Skip to main content
SpringerLink
Log in

Baclofen reverses the reduction in prepulse inhibition of the acoustic startle response induced by dizocilpine, but not by apomorphine

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

Abstract

Rationale

Since baclofen, the prototypical GABAB receptor agonist, is known to reduce the activity of dopaminergic mesolimbic neurons, a putative antipsychotic property of this compound has been suggested, but the evidence for this is still controversial.

Objectives

The aim of the present study was to elucidate the effects of baclofen on the prepulse inhibition (PPI) of the acoustic startle response (ASR), a behavioral paradigm considered to be one of the most powerful tools for the evaluation of sensorimotor gating and for the screening of antipsychotics.

Methods

We tested the effects of baclofen (1.25, 2.5, 5 and 10 mg/kg IP) in rats, per se and in co-treatment with some of the substances known to induce a robust reduction of PPI, such as apomorphine (0.25 mg/kg SC) and dizocilpine (0.1 mg/kg SC). Finally, in order to ascertain whether the effects of baclofen could be ascribed to its activity on GABAB receptors, we analyzed whether its action could be prevented by pretreatment with SCH 50911, a selective GABAB receptor antagonist (20 mg/kg IP). All the experiments were carried out using standard procedures for the assessment of PPI of the ASR.

Results

Baclofen per se produced no significant change in PPI parameters. Moreover, while no effect on apomorphine-mediated alterations in PPI parameters was observed, baclofen proved able to reverse dizocilpine-induced PPI disruption, and this effect was significantly prevented by SCH 50911. On the other hand, this last compound exhibited no effects per se at the same dose.

Conclusions

These results indicate that GABAB receptors are implicated in the neurobiological circuitry accounting for glutamatergic action in sensorimotor gating, and therefore can be proposed as putative new targets in the pharmacological therapy of psychotic disorders. Further studies should be addressed to evaluate more closely the clinical efficacy of baclofen in this respect.

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.

Similar content being viewed by others

References

  • Abbruzzese G (2002) The medical management of spasticity. Eur J Neurol 9:30–34

    Article  PubMed  Google Scholar 

  • Angrist B (1994) Clinical variations of amphetamine psychosis. In: Cho AK, Segal DS (eds) Amphetamine and its analogs: psychopharmacology, toxicology, and abuse. Academic Press, New York, pp 387–414

  • Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394–8401

    CAS  PubMed  Google Scholar 

  • Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794

    CAS  PubMed  Google Scholar 

  • Bartholini G (1985) GABA receptor agonists: pharmacological spectrum and therapeutic action. Med Res Rev 5:55–75

    CAS  PubMed  Google Scholar 

  • Bast T, Zhang W, Feldon J, White IM (2000) Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats. Pharmacol Biochem Behav 67:647–658

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Beskid M, Rozycka Z, Taraszewska A (1999) Quinolinic acid and GABA-B receptor ligand: effect on pyramidal neurons of the CA1 sector of rat's dorsal hippocampus following peripheral administration. Folia Neuropathol 37:99–106

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Bubser M, Keseberg U, Notz PK, Schmidt WJ (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol 229:75–82

    Article  CAS  PubMed  Google Scholar 

  • Caine SB, Geyer MA, Swerdlow NR (1992) Hippocampal modulation of acoustic startle and prepulse inhibition in the rat. Pharmacol Biochem Behav 43:1201–1208

    CAS  PubMed  Google Scholar 

  • Charles KJ, Evans ML, Robbins MJ, Calver AR, Leslie RA, Pangalos MN (2001) Comparative immunohistochemical localisation of GABA(B1a), GABA(B1b) and GABA(B2) subunits in rat brain, spinal cord and dorsal root ganglion. Neuroscience 106:447–467

    Article  CAS  PubMed  Google Scholar 

  • Cott J, Carlsson A, Engel J, Lindqvist M (1976) Suppression of ethanol-induced locomotor stimulation by GABA-like drugs. Naunyn-Schmiedeberg's Arch Pharmacol 295:203–209

