, Volume 226, Issue 3, pp 459–474 | Cite as

Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task

  • Karina A. Zanin
  • Camilla L. PattiEmail author
  • Leandro Sanday
  • Luciano Fernandes-Santos
  • Larissa C. Oliveira
  • Dalva Poyares
  • Sergio Tufik
  • Roberto Frussa-FilhoEmail author
Original Investigation



Zolpidem (Zolp), a hypnotic drug prescribed to treat insomnia, may have negative effects on memory, but reports are inconsistent.


We examined the effects of acute doses of Zolp (2, 5, or 10 mg/kg, i.p.) on memory formation (learning, consolidation, and retrieval) using the plus-maze discriminative avoidance task.


Mice were acutely treated with Zolp 30 min before training or testing. In addition, the effects of Zolp and midazolam (Mid; a classic benzodiazepine) on consolidation at different time points were examined. The possible role of state dependency was investigated using combined pre-training and pre-test treatments.


Zolp produced a dose-dependent sedative effect, without modifying anxiety-like behavior. The pre-training administration of 5 or 10 mg/kg resulted in retention deficits. When administered immediately after training or before testing, memory was preserved. Zolp post-training administration (2 or 3 h) impaired subsequent memory. There was no participation of state dependency phenomenon in the amnestic effects of Zolp. Similar to Zolp, Mid impaired memory consolidation when administered 1 h after training.


Amnestic effects occurred when Zolp was administered either before or 2–3 h after training. These memory deficits are not related to state dependency. Moreover, Zolp did not impair memory retrieval. Notably, the memory-impairing effects of Zolp are similar to those of Mid, with the exception of the time point at which the drug can modify consolidation. Finally, the memory effects were unrelated to sedation or anxiolysis.


Zolpidem Memory Consolidation State dependency Plus-maze discriminative avoidance task PM-DAT 



This research was supported by fellowships from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP: CEPID #1998/14303-3; KAZ #2008/08823-8; CLP #2009/00465-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Associação Fundo de Incentivo à Pesquisa (AFIP). This manuscript was checked for English language by the American Journal Experts (AJE) and by Dr. Eileen Sawyer, but we are entirely responsible for the scientific content of the paper. The authors would like to thank Ms. Teotila R. R. Amaral, Ms. Claudenice M. Santos, Mr. Cleomar S. Ferreira, and Mr. Antonio Rodrigues dos Santos Ferreira for capable technical assistance. D.P., S.T, and R.F.F. are recipients of the CNPq fellowship. Animals were maintained in accordance with the Brazilian Law for Procedures for Animal Scientific Use (#11794/2008) and all the experimental procedures were approved by the Institutional Animal Care and Use Committee (#1126/08).

Conflict of interest

All authors declare no conflict of interests and had no disclosures.


