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Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice

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Abstract

Rationale

Gamma-amino-butyric acid (GABA)B receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical GABAB agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia.

Objectives

We studied the role of GABAB receptors in the spontaneous PPI deficits displayed by DBA/2J mice.

Materials and methods

We tested the effects of baclofen (1.25–5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, we investigated the expression of GABAB receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography.

Results

Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABAB antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABAB receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions.

Conclusions

Our data highlight GABAB receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABAB receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances.

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References

  • Adachi N, Onuma T, Nishiwaki S, Murauchi S, Akanuma N, Ishida S, Takei N (2000) Inter-ictal and post-ictal psychoses in frontal lobe epilepsy: a retrospective comparison with psychoses in temporal lobe epilepsy. Seizure 9:328–335

    Article  PubMed  CAS  Google Scholar 

  • Akanuma N, Kanemoto K, Adachi N, Kawasaki J, Ito M, Onuma T (2005) Prolonged postictal psychosis with forced normalization (Landolt) in temporal lobe epilepsy. Epilepsy Behav 6:456–459

    Article  PubMed  Google Scholar 

  • Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG (1995) Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52:258–266

    PubMed  CAS  Google Scholar 

  • Ammassari-Teule M, Caprioli A (1985) Spatial learning and memory, maze running strategies and cholinergic mechanisms in two inbred strains of mice. Behav Brain Res 17:9–16

    Article  PubMed  CAS  Google Scholar 

  • Ammassari-Teule M, Hoffmann HJ, Rossi-Arnaud C (1993) Learning in inbred mice: strain-specific abilities across three radial maze problems. Behav Genet 23:405–412

    Article  PubMed  CAS  Google Scholar 

  • Anisman H (1975) Differential effects of scopolamine and D-amphetamine on avoidance: strain interactions. Pharmacol Biochem Behav 3:809–817

    Article  PubMed  CAS  Google Scholar 

  • Beckmann H, Frische M, Ruther E, Zimmer R (1977) Baclofen (para-chlorphenyl-GABA) in schizophrenia. Pharmakopsychiatr Neuro-psychopharmakol 10:26–31

    CAS  Google Scholar 

  • Benes FM, Berretta S (2001) GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25:1–27

    Article  PubMed  CAS  Google Scholar 

  • Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991) Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48:996–1001

    PubMed  CAS  Google Scholar 

  • Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP (1992) Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 12(3):924–929

    PubMed  CAS  Google Scholar 

  • Bigelow LB (1977) Baclofen in chronic schizophrenia. Psychopharmacol Bull 13:4–5

    PubMed  CAS  Google Scholar 

  • Bischoff S, Leonhard S, Reymann N, Schuler V, Shigemoto R, Kaupmann K, Bettler B (1999) Spatial distribution of GABA(B)R1 receptor mRNA and binding sites in the rat brain. J Comp Neurol 412:1–16

    Article  PubMed  CAS  Google Scholar 

  • Boehm SL, Piercy MM, Bergstrom HC, Phillips TJ (2002) Ventral tegmental area region governs GABAB receptor modulation of ethanol stimulated activity in mice. Neuroscience 115:185–200

    Article  PubMed  CAS  Google Scholar 

  • Bortolato M, Frau R, Aru GN, Orru M, Gessa GL (2004) Baclofen reverses the reduction in prepulse inhibition of the acoustic startle response induced by dizocilpine, but not by apomorphine. Psychopharmacology (Berl) 171:322–330

    Article  CAS  Google Scholar 

  • Braff DL, Geyer MA, Swerdlow NR (2001a) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–258

    Article  CAS  Google Scholar 

  • Braff DL, Geyer MA, Light GA, Sprock J, Perry W, Cadenhead KS, Swerdlow NR (2001b) Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophr Res 49:171–178

    Article  CAS  Google Scholar 

  • Carai MA, Colombo G, Brunetti G, Melis S, Serra S, Vacca G, Mastinu S, Pistuddi AM, Solinas C, Cignarella G, Minardi G, Gessa GL (2001) Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid. Eur J Pharmacol 428:315–321

    Article  PubMed  CAS  Google Scholar 

  • Chapman AG, Woodburn VL, Woodruff GN, Meldrum BS (1996) Anticonvulsant effect of reduced NMDA receptor expression in audiogenic DBA/2 mice. Epilepsy Res 26:25–35

    Article  PubMed  CAS  Google Scholar 

  • Cross AJ, Crow TJ, Owen F (1979) Gamma-aminobutyric acid in the brain in schizophrenia. Lancet 1:560–561

    Article  PubMed  CAS  Google Scholar 

  • Crusio WE, Schwegler H, Lipp HP (1987) Radial-maze performance and structural variation of the hippocampus in mice: a correlation with mossy fibre distribution. Brain Res 425:182–185

    Article  PubMed  CAS  Google Scholar 

  • Elias PK, Elias MF, Eleftheriou BE (1975) Emotionality, exploratory behavior, and locomotion in aging inbred strains of mice. Gerontologia 21:46–55

    PubMed  CAS  Google Scholar 

  • Flor-Henry P (1983) Determinants of psychosis in epilepsy: laterality and forced normalization. Biol Psychiatry 18:1045–1057

