Skip to main content
Log in

Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Gating of sensory responses is impaired in schizophrenic patients and animal models of schizophrenia. Ketamine, an N-methyl-d-aspartate receptor antagonist, is known to induce schizophrenic-like symptoms including sensory gating deficits in humans.

Objective

This study aims to investigate the mechanisms underlying ketamine’s effect on gating of auditory evoked potentials in the hippocampus of freely moving rats.

Methods

Gating was measured by the ratio of the test-click response (T) to the conditioning-click response (C), or T/C, with T and C measured as peak amplitudes.

Results

Ketamine (1, 3, or 6 mg/kg s.c.) injection dose-dependently increased T/C ratio as compared to saline injection (s.c.). T/C ratio was 0.48 ± 0.05 after saline injection and 0.73 ± 0.17 after ketamine (3 mg/kg s.c.) injection. The increase in T/C ratio after ketamine was blocked by prior inactivation of the medial septum with GABAA receptor agonist muscimol or by systemic administration of antipsychotic drugs, including chlorpromazine (5 mg/kg i.p.), haloperidol (1 mg/kg i.p.), or clozapine (7.5 mg/kg i.p.). Infusion of muscimol into the medial septum or injection of an antipsychotic drug alone did not affect the T/C ratio. However, rats with selective lesion of the septohippocampal cholinergic neurons by 192 IgG-saporin showed a significantly higher T/C ratio (0.86 ± 0.10) than sham lesion rats (0.26 ± 0.07), and ketamine did not further increase T/C ratio in rats with septohippocampal cholinergic neuron lesion.

Conclusions

Ketamine’s disruption of hippocampal auditory gating was normalized by inactivation of the medial septum; in addition, septal cholinergic neurons participate in normal auditory gating.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Adler LE, Pachtman E, Fanks RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17:639–654

    PubMed  CAS  Google Scholar 

  • Adler LE, Rose G, Freedman R (1986) Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol. Biol Psychiatry 21:787–798

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R (1998) Schizophrenia, sensory gating, and nicotinic receptors. Schizo Bull 24:189–202

    CAS  Google Scholar 

  • Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:183–192

    Article  PubMed  CAS  Google Scholar 

  • Boeijinga PH, Soufflet L, Santoro F, Luthringer R (2007) Ketamine effects on CNS responses assessed with MEG/EEG in a passive auditory sensory-gating paradigm: an attempt for modelling some symptoms of psychosis in man. J Psychopharmacol 21:321–337

    Article  PubMed  CAS  Google Scholar 

  • Brankack J, Buzsaki G (1986) Hippocampal responses evoked by tooth pulp and acoustic stimulation: depth profiles and effect of behavior. Brain Res 378:303–314

    Article  PubMed  CAS  Google Scholar 

  • Buhler AV, Dunwiddie T (2001) Regulation of the activity of hippocampal stratum oriens interneurons by α7 nicotinic acetylcholine receptors. Neuroscience 106:55–67

    Article  PubMed  CAS  Google Scholar 

  • Bunney BS (1979) The electrophysiological pharmacology of midbrain dopaminergic systems. In: Horn AS, Korf J, Westerink BHC (eds) The neurobiology of dopamine. Academic, London, pp 417–452

    Google Scholar 

  • Chung Y-C, Li Z, Dai J, Meltzer HY, Ichikawa J (2004) Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res 1023:54–63

    Article  PubMed  CAS  Google Scholar 

  • Clementz BA, Blumenfeld LD, Cobb S (1997) The gamma band response may account for poor P50 suppression in schizophrenia. NeuroReport 18:3889–3893

    Article  Google Scholar 

  • Day JC, Fibiger HC (1994) Dopaminergic regulation of septohippocampal cholinergic neurons. J Neurochem 63:2086–2092

    PubMed  CAS  Google Scholar 

  • Deadwyler SA, West MO, Robinson JH (1981) Entorhinal and septal inputs differentially control sensory-evoked responses in the rat dentate gyrus. Science 211:1181–1183

    Article  PubMed  CAS  Google Scholar 

  • de Bruin NM, Ellenbroek BA, Cools AR, Coenen AM, van Luijtelaar EL (1999) Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats. Psychopharmacology 142:9–17

    Article  PubMed  Google Scholar 

  • de Bruin NM, Ellenbroek BA, van Luijtelaar EL, Cools AR, Stevens KE (2001) Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell. Neuroscience 105:169–180

    Article  PubMed  Google Scholar 

  • Duncan GE, Miyamoto S, Leipzig JN, Lieberman JA (1999) Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine. Brain Res 843:171–183