  1. Alvarenga TA, Patti CL, Andersen ML, Silva RH, Calzavara MB, Lopez GB, Frussa-Filho R, Tufik S (2008) Paradoxical sleep deprivation impairs acquisition, consolidation, and retrieval of a discriminative avoidance task in rats. Neurobiol Learn Mem 90:624–632PubMedCrossRefGoogle Scholar
  2. American Sleep Disorder Association. Diagnostic Classification Steering Committee of the American Sleep Disorders Association (1990) International classification of sleep disorders—diagnostic and coding manual. American Sleep Disorders Association, RochesterGoogle Scholar
  3. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH (2007) Persistence of long-term memory storage requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Neuron 53:261–277PubMedCrossRefGoogle Scholar
  4. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci USA 105:2711–2716PubMedCrossRefGoogle Scholar
  5. Bekinschtein P, Katche C, Slipczuk L, Gonzalez C, Dorman G, Cammarota M, Izquierdo I, Medina JH (2010) Persistence of long-term memory storage: new insights into its molecular signatures in the hippocampus and related structures. Neurotox Res 18:377–385PubMedCrossRefGoogle Scholar
  6. Bensimon G, Foret J, Warot D, Lacomblez L, Thiercelin JF, Simon P (1990) Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo. Br J Clin Pharmacol 30:463–469PubMedCrossRefGoogle Scholar
  7. Berlin I, Warot D, Hergueta T, Molinier P, Bagot C, Puech AJ (1993) Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects. J Clin Psychopharmacol 13:100–106PubMedCrossRefGoogle Scholar
  8. Bourtchouladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER (1998) Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 5:365–374PubMedGoogle Scholar
  9. Bruins Slot LA, Colpaert FC (1999) Opiate states of memory: receptor mechanisms. J Neurosci 19:10520–10529PubMedGoogle Scholar
  10. Bruins Slot LA, Koek W, Colpaert FC (1999) Ethanol state dependence involving a lever press response requirement in rats. Behav Pharmacol 10:229–233PubMedCrossRefGoogle Scholar
  11. Calzavara MB, Lopez GB, Abílio VC, Silva RH, Frussa-Filho R (2004) Role of anxiety levels in memory performance of spontaneously hypertensive rats. Behav Pharmacol 15:545–553PubMedCrossRefGoogle Scholar
  12. Calzavara MB, Patti CL, Lopez GB, Abílio VC, Silva RH, Frussa-Filho R (2005) Role of learning of open arm avoidance in the phenomenon of one-trial tolerance to the anxiolytic effect of chlordiazepoxide in mice. Life Sci 76:2235–2246PubMedCrossRefGoogle Scholar
  13. Carvalho RC, Patti CC, Takatsu-Coleman AL, Kameda SR, Souza CF, Garcez-do-Carmo L, Abílio VC, Frussa-Filho R, Silva RH (2006) Effects of reserpine on the plus-maze discriminative avoidance task: dissociation between memory and motor impairments. Brain Res 1122:179–183PubMedCrossRefGoogle Scholar
  14. Cashman JN, Power SJ, Jones RM (1987) Assessment of a new hypnotic imidazo-pyridine (zolpidem) as oral premedication. Br J Clin Pharmac 24:85–92CrossRefGoogle Scholar
  15. Ceretta AP, Camera K, Mello CF, Rubin MA (2008) Arcaine and MK-801 make recall state-dependent in rats. Psychopharmacology (Berl) 201:405–411CrossRefGoogle Scholar
  16. Chapouthier G, Venault P (2002) GABA-A receptor complex and memory processes. Curr Top Med Chem 2:841–851PubMedCrossRefGoogle Scholar
  17. Chodera A, Nowakowska E, Bartczak G (1994) Tolerance to a new class of non-benzodiazepine anxiolytics. Pol J Pharmacol 46:479–481PubMedGoogle Scholar
