limitations of indices derived from signal detection theory: evaluation of an alternative index for measuring bias in memory tasks. Psychopharmacology 91:517–520PubMedGoogle Scholar
  53. Sands SA, McCarson KE, Enna SJ (2003) Differential regulation of GABAB receptor subunit expression and function. J Pharmacol Exp Ther 305:191–196CrossRefPubMedGoogle Scholar
  54. Shen EH, Dorow J, Harland R, Burkhart-Kasch S, Phillips TJ (1998) Seizure sensitivity and GABAergic modulation of ethanol sensitivity in selectively bred FAST and SLOW mouse lines. J Pharmacol Exp Ther 287:606–615PubMedGoogle Scholar
  55. Stirling JM, Cross AJ, Robinson TN, Green AR (1989) The effects of GABAB receptor agonists and antagonists on potassium-stimulated [Ca2+]i in rat brain synaptosomes. Neuropharmacology 28:699–804CrossRefPubMedGoogle Scholar
  56. Upchurch M, Wehner JM (1988a) Differences between inbred strains of mice in Morris water maze performance. Behav Genet 18:55–68PubMedGoogle Scholar
  57. Upchurch M, Wehner JM (1988b) DBA/2lbg mice are incapable of cholinergically-based learning in the Morris water task. Pharmacol Biochem Behav 29:325–329CrossRefPubMedGoogle Scholar
  58. Upchurch M, Wehner JM (1989) Inheritance of spatial learning ability in inbred mice: a classical genetic analysis. Behav Neurosci 103:1251–1258PubMedGoogle Scholar
  59. Wan FJ, Berton F, Madamba SG, Francesconi W, Siggins GR (1996) Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials in hippocampal pyramidal neurons only after block of GABAB receptors. Proc Natl Acad Sci USA 93:5049–5054CrossRefPubMedGoogle Scholar
  60. Winer BJ, Brown DR, Michels KM (1991) Statistical principles in experimental design, 3rd edn. McGraw-Hill, BostonGoogle Scholar
  61. Zaleski MJB, Filho JRN, Lemos T, Morato GS (2001) GABAB receptors play a role in the development of tolerance to ethanol in mice. Psychopharmacology 153:415–424CrossRefPubMedGoogle Scholar
  62. Zarrindast MR, Lahji P, Shafaghi B, Sadegh M (1998) Effects of GABAergic drugs on physiostigmine-induced improvement in memory acquisition of passive avoidance learning in mice. Gen Pharmacol 31:81–86CrossRefPubMedGoogle Scholar
  63. Zilles K, Wu J, Crusio WE, Schwgler H (2000) Water maze and radial maze learning and the density of binding sites of glutamate, GABA, and serotonin receptors in the hippocampus of inbred mouse strains. Hippocampus 10:213–225PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of MemphisMemphisUSA

Personalised recommendations