    Article  PubMed  CAS  Google Scholar 

  • Dutar P, Bassant M, Senut M-C, Lamour Y (1995) The septohippocampal pathway: structure and function of a central cholinergic system. Physiol Rev 75:393–427

    PubMed  CAS  Google Scholar 

  • Ebert B, Wafford KA, Whiting PJ, Krogsgaard-Larsen P, Kemp JA (1994) Molecular pharmacology of γ-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different α, β, and γ receptor subunit combinations. Mol Pharmacol 46:957–963

    PubMed  CAS  Google Scholar 

  • Ehrlichman RS, Gandal MJ, Maxell CR, Lazarwicz MT, Finkel LH, Contreras D, Turetsky BI, Siegel SJ (2009) (2009) N-methyl-D-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia. Neuroscience 158:705–712

    Article  PubMed  CAS  Google Scholar 

  • Ellenbroek BA, Lubbers LJ, Cools AR (2002) The role of hippocampal dopamine receptors in prepulse inhibition. Eur J NeuroSci 15:1237–1243

    Article  PubMed  Google Scholar 

  • Fitch TE, Sahr RN, Eastwood BJ, Zhou FC, Yang CR (2006) Dopamine D1/5 receptor modulation of firing rate and bidirectional theta burst firing in medial septal/vertical limb of diagonal band neurons in vivo. J Neurophysiol 95:2808–2820

    Article  PubMed  CAS  Google Scholar 

  • Freund TF, Antal M (1988) GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus. Nature 336:170–173

    Article  PubMed  CAS  Google Scholar 

  • Frotscher M, Leranth C (1985) Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study. J Comp Neurol 239:237–246

    Article  PubMed  CAS  Google Scholar 

  • Gao B, Hornung JP, Fritschy JM (1995) Identification of distinct GABAA-receptor subtype in cholinergic and parvalbumin-positive neurons of the rat and marmoset medial septum-diagonal band complex. Neuroscience 65:101–117

    Article  PubMed  CAS  Google Scholar 

  • Gasbarri A, Verney C, Innocenzi R, Campana E, Pacitti C (1994) Mesolimbic dopaminergic neurons innervating the hippocampal formation in the rat: a combined retrograde tracing and immunohistochemical study. Brain Res 668:71–79

    Article  PubMed  Google Scholar 

  • Gavello-Baudy S, Merrer JL, Decorte L, David V, Cazala P (2008) Self-administration of the GABAA agonist muscimol into the medial septum: dependence on dopaminergic mechanisms. Psychopharmacology 201:219–228

    Article  PubMed  CAS  Google Scholar 

  • Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW (1996) NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16:2034–2043

    PubMed  CAS  Google Scholar 

  • Hajos N, Papp EC, Acsady L, Levey AI, Freund TF (1998) Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus. Neuroscience 82:355–376

    Article  PubMed  CAS  Google Scholar 

  • Herrmann CS, Demiralp T (2005) Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol 116:2719–2733

    Article  PubMed  CAS  Google Scholar 

  • Ji D, Dani JA (2000) Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons. J Neurophysiol 83:2682–2690

    PubMed  CAS  Google Scholar 

  • Jirsa R, Poc O, Radil T (1992) Hippocampal auditory evoked response threshold in the rat: behavioral modulation. Brain Res Bull 28:149–153

    Article  PubMed  CAS  Google Scholar 

  • Johnson DE, Nedza FM, Spracklin DK, Ward KM, Schmidt AW, Iredale PA, Godek DM, Rollema H (2005) The role of muscarinic receptor antagonism in antipsychotic-induced hippocampal acetylcholine release. Eur J Pharmacol 506:209–219

    Article  PubMed  CAS  Google Scholar 

  • Karami M, Zarrindast MR, Sepehri H, Sahraei H (2003) Sulpiride injection into the medial septum reverse the influence of intra-medial septum injection of L-arginine on expression of place conditioning-induced by morphine in rats. Brain Res 976:30–40

    Article  PubMed  CAS  Google Scholar 

  • Kelly PH, Iversen SD (1976) Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40:45–56

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    PubMed  CAS  Google Scholar 

  • Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Wynn JK, Green MF, Kim H, Lee KJ, Nam M, Park JK, Chung YC (2006) Quantitative EEG and low resolution electromagnetic tomography (LORETA) imaging of patients with persistent auditory hallucinations. Schizophr Res 83:111–119

    Article  PubMed  Google Scholar 

  • Leung LS (1985) Spectral analysis of hippocampal EEG in the freely moving rat: effects of centrally active drugs and relations to evoked potentials. Electroencephalogr Clin Neurophysiol 60:65–77