  18. Claro FT, Silva RH, Frussa-Filho R (1999) Bovine brain phosphatidylserine attenuates scopolamine induced amnesia. Physiol Behav 67:551–554PubMedCrossRefGoogle Scholar
  19. Colpaert FC (1986) A method for quantifying state-dependency with chlordiazepoxide in rats. Psychopharmacology (Berl) 90:144–146Google Scholar
  20. Colpaert FC (1990) Amnestic trace locked into the benzodiazepine state of memory. Psychopharmacology (Berl) 102:28–36CrossRefGoogle Scholar
  21. Colpaert FC, Koek W, Bruins Slot LA (2001) Evidence that amnesic state govern normal and disordered memory. Behav Pharmacol 12:575–589PubMedCrossRefGoogle Scholar
  22. Crestani F, Martin JR, Möhler H, Rudolph U (2000) Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 131:1251–1254PubMedCrossRefGoogle Scholar
  23. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U (2002) Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 99:8980–8985Google Scholar
  24. Cui XY, Zhao X, Chu QP, Chen BQ, Zhang YH (2007) Influence of diltiazem on the behavior of zolpidem-treated mice in the elevated-plus maze test. J Neural Transm 114:155–160PubMedCrossRefGoogle Scholar
  25. Danjou P, Paty I, Fruncillo R, Worthington P, Unruh M, Cevallos W, Martin P (1999) A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. J Clin Pharmacol 48:367–374Google Scholar
  26. Davies MF, Onaivi ES, Chen SW, Maguire PA, Tsai NF, Loew GH (1994) Evidence for central benzodiazepine receptor heterogeneity from behavior tests. Pharmacol Biochem Behav 49:47–56PubMedCrossRefGoogle Scholar
  27. Declerk A, Bisserbe J (1997) Short-term safety profile of zolpidem: objective measures of cognitive effects. Eur Psychiatry 1:15–20CrossRefGoogle Scholar
  28. Depoortere HB, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986) Zolpidem, a novel nonbenzodiazepine hypnotic I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 237:649–657PubMedGoogle Scholar
  29. Dingemanse J, Bury M, Hussain Y, Van Giersbergen P (2000) Comparative tolerability, pharmacodynamics, and pharmacokinetics of a metabolite of a quinolizinone hypnotic and zolpidem in healthy subjects. Am Soc Pharmacol Expe Ther 25:1411–1416Google Scholar
  30. Edgar DM, Seidel WF, Gee KW, Lan NC, Field G, Xia H, Hawkinson JE, Wieland S, Carter RB, Wood PL (1997) CCd-3693: an orally bioavailable analog of the endogenous neuroactive steroid, pregnanolone, demonstrates potent sedative hypnotic actions in the rat. J Pharmacol Exp Ther 282:420–429PubMedGoogle Scholar
  31. Elliot EE, White JM (2001) The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry. Neuropharmacol 40:717–721CrossRefGoogle Scholar
  32. Evans SM, Funderburk FR, Griffiths RR (1990) Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 255:1246–1255PubMedGoogle Scholar
  33. Fahey JM, Grassi JM, Reddi JM, Greenblatt DJ (2006) Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses. Pharmacol Biochem Behav 83(1):21–27PubMedCrossRefGoogle Scholar
  34. Fairweather DB, Kerr JS, Hindmarch I (1992) The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol 43:597–601PubMedCrossRefGoogle Scholar
  35. Frussa-Filho R, Ribeiro RA (2002) One-trial tolerance to the effects of chlordiazepoxide in the elevated plus-maze is not due to acquisition of a phobic avoidance of open arms during initial exposure. Life Sci 71:519–525PubMedCrossRefGoogle Scholar
  36. Frussa-Filho R, Patti CL, Fukushiro DF, Ribeiro LTC, Kameda SR, Carvalho RC (2010) The plus-maze discriminative avoidance task: an ethical rodent model for concomitant evaluation of learning, memory, anxiety, motor activity and their interactions. In: Andersen ML, Tufik S (eds) Animal models as ethical tools in biomedic research, 1st edn. Universidade Federal de São Paulo, São Paulo, pp 364–381Google Scholar
