Skip to main content

Advertisement

SpringerLink
Log in

The influence of NMDA and GABAA receptors and glutamic acid decarboxylase (GAD) activity on attention

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

Abstract

Rationale

Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors.

Objective

The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing.

Methods

Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats.

Results

Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC.

Conclusions

These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  • Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. American Journal of Psychiatry 156:1646–1649

    PubMed  CAS  Google Scholar 

  • Ahn K, Gil R, Seibyl J, Sewell RA, D’Souza DC (2011) Probing GABA receptor function in schizophrenia with iomazenil. Neuropsychopharmacology 36:677–683

    Article  PubMed  CAS  Google Scholar 

  • Akbarian Rt (1995) Reduced inhibitory capacity in prefrontal cortex of schizophrenics. Archives of General Psychiatry 52:267–278

    Article  Google Scholar 

  • Andreasen NC (1999) A unitary model of schizophrenia—Bleuler’s “fragmented phrene” as schizencephaly. Archives of General Psychiatry 56:781–787

    Article  PubMed  CAS  Google Scholar 

  • Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature neuroscience 13:76–83

    Article  PubMed  CAS  Google Scholar 

  • Brier A, Davis O, Buchanan R, Listwak SJ, Holmes C, Pickar D, Goldstein DS (1992) Effects of alprazolam on pituitary-adrenal and catecholaminergic response to metabolic stress in humans. Biological Psychiatry 32:880–890

    Article  Google Scholar 

  • Bussey T, Muir J, Everitt B, Robbins T (1997) Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. Behavioral Neuroscience 11:920–936

    Article  Google Scholar 

  • Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380

    Article  PubMed  CAS  Google Scholar 

  • Carli M, Baviera M, Invernizzi RW, Balducci C (2006) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 31:757–767

    Article  CAS  Google Scholar 

  • Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119

    Article  PubMed  CAS  Google Scholar 

  • Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE (1991) Selective and divided attention during visual discriminations of shape, color, and speed: functional anatomy by positron emission tomography. J Neurosci 11:2383–2402

    PubMed  CAS  Google Scholar 

  • Curley AA, Lewis DA (2012) Cortical basket cell dysfunction in schizophrenia. J Physiol 590:715–724

    PubMed  CAS  Google Scholar 

  • Francois J, Ferrandon A, Koning E, Angst MJ, Sandner G, Nehlig A (2009) Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats. Int J Neuropsychopharmacol 12:1097–1110

    Article  PubMed  CAS  Google Scholar 

  • Gold JM (2004) Cognitive deficits as treatment targets in schizophrenia. Schizophr Res 72:21–28

    Article  PubMed  Google Scholar 

  • Gold S, Arndt S, Nopoulos P, O’Leary DS, Andreasen NC (1999) Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. American Journal of Psychiatry 156:1342–1348

    PubMed  CAS  Google Scholar 

  • Goldberg TE, Weinberger DR (1987) Methodological issues in the neuropsychological approach to schizophrenia. Elsevier Science, New York

    Google Scholar 

  • Gonzalez-Burgos G, Hashimoto T, Lewis DA (2010) Alterations of cortical GABA neurons and network oscillations in schizophrenia. Curr Psychiatry Rep 12:335–344

    Article  PubMed  Google Scholar 

  • Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A, Umene-Nakano W, Hayashi K, Oonari N, Korogi Y, Nakamura J (2009) Reduction of brain gamma-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3 T Proton MRS study. Schizophr Res 112:192–193

    Article  PubMed  Google Scholar 

  • Green M (1996) What are the functional consequences of neurocognitive deficits in schizophrenia. American Journal of Psychiatry 153:321–330

    PubMed  CAS  Google Scholar 

  • Green MF, Kern RS, Braff DL, Mintz J (2000) Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"? Schizophr Bull 26:119–136

    Article  PubMed  CAS  Google Scholar 

  • Grottick AJ, Higgins GA (2000) Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117:197–208

    Article  PubMed  CAS  Google Scholar 

  • Herbison AE, Heavens RP, Dyer RG (1990) Endogenous release of gamma-aminobutyric acid from the medial preoptic area measured by microdialysis in the anaesthetised rat. J. Neurochem 55(5):1617–1623

    Google Scholar 

  • Huang-Pollock CL, Karalunas SL, Tam H, Moore AN (2012) Evaluating vigilance deficits in ADHD: a meta-analysis of CPT performance. J Abnormal Psychol 121:360–371

    Google Scholar 

  • Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, Gil R, Slifstein M, Abi-Dargham A, Lisanby SH, Shungu DC (2012) Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 69:449–459

    Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, 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

    Article  PubMed  CAS  Google Scholar 

  • Lamar C Jr (1970) Mercaptopropionic acid: a convulsant that inhibits glutamate decarboxylase. J Neurochem 17:165–170

    Article  PubMed  CAS  Google Scholar 

  • Laurent A, Saoud M, Bougerol T, d’Amato T, Anchisi AM, Biloa-Tang M, Dalery J, Rochet T (1999) Attentional deficits in patients with schizophrenia and in their non-psychotic first-degree relatives. Psychiatry Res 89:147–159

    Article  PubMed  CAS  Google Scholar 

  • Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376

    Article  PubMed  Google Scholar 

  • Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    Article  PubMed  CAS  Google Scholar 

  • Lipska BK, Lerman DN, Khaing ZZ, Weickert CS, Weinberger DR (2003) Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J Neurosci 18:391–402

    Article  PubMed  Google Scholar 

  • Luck SJ, Ford JM, Sarter M, Lustig C (2012) CNTRICS final biomarker selection: control of attention. Schizophrenia bulletin 38:53–61