    Article  PubMed  CAS  Google Scholar 

  • Leung LS (1990) Field potentials in the central nervous system—recording, analysis and modeling. In: Boulton AA, Baker GB, Vanderwolf CH (eds) Neurophysiological techniques. Applications to neural systems (NeuroMethods), vol 15. Humana, Clifton, pp 277–312

    Google Scholar 

  • Leung LS, Shen B (1995) Long-term potentiation at the apical and basal dendritic synapses of CA1 after local stimulation in behaving rats. J Neurophysiol 73:1938–1946

    PubMed  CAS  Google Scholar 

  • Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 587:130–136

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Leung LS (2000) Relation between hippocampal γ waves and behavioral disturbances induced by phencyclidine and methamphetamine. Behav Brain Res 111:1–11

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Leung LS (2007) The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats. Psychopharmacology 191:961–974

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Brudzynski SM, Leung LW (1996) Involvement of the nucleus accumbens-ventral pallidal pathway in postictal behavior induced by a hippocampal after discharge in rats. Brain Res 739:26–35

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Shen B, Rajakumar N, Leung LS (2004) The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine. Behav Brain Res 155:153–166

    Article  PubMed  Google Scholar 

  • Maxwell CR, Ehrlichman RS, Liang Y, Trief D, Kanes SJ, Karp J, Siegel SJ (2006) Ketamine produces lasting disruptions in encoding of sensory stimuli. J Pharm Exp Therapeutics 316:315–324

    Article  CAS  Google Scholar 

  • McQuiston AR, Madison DV (1999) Muscarinic receptor activity has multiple effects on the resting membrane potentials of CA1 hippocampal interneurons. J Neurosci 19:5693–5702

    PubMed  CAS  Google Scholar 

  • Miller CL, Freedman R (1993) Medial septal neuron activity in relation to an auditory sensory gating paradigm. Neuroscience 55:373–380

    Article  PubMed  CAS  Google Scholar 

  • Miller CL, Freedman R (1995) The activity of hippocampal interneurons and pyramidal cells during the response of the hippocampus to repeated auditory stimuli. Neuroscience 69:371–381

    Article  PubMed  CAS  Google Scholar 

  • Moxon KA, Gerhardt GA, Adler LE (2003a) Dopaminergic modulation of the P50 auditory-evoked potential in a computer model of the CA3 region of the hippocampus: its relationship to sensory gating in schizophrenia. Biol Cybern 88:265–275

    Article  PubMed  Google Scholar 

  • Moxon KA, Gerhardt GA, Gulinello M, Adler LE (2003b) Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus. Biol Cybern 88:247–264

    Article  PubMed  Google Scholar 

  • Olincy A, Stevens KE (2007) Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men. Biochem Pharmacol 74:1192–1201

    Article  PubMed  CAS  Google Scholar 

  • Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Archiv Gen Psychiatry 63:630–638

    Article  CAS  Google Scholar 

  • Olsen RW, Avoli M (1997) GABA and epileptogenesis. Epilepsia 38:399–407

    Article  PubMed  CAS  Google Scholar 

  • Owens MJ, Risch SC (1998) Atypical antipsychotics. In: Schatzberg AF, Nemeroff CB (eds) Textbook of psychopharmacology. American Psychiatric, London, pp 323–348

    Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, Sydney

    Google Scholar 

  • Siegel C, Waldo M, Mizner G, Adler LE, Freedman R (1984) Deficits in sensory gating in schizophrenic patients and their relatives. Evidence obtained with auditory evoked responses. Archiv Gen Psychiatry 41:607–612

    CAS  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (1990) GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats. Brain Res 532:146–150

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Bakshi V, Waikar M, Taaid N, Geyer MA (1998) Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats. Psychopharmacology 140:75–80

    Article  PubMed  CAS  Google Scholar 

  • Thinschmidt JS, Frazier CJ, King MA, Meyer EM, Papke RL (2005) Septal innervation regulates the function of α7 nicotinic receptors in CA1 hippocampal interneurons. Exp Neurol 195:342–352

    Article  PubMed  CAS  Google Scholar 

  • Toth K, Freund TF, Miles R (1997) Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum. J Physiol (London) 500:463–474

    CAS  Google Scholar 

Download references

Acknowledgements

This study was financially supported by operating grants from the Natural Sciences and Engineering Research Council (Canada), Canadian Institutes of Health Research (IFN15685) and a Canadian Commonwealth Scholarship to S. K. Tai. The authors thank M. Crutchley for her technical assistance and R. Boyce for reading this manuscript.

Conflict of interest statement

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jingyi Ma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, J., Tai, S.K. & Leung, L.S. Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs. Psychopharmacology 206, 457–467 (2009). https://doi.org/10.1007/s00213-009-1623-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1623-3

Keywords

Navigation