  37. Goldstein PA, Elsen FP, Ying SW, Ferguson C, Homanics GE, Harrison NL (2002) Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABA(A) receptor alpha1 subunit. J Neurophysiol 88:3208–3217PubMedCrossRefGoogle Scholar
  38. González-Pardo H, Conejo NM, Arias JL (2006) Oxidative metabolism of limbic structures after acute administration of diazepam, alprazolam and zolpidem. Prog Neuropsychopharmacol Biol Psychiatry 30:1020–1026PubMedCrossRefGoogle Scholar
  39. Griebel G, Sanger DJ, Perrault G (1996a) The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands. Psychopharmacology (Berl) 124:245–254CrossRefGoogle Scholar
  40. Griebel G, Sanger DJ, Perrault G (1996b) Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of “state” and “trait” anxiety. Neuropharmacology 35:1081–1091PubMedCrossRefGoogle Scholar
  41. Griebel G, Sanger DJ, Perrault G (1996c) The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands. Behav Pharmacol 7:560–572PubMedGoogle Scholar
  42. Griebel G, Perrault G, Sanger DJ (1998) Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents. J Psychopharmacol 12:356–365PubMedCrossRefGoogle Scholar
  43. Griebel G, Perrault G, Letang V, Granger P, Avenet P, Schoemaker H et al (1999) New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes. Psychoparmacology (Berl) 146:205–213CrossRefGoogle Scholar
  44. Gulick D, Gould TJ (2009a) Effects of ethanol and caffeine on behavior in C57BL/6 mice in the plus-maze discriminative avoidance task. Behav Neurosci 123(6):1271–1278PubMedCrossRefGoogle Scholar
  45. Gulick D, Gould TJ (2009b) Interactive effects of ethanol and nicotine on learning, anxiety, and locomotion in C57BL/6 mice in the plus-maze discriminative avoidance task. Neuropharmacology 57(3):302–310PubMedCrossRefGoogle Scholar
  46. Gulick D, Gould TJ (2011) Nicotine acts in the anterior cingulate, but not dorsal or ventral hippocampus, to reverse ethanol-induced learning impairments in the plus-maze discriminative avoidance task. Addict Biol 16:176–188PubMedCrossRefGoogle Scholar
  47. Herzog CD, Gandhi C, Bhattacharya P, Walsh TJ (2000) Effects of intraseptal zolpidem and chlordiazapoxide on spatial working memory and high-affinity choline uptake in the hippocampus. Neurobiol Learn Mem 73:168–179PubMedCrossRefGoogle Scholar
  48. Higashima M, Kinoshita H, Koshino Y (1998) Differences in the effects of zolpidem and diazepam on recurrent inhibition and long-term potentiation in rat hippocampal slices. Neurosci Lett 245:77–80PubMedCrossRefGoogle Scholar
  49. Holmes A, Rodgers RJ (1999) Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze. Neurosci Biobehav Ver 23:971–980CrossRefGoogle Scholar
  50. Huang MP, Radadia K, Macone BW, Auerbach SH, Datta S (2010) Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats. Behav Brain Res 210:54–66PubMedCrossRefGoogle Scholar
  51. Huopaniemi L, Keist R, Randolph A, Certa U, Rudolph U (2004) Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling. J Neurochem 88:1059–1067PubMedCrossRefGoogle Scholar
  52. Izquierdo I, Perry ML, Dias RD, Souza DO, Elizabetsky E, Carrasco MA, Orsingher OA, Netto CA (1981) Endogenous opioids memory modulation and state dependency. In: Martinez JL, Jensen RA, Messing RB, Rigter H, McGaugh JL (eds) Endogenous peptides and learning and memory process. Academic, New York, pp 269–290Google Scholar