    PubMed  CAS  Google Scholar 

  • Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego, CA

    Google Scholar 

  • Frederiksen PK (1975) Letter: baclofen in the treatment of schizophrenia. Lancet 1:702

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154

    Article  CAS  Google Scholar 

  • Gulmann NC, Bahr B, Andersen B, Eliassen HM (1976) A double-blind trial of baclofen against placebo in the treatment of schizophrenia. Acta Psychiatr Scand 54:287–293

    Article  PubMed  CAS  Google Scholar 

  • Harrison PJ (2004) The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 174:151–162

    CAS  Google Scholar 

  • Harte M, O’Connor WT (2005) Evidence for a selective prefrontal cortical GABA(B) receptor-mediated inhibition of glutamate release in the ventral tegmental area: a dual probe microdialysis study in the awake rat. Neuroscience 130:215–222

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa M, Mizukami K, Iwakiri M, Asada T (2005) Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. Neurosci Lett 383:272–277

    Article  CAS  Google Scholar 

  • Kanes SJ, Hitzemann BA, Hitzemann RJ (1993) On the relationship between D2 receptor density and neuroleptic-induced catalepsy among eight inbred strains of mice. J Pharmacol Exp Ther 267:538–547

    PubMed  CAS  Google Scholar 

  • Kanner AM (2000a) Psychosis of epilepsy: a neurologist’s perspective. Epilepsy Behav 1:219–227

    Article  Google Scholar 

  • Kanner AM (2000b) Comorbid psychiatric symptoms in temporal lobe epilepsy. To the editor. Epilepsy Behav 1:288–289

    Article  Google Scholar 

  • Krishnamoorthy ES, Trimble MR, Sander JW, Kanner AM (2002) Forced normalization at the interface between epilepsy and psychiatry. Epilepsy Behav 4:303–308

    Article  Google Scholar 

  • Kumari V, Sharma T (2002) Effects of typical and atypical antipsychotics on prepulse inhibition in schizophrenia: a critical evaluation of current evidence and directions for future research. Psychopharmacology (Berl) 162:97–101

    Article  CAS  Google Scholar 

  • Landolt H (1953) Some clinical electroencephalographical correlations in epileptic psychoses (twilight states). EEG Clin Neurophysiol 5:122

    Article  Google Scholar 

  • Lewis DA (2000) GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res Brain Res Rev 31:270–276

    Article  PubMed  CAS  Google Scholar 

  • Lewis DA, Gonzales-Burgos G (2000) Intrinsic excitatory connections in the prefrontal cortex and the pathophysiology of schizophrenia. Brain Res Bull 52:309–317

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Wehner JM (1997) Enhancement of contextual fear-conditioning by putative (+/−)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators and N-methyl-D-aspartate (NMDA) receptor antagonists in DBA/2J mice. Brain Res 768:197–207

    Article  PubMed  CAS  Google Scholar 

  • Marrosu F, Santoni F, Fa M, Puligheddu M, Barberini L, Genugu F, Frau R, Manunta M, Mereu G (2006) Beta and gamma range EEG power-spectrum correlation with spiking discharges in DBA/2J mice absence model: role of GABA receptors. Epilepsia 47:489–494

    Article  PubMed  CAS  Google Scholar 

  • McCormick LM, Flaum M (2005) Diagnosing schizophrenia circa: how and why? Curr Psychiatry Rep 7:311–315

    Article  PubMed  Google Scholar 

  • Meduna L (1934) Über experimentelle Campherepilepsie. Arch Psychiatr 102:333–39

    Article  Google Scholar 

  • Mizukami K, Sasaki M, Ishikawa M, Iwakiri M, Hidaka S, Shiraishi H, Iritani S (2000) Immunohistochemical localization of gamma-aminobutyric acid(B) receptor in the hippocampus of subjects with schizophrenia. Neurosci Lett 283:101–104

    Article  PubMed  CAS  Google Scholar 

  • Moore JA, Kakihana R (1978) Ethanol-induced hypothermia in mice: influence of genotype on development of tolerance. Life Sci 23:2331–2337

    Article  PubMed  CAS  Google Scholar 

  • Mott DD, Lewis DV (1994) The pharmacology and function of central GABAB receptors. Int Rev Neurobiol 36:97–223

    Article  PubMed  CAS  Google Scholar 

  • Ng GY, O’Dowd BF, George SR (1994) Genotypic differences in brain dopamine receptor function in the DBA/2J and C57BL/6J inbred mouse strains. Eur J Pharmacol 269:349–364

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Leahy C, Mullen T, Paylor R, Groppi VE, Sarnyai Z, Brunner D (2001) The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics? Psychopharmacology (Berl) 156:284–290

    Article  CAS  Google Scholar 

  • Pakalnis A, Drake ME, John K, Kellum JB (1987) Forced normalization. Acute psychosis after seizure control in seven patients. Arch Neurol 44:289–292

    PubMed  CAS  Google Scholar 

  • Parisi T, Ison JR (1979) Development of the acoustic startle response in the rat: ontogenetic changes in the magnitude of inhibition by prepulse stimulation. Dev Psychobiol 12:219–230