    Article  PubMed  Google Scholar 

  • Martin DL, Rimvall K (1993) Regulation of gamma-aminobutyric acid synthesis in the brain. Journal of Neurochemistry 60:395–407

    Article  PubMed  CAS  Google Scholar 

  • Marvel CL, Paradiso S (2004) Cognitive and neurological impairment in mood disorders. Psychiatr Clin North Am 27:19–36, vii-viii

    Article  PubMed  Google Scholar 

  • Mazurkiewicz M, Sirvio J, Riekkinen P Sr (1992) Effects of single and repeated administration of vigabatrin on the performance of rats in a 5-choice serial reaction time task. Epilepsy Res 13:231–237

    Article  PubMed  CAS  Google Scholar 

  • Miner LA, Sarter M (1999) Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat. Brain Res Cogn Brain Res 7:269–283

    Article  PubMed  CAS  Google Scholar 

  • Muir JL, Everitt BJ, Robbins TW (1996) The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cerebral Cortex 6:470–481

    Article  PubMed  CAS  Google Scholar 

  • Murphy ER, Fernando AB, Urcelay GP, Robinson ES, Mar AC, Theobald DE, Dalley JW, Robbins TW (2012) Impulsive behaviour induced by both NMDA receptor antagonism and GABA(A) receptor activation in rat ventromedial prefrontal cortex. Psychopharmacology 219:401–410

    Article  PubMed  CAS  Google Scholar 

  • Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF (2010) Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biological psychiatry 68:667–670

    Article  PubMed  Google Scholar 

  • Paine TA, Carlezon WA Jr (2009) Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats. Neuropharmacology 56:788–797

    Article  PubMed  CAS  Google Scholar 

  • Paine TA, Tomasiewicz HC, Zhang K, Carlezon WA Jr (2007) Sensitivity of the five-choice serial reaction time task to the effects of various psychotropic drugs in Sprague–Dawley rats. Biol Psychiatry 62:687–693

    Article  PubMed  CAS  Google Scholar 

  • Paine TA, Slipp LE, Carlezon WA Jr (2011) Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors. Neuropsychopharmacology 36:1703–1713

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Payne R (1961) Cognitive abnormalities. Basic Books, New York

    Google Scholar 

  • Porter RJ, Bourke C, Gallagher P (2007) Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust N Z J Psychiatry 41:115–128

    Article  PubMed  Google Scholar 

  • Ragozzino ME, Rozman S (2007) The effect of rat anterior cingulate inactivation on cognitive flexibility. Behav Neurosci 121:698–706

    Article  PubMed  Google Scholar 

  • Ross SM (2003) Peirce’s criterion for the elimination of suspect experimental data. J Eng Technol 20:38–41

    Google Scholar 

  • Rudolph U, Knoflach F (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10:685–697

    Article  PubMed  CAS  Google Scholar 

  • Tayoshi S, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J, Ueno S, Harada M, Ohmori T (2010) GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schiz research 117:83–91

    Article  Google Scholar 

  • Thompson M, Weickert CS, Wyatt E, Webster MJ (2009) Decreased glutamic acid decarboxylase(67) mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders. J Psychiatr Res 43:970–977

    Article  PubMed  Google Scholar 

  • Totah NK, Kim YB, Homayoun H, Moghaddam B (2009) Anterior cingulate neurons represent errors and preparatory attention within the same behavioral sequence. The Journal of neuroscience: the official journal of the Society for Neuroscience 29:6418–6426

    Article  CAS  Google Scholar 

  • Totah NK, Jackson ME, Moghaddam B (2012) Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex. Cerebral Cortex doi:10.1093/cercor/bhs057

  • Turner CP, DeBenedetto D, Ware E, Stowe R, Lee A, Swanson J, Walburg C, Lambert A, Lyle M, Desai P, Liu C (2010) Postnatal exposure to MK801 induces selective changes in GAD67 or parvalbumin. Exp Brain Res 201:479–488

    Article  PubMed  CAS  Google Scholar 

  • Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11:100–113

    Article  PubMed  CAS  Google Scholar 

  • Vanini G, Watson CJ, Lydic R, Baghdoyan HA (2008) Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia. Anesthesiology 109(6):978–988.

    Google Scholar 

  • Volk DW, Lewis DA (2002) Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction. Physiol Behav 77:501–505

    Article  PubMed  CAS  Google Scholar 

  • Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA (2000) Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 57:237–245

    Article  PubMed  CAS  Google Scholar 

  • Volk D, Austin M, Pierri J, Sampson A, Lewis D (2001) GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am J Psychiatry 158:256–265

    Article  PubMed  CAS  Google Scholar 

  • Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, Carter CS (2010) GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 30:3777–3781

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institute of Mental Health Grant MH84906, Andrew Mellon Foundation Predoctoral Fellowship Grant (to N. K. B. T.), and NRSA Training Grant T32 MH018273 (to C. O. B.)

Author information

Author notes

  1. Alan L. Pehrson

    Present address: Lundbeck Research USA, Inc., Paramus, USA

  2. Nelson K. B. Totah

    Present address: Max Planck Institute for Biological Cybernetics, Tübingen, Germany

Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA, 15260, USA

    Alan L. Pehrson, Corina O. Bondi, Nelson K. B. Totah & Bita Moghaddam

Authors
  1. Alan L. Pehrson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corina O. Bondi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nelson K. B. Totah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bita Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bita Moghaddam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pehrson, A.L., Bondi, C.O., Totah, N.K.B. et al. The influence of NMDA and GABAA receptors and glutamic acid decarboxylase (GAD) activity on attention. Psychopharmacology 225, 31–39 (2013). https://doi.org/10.1007/s00213-012-2792-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2792-z

Keywords

Search

Navigation