  53. Jackson A (1995) State-dependent effects of atypical benzodiazepine-receptor agonists. Psychopharmacology (Berl) 119:399–404CrossRefGoogle Scholar
  54. Jackson A, Koek W, Colpaert FC (1992) NMDA antagonists make learning and recall state-dependent. Behav Pharmacol 3:415–421PubMedCrossRefGoogle Scholar
  55. Jensen RA, Martinez JL Jr, Vasquez BJ, McGaugh J (1979) Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice. Psychopharmacology (Berl) 64:125–126CrossRefGoogle Scholar
  56. Kameda SR, Frussa-Filho R, Carvalho RC, Takatsu-Coleman AL, Ricardo VP, Patti CL, Calzavara MB, Lopez GB, Araujo NP, Abílio VC, Ribeiro RA, D'Almeida V, Silva RH (2007) Dissociation of the effects of ethanol on memory, anxiety, and motor behavior in mice tested in the plus-maze discriminative avoidance task. Psychopharmacology (Berl) 192:39–48CrossRefGoogle Scholar
  57. Knapp DJ, Overstreet DH, Moy SS, Breese GR (2004) SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats. Alcohol 32:101–111PubMedCrossRefGoogle Scholar
  58. Kralic JE, Korpi ER, O'Buckley TK, Homanics GE, Morrow AL (2002) Molecular and pharmacological characterization of GABA(A) receptor alpha1 subunit knockout mice. J Pharmacol Exp Ther 302:1037–1045PubMedCrossRefGoogle Scholar
  59. Krystal AD, Erman M, Zammit GK, Soubrance C, Roth T (2008) Long-term efficacy and safety of zolpidemextended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep 31:79–90PubMedGoogle Scholar
  60. Langtry HD, Benfield P (1990) Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 40:291–313PubMedCrossRefGoogle Scholar
  61. Leslie JC, Shaw D, McCabe C, Reynolds DS, Dawson GR (2004) Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour. Neurosci Biobehav Rev 28:229–238PubMedCrossRefGoogle Scholar
  62. Lloyd KG, Zivkovic B (1988) Specificity within the GABA receptor supramolecular complex: a consideration of the new omega 1 receptor selective imidazopyridine hypnotic zolpidem. Pharmacol Biochem Behav 129:781–783CrossRefGoogle Scholar
  63. Lobarinas E, Falk JL (2000) Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats. Psychopharmacology (Berl) 149:176–180CrossRefGoogle Scholar
  64. 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
  65. Mathews A (1990) Why worry? The cognitive function of anxiety. Behav Res Ther 28:455–568PubMedCrossRefGoogle Scholar
  66. Mathiasen L, Mirza NR (2008) A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology (Berl) 182:475–484CrossRefGoogle Scholar
  67. Mathiasen LS, Rodgers RJ, Mirza NR (2007) Comparative effects of nonselective and subtype-selective gamma-aminobutyric acidA receptor positive modulators in the rat-conditioned emotional response test. Behav Pharmacol 18:191–203PubMedCrossRefGoogle Scholar
  68. Mayo W, Dellu F, Chekaoui J, Chapouthier G, Dodd RH, Le Moal L et al (1992) Cognitive enhancing properties of beta-CCM infused into the nucleus basalis magnocellularis of the rat. Brain Res 589:109–114PubMedCrossRefGoogle Scholar
  69. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 3:587–592PubMedCrossRefGoogle Scholar
  70. Meléndez J, Galli I, Boric K, Ortega A, Zuñiga L, Henríquez-Roldán CF, Cárdenas AM (2005) Zolpidem and triazolam do not affect the nocturnal sleep-induced memory improvement. Psychopharmacology (Berl) 181:21–26CrossRefGoogle Scholar
  71. Mintzer MZ, Griffiths RR (1999) Selective effects of zolpidem on human memory functions. J Psychopharmacol 13:18–31PubMedCrossRefGoogle Scholar
  72. Mintzer MZ, Frey JM, Yingling JE, Griffiths RR (1997) Triazolam and zolpidem: a comparison of their psychomotor, cognitive, and subjective effects in healthy volunteers. Behav Pharmacol 8:561–574PubMedCrossRefGoogle Scholar