    Article  PubMed  CAS  Google Scholar 

  • Patel N, Hitzemann B, Hitzemann R (1998) Genetics, haloperidol, and the Fos response in the basal ganglia: a comparison of the C57BL/6J and DBA/2J inbred mouse strains. Neuropsychopharmacology 18:480–491

    Article  PubMed  CAS  Google Scholar 

  • Paylor R, Crawley JN (1997) Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology (Berl) 132:169–180

    Article  CAS  Google Scholar 

  • Paylor R, Tracy R, Wehner J, Rudy JW (1994) DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning. Behav Neurosci 108:810–817

    Article  PubMed  CAS  Google Scholar 

  • Poon N, Kloosterman F, Wu C, Leung LS (2006) Presynaptic GABA(B) receptors on glutamatergic terminals of CA1 pyramidal cells decrease in efficacy after partial hippocampal kindling. Synapse 59:125–134

    Article  PubMed  CAS  Google Scholar 

  • Prosser HM, Gill CH, Hirst WD, Grau E, Robbins M, Calver A, Soffin EM, Farmer CE, Lanneau C, Gray J, Schenck E, Warmerdam BS, Clapman C, Reavill C, Rogers DC, Stean T, Upton N, Humphreys K, Randall A, Geppert M, Davies CH, Pangalos MN (2001) Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol Cell Neurosci 17:1059–1070

    Article  PubMed  CAS  Google Scholar 

  • Ralph RJ, Caine SB (2005) Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion:comparison of Sprague–Dawley rats to Swiss–Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice. J Pharmacol Exp Ther 312:733–741

    Article  PubMed  CAS  Google Scholar 

  • Randt CT, Blizard DA, Friedman E (1975) Early life undernutrition and aggression in two mouse strains. Dev Psychobiol 8:275–279

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Corbett R, Van Tol HH (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 16:93–110

    Article  PubMed  CAS  Google Scholar 

  • Simpson GM, Branchey MH, Shrivastava RK (1976) Letter: baclofen in schizophrenia. Lancet 1:966–967

    Article  PubMed  CAS  Google Scholar 

  • Simpson MD, Slater P, Deakin JF, Royston MC, Skan WJ (1989) Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neurosci Lett 107:211–215

    Article  PubMed  CAS  Google Scholar 

  • Stavnes KL, Sprott RL (1975) Genetic analysis of active avoidance performance in mice. Psychol Rep 36:515–521

    PubMed  CAS  Google Scholar 

  • Stevens JR (1999) Epilepsy, schizophrenia, and the extended amygdala. Ann NY Acad Sci 877:548–561

    Article  PubMed  CAS  Google Scholar 

  • Straessle A, Loup F, Arabadzisz D, Ohning GV, Fritschy JM (2003) Rapid and long-term alterations of hippocampal GABAB receptors in a mouse model of temporal lobe epilepsy. Eur J Neurosci 18:2213–2226

    Article  PubMed  Google Scholar 

  • Swerdlow NR, Martinez ZA, Hanlon FM, Platten A, Farid M, Auerbach P, Braff DL, Geyer MA (2000) Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists. J Neurosci 20:4325–4336

    PubMed  CAS  Google Scholar 

  • Upchurch M, Wehner JM (1988) Differences between inbred strains of mice in Morris water maze performance. Behav Genet 18:55–68

    Article  PubMed  CAS  Google Scholar 

  • Willott JF, Erway LC (1998) Genetics of age-related hearing loss in mice. IV. Cochlear pathology and hearing loss in 25 BXD recombinant inbred mouse strains. Hear Res 119:27–36

    Article  PubMed  CAS  Google Scholar 

  • Wolf P (1991) Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or “forced” normalization. Adv Neurol 55:127–142

    PubMed  CAS  Google Scholar 

  • Wolf P, Trimble MR (1985) Biological antagonism and epileptic psychosis. Br J Psychiatry 146:272–276

    Article  PubMed  CAS  Google Scholar 

  • Wu C, Leung LS (1997) Partial hippocampal kindling decreases efficacy of presynaptic GABAB autoreceptors in CA1. J Neurosci 17:9261–9269

    PubMed  CAS  Google Scholar 

  • Zhang M, Ballard ME, Kohlhaas KL, Browman KE, Jongen-Relo AL, Unger LV, Fox GB, Gross G, Decker MW, Drescher KU, Rueter LE (2006) Effect of dopamine D3 antagonists on PPI in DBA/2J mice or PPI deficit induced by neonatal ventral hippocampal lesions in rats. Neuropsychopharmacology 31:382–1392

    Article  CAS  Google Scholar 

  • Zheng QY, Johnson KR, Erway LC (1999) Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 130:94–107

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Marco Bortolato.

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M. Paola Castelli, Giampaolo Mereu, and Francesco Marrosu have contributed equally to the study.

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Bortolato, M., Frau, R., Orrù, M. et al. Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice. Psychopharmacology 194, 361–369 (2007). https://doi.org/10.1007/s00213-007-0845-5

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  • DOI: https://doi.org/10.1007/s00213-007-0845-5

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