  73. Mitchell CP, Ost ML, Flaherty CF (2004) Evidence for zolpidem-induced hyperphagia, but not anxiolysis, in a successive negative contrast paradigm. Pharmacol Biochem Behav 79:523–531PubMedCrossRefGoogle Scholar
  74. Monti JM (1989) Effect of zolpidem on sleep in insomniac patients. Eur J Clin Pharmacol 36:461–466PubMedCrossRefGoogle Scholar
  75. Morselli PL (1990) On the therapeutic action of alpidem in anxiety disorders: an overview of European data. Pharmacopsychiatry 23:129–134PubMedCrossRefGoogle Scholar
  76. Moy SS, Knapp DJ, Criswell HE, Breese GR (1997) Flumazenil blockade of anxiety following ethanol withdrawal in rats. Psychopharmacology (Berl) 131:354–360CrossRefGoogle Scholar
  77. Murphy HM, Ihekoronze C, Wideman CH (2011) Zolpidem-induced changes in activity, metabolism, and anxiety in rats. Pharmacol Biochem Behav 98:81–86PubMedCrossRefGoogle Scholar
  78. Nazar M, Jessa M, Plaznik A (1997) Benzodiazepine–GABAA receptor complex ligands in two models of anxiety. J Neural Transm 104:733–746PubMedCrossRefGoogle Scholar
  79. Niigaki ST, Silva RH, Patti CL, Cunha JL, Kameda SR, Correia-Pinto JC, Takatsu-Coleman AL, Levin R, Abílio VC, Frussa-Filho R (2010) Amnestic effect of cocaine after the termination of its stimulant action. Prog Neuropsychopharmacol Biol Psychiatry 34:212–218PubMedCrossRefGoogle Scholar
  80. Patti CL, Kameda SR, Carvalho RC, Takatsu-Coleman AL, Lopez GB, Niigaki ST, Abílio VC, Frussa-Filho R, Silva RH (2006) Effects of morphine on the plus-maze discriminative avoidance task: role of state-dependent learning. Psychopharmacology (Berl) 184:1–12CrossRefGoogle Scholar
  81. Patti CL, Zanin KA, Sanday L, Kameda S, Fernandes-Santos L, Fernandes HA, Andersen ML, Tufik S, Frussa-Filho R (2010) Effects of sleep deprivation on memory in mice: role of state-dependent learning. Sleep 33:1669–1679PubMedGoogle Scholar
  82. Pereira JK, Vieira RJ, Konishi CT, Ribeiro RA, Frussa-Filho R (1999) The phenomenon of "one-trial tolerance" to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze is abolished by the introduction of a motivational conflict situation. Life Sci 65:101–107CrossRefGoogle Scholar
  83. Perrault G, Morel E, Sanger DJ, Zivkovic B (1990) Differences in pharmacological profiles of a new generation of benzodiazepine and nonbenzodiazepine hypnotics. Eur J Pharmacol 187:487–494PubMedCrossRefGoogle Scholar
  84. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABAA receptors: immunocytochemichal distribution of 13 subunit in the adult rat brain. Neuroscience 101:815–850PubMedCrossRefGoogle Scholar
  85. Puia G, Vicini S, Seeburg PH, Costa E (1991) Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl − currents. Mol Pharmacol 39:691–696PubMedGoogle Scholar
  86. Rodgers RJ, Cao BJ, Dalvi A, Holmes A (1997) Animal models of anxiety: an ethological perspective. Braz J Med Biol Res 30:289–304PubMedCrossRefGoogle Scholar
  87. Roesler R, Quevedo J, Da Silva MC, Ferreira MB, Quillfeldt JA (1997) Age-related effects of diazepam on retention of inhibitory avoidance and shuttle avoidance tasks in rats. An Acad Bras Cienc 69:89–93PubMedGoogle Scholar
  88. Rowlett JK, Lelas S (2007) Comparison of zolpidem and midazolam self-administration under progressive-ratio schedules: consumer demand and labor supply analyses. Exp Clin Psychopharmacol 15:328–337PubMedCrossRefGoogle Scholar
  89. 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
  90. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Möhler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800PubMedCrossRefGoogle Scholar
  91. Salvà P, Costa J (1995) Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet 29:142–153PubMedCrossRefGoogle Scholar
  92. Sancar F, Ericksen SS, Kucken AM, Teissére JA, Czajkowski C (1997) Structural determinants for high-affinity zolpidem binding to GABA-A receptors. Mol Pharmacol 71:38–46CrossRefGoogle Scholar
  93. Sanday L, Zanin KA, Patti CL, Tufik S, Frussa-Filho R (2012a) Role of state-dependency in memory impairment induced by acute administration of midazolam in mice. Prog Neuropsychopharmacol Biol Psychiatry 37:1–7PubMedCrossRefGoogle Scholar
  94. Sanday L, Patti CL, Zanin KA, Tufik S, Frussa-Filho R (2012b) Amphetamine-induced memory impairment in a discriminative avoidance task is state-dependent in mice. Int J Neuropsychopharmacol. doi: 10.1017/S1461145712000296
  95. Sanger DJ, Joly D, Zivkovic B (1986) Effects of zolpidem, a new imidazopyridine hypnotic, on the acquisition of conditioned fear in mice. Comparison with triazolam and CL 218,872. Psychopharmacology (Berl) 90:207–210CrossRefGoogle Scholar
  96. Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B (1994) Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes (review). Neurosci Biobehav Rev 18:335–372CrossRefGoogle Scholar
  97. Sanger DJ, Morel E, Perrault G (1996) Comparison of the pharmacological profiles of the hypnotic drugs zaleplon and zolpidem. Eur Pharmacol 313:35–42CrossRefGoogle Scholar
  98. Sarantis K, Sotiriou E, Papatheodoropoulos C, Matsokis N, Angelatou F (2008) Differential pharmacological properties of GABAA/benzodiazepine receptor complex in dorsal compared to ventral rat hippocampus. Neurochem Int 52:1019–1029PubMedCrossRefGoogle Scholar
  99. Savić MM, Obradović DI, Ugresić ND, Cook JM, Yin W, Bokonjić DR (2004) Bidirectional effects of benzodiazepine binding site ligands in the elevated plus-maze: differential antagonism by flumazenil and beta-CCt. Pharmacol Biochem Behav 79:279–290PubMedCrossRefGoogle Scholar
  100. Savić MM, Obradović DI, Ugresić ND, Cook JM, Sarma PVVS, Bokonjić DR (2005a) Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and beta-CCt. Psychopharmacology (Berl) 180:455–465CrossRefGoogle Scholar
  101. Savić MM, Obradović DI, Ugresić ND, Cook JM, Yin W, Bokonjić DR (2005b) Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt. Behav Brain Res 158:293–300PubMedCrossRefGoogle Scholar
  102. Seibt J, Aton SJ, Jha SK, Coleman T, Dumoulin MC, Frank MG (2008) The non-benzodiazepine hypnotic zolpidem impairs sleep-dependent cortical plasticity. Sleep 31:1381–1391PubMedGoogle Scholar
  103. Siemiatkowski M, Sienkiewicz-Jarosz H, Członkowska AI, Bidziński A, Płaźnik A (2000) Effects of buspirone, diazepam, and zolpidem on open field behavior, and brain [3H]muscimol binding after buspirone pretreatment. Pharmacol Biochem Behav 66:645–651PubMedCrossRefGoogle Scholar
  104. Silva RH, Frussa-Filho (2000) The plus-maze discriminative avoidance task: a new model to study memory-anxiety interactions. Effects of chlordiazepoxide and caffeine. J Neurosci Methods 102:117–125PubMedCrossRefGoogle Scholar
  105. Silva RH, Frussa-Filho R (2002) Naltrexone potentiates both amnestic and anxiolytic effects of chlordiazepoxide in mice. Life Sci 72:721–730PubMedCrossRefGoogle Scholar
  106. Silva RH, Bellot RG, Vital MABF, Frussa-Filho R (1997) Effects of long-term ganglioside GM1 administration on a new discriminative avoidance test in normal adult mice. Psychopharmacology (Berl) 129:322–328Google Scholar
  107. Silva RH, Felício LF, Frussa-Filho R (1999) Ganglioside GM1 attenuates scopolamine-induced amnesia. Psychopharmacology (Berl) 160:9–18Google Scholar
  108. Silva RH, Abílio VC, Torres-Leite D, Bergamo M, Chinen CC, Claro FT, Carvalho RC, Frussa-Filho R (2002a) Concomitant development of oral dyskinesia and memory deficits in reserpine-treated male and female mice. Behav Brain Res 132:171–177PubMedCrossRefGoogle Scholar
  109. Silva RH, Kameda SR, Carvalho RC, Rigo GS, Costa KLB, Taricano ID, Frussa-Filho R (2002b) Effects of amphetamine on the plus-maze discriminative avoidance task in mice. Psychopharmacology (Berl) 160:9–18CrossRefGoogle Scholar
  110. Silva RH, Chehin AB, Kameda SR, Takatsu-Coleman AL, Abílio VC, Tufik S, Frussa-Filho R (2004) Effects of pre- or post-training paradoxical sleep deprivation on two animal models of learning and memory in mice. Neurobiol Learn Mem 82:90–98PubMedCrossRefGoogle Scholar
  111. Sun C, Sieghart W, Kapur J (2004) Distribution of alpha1, alpha4, gamma2, and delta subunits of GABAA receptors in hippocampal granule cells. Brain Res 1029:207–216PubMedCrossRefGoogle Scholar
  112. Tang AH, Smith MW, Carter DB, Im WB, Von Voigtlander PF (1995) U-90042, a sedative/hypnotic compound that interacts differentially with the GABA-A receptor subtypes. J Pharmacol Exp Ther 275:761–767PubMedGoogle Scholar
  113. Vargas-Caballero M, Martin LJ, Salter MW, Orser BA, Paulsen O (2010) Alpha5 subunit-containing GABA(A) receptors mediate a slowly decaying inhibitory synaptic current in CA1 pyramidal neurons following Schaffer collateral activation. Neuropharmacology 58:668–675PubMedCrossRefGoogle Scholar
  114. Visser SA, Wolters FL, van der Graaf PH, Peletier LA, Danhof M (2003) Dose-dependent EEG effects of zolpidem provide evidence for GABA(A) receptor subtype selectivity in vivo. J Pharmacol Exp Ther 304:1251–1257PubMedCrossRefGoogle Scholar
  115. Wesensten NJ, Balkin TJ, Belenkey GL (1996) Effects of daytime administration of zolpidem and triazolam on performance. Aviat Space Environ Med 67:115–120PubMedGoogle Scholar
  116. Wichlinski LJ, Jensen RA (1996) Effects of beta-CCE on retention of aversively- and appetitively-motivated tasks in rats. Physiol Behav 60:1121–1124PubMedCrossRefGoogle Scholar
  117. Yee BK, Hauser J, Dolgov VV, Keist R, Möhler H, Rudolph U, Feldon J (2004) GABA receptors containing the alpha5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear. Eur J Neurosci 20:1928–1936PubMedCrossRefGoogle Scholar
  118. Zanin KA, Patti CL, Tufik S, Poyares D, Frussa-Filho R (2011) Zolpidem impairs non-associative memory in mice. Sleep Sci 3:81–87Google Scholar
  119. Zivkovic B, Perrault G, Morel E et al (1988) Comparative pharmacology of zolpidem and other hypnotics and sleep inducers. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders: a novel experimental and therapeutic approach. Raven, New York, pp 97–109Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Karina A. Zanin
    • 1
    • 2
  • Camilla L. Patti
    • 1
    • 2
    Email author
  • Leandro Sanday
    • 2
  • Luciano Fernandes-Santos
    • 1
    • 2
  • Larissa C. Oliveira
    • 2
  • Dalva Poyares
    • 1
  • Sergio Tufik
    • 1
  • Roberto Frussa-Filho
    • 2
    Email author
  1. 1.Departamento de PsicobiologiaUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Departamento de FarmacologiaUniversidade Federal de São PauloSão PauloBrazil

Personalised recommendations