    Google Scholar 

  • Cousins MS, Roberts DC, De Wit H (2002) GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Drug Alcohol Depend 65:209–220

    Article  CAS  PubMed  Google Scholar 

  • Danober L, Heinbockel T, Driesang RB, Pape HC (2000) Synaptic mechanisms of NMDA-mediated hyperpolarization in lateral amygdaloid projection neurons. Neuroreport 11:2501–2506

    CAS  PubMed  Google Scholar 

  • Decker MW, Curzon P, Brioni JD (1995) Influence of separate and combined septal and amygdala lesions on memory, acoustic startle, anxiety, and locomotor activity in rats. Neurobiol Learn Mem 64:156–168

    CAS  PubMed  Google Scholar 

  • Durkin MM, Gunwaldsen CA, Borowsky B, Jones KA, Branchek TA (1999) An in situ hybridization study of the distribution of the GABA(B2) protein mRNA in the rat CNS. Brain Res Mol Brain Res 71:185–200

    Article  CAS  PubMed  Google Scholar 

  • Engberg G, Kling-Petersen T, Nissbrandt H (1993) GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra. Synapse 15:229–238

    PubMed  Google Scholar 

  • Erhardt S, Mathe JM, Chergui K, Engberg G, Svensson TH (2002) GABA(B) receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 365:173–180

    Google Scholar 

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

    CAS  Google Scholar 

  • Furuya Y, Kagaya T, Ogura H, Nishizawa Y (1999) Competitive NMDA receptor antagonists disrupt prepulse inhibition without reduction of startle amplitude in a dopamine receptor-independent manner in mice. Eur J Pharmacol 364:133–140

    CAS  PubMed  Google Scholar 

  • Geyer MA, Swerdlow NR (1998) Measurement of startle response, prepulse inhibition, and habituation. In: Crawley JN, Skolnick P (eds) Current protocols in neuroscience. Wiley, New York, pp 1–15

  • Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25:485–498

    CAS  PubMed  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 156:117–154

    CAS  PubMed  Google Scholar 

  • Graham FK (1975) The more or less startling effects of weak prestimulation. Psychophysiology 1:238–248

    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

    CAS  PubMed  Google Scholar 

  • Hide TM, Casanova MF, Kleinman JE (1991) Neuroanatomical and neurochemical pathology in schizophrenia. In: Tasman A, Goldfinger SM (eds) American Psychiatric Press review of psychiatry, vol 10. American Psychiatric Press, Washington, pp 7–23

  • Hoffman DC, Donovan H, Cassella JV (1993) The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801. Psychopharmacology 116:437–442

    Google Scholar 

  • Kato K, Goto M, Fukuda H (1982) Baclofen: inhibition of the release of l-[3H]glutamate and l-[3H]aspartate from rat whole brain synaptosomes. Gen Pharmacol 13:445–447

    Article  CAS  PubMed  Google Scholar 

  • Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle. Biol Psychiatry 30:557–566

    CAS  PubMed  Google Scholar 

  • Knable MB, Kleinman JE, Weinberger DR (1998) Neurobiology of schizophrenia. In: Schatzberg AF, Nemeroff CB (eds) American Psychiatric Press textbook of psychopharmacology, 2nd edn. American Psychiatric Press, Washington, pp 589–607

  • Koch M, Fendt M, Kretschmer BD (2000) Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats. Behav Brain Res 117:153–162

    CAS  PubMed  Google Scholar 

  • Lehmann-Masten VD, Geyer MA (1991) Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats. Neuropharmacology 30:629–636

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308

    CAS  PubMed  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514

    CAS  PubMed  Google Scholar 

  • McGhie A, Chapman J (1961) Disorders of attention and perception in early schizophrenia. Br J Pharmacol 34:102–116

    Google Scholar 

  • Menon MK, Clark WG, Vivonia C (1980) Interaction between phencyclidine (PCP) and GABA-ergic drugs: clinical implications. Pharmacol Biochem Behav 12:113–117

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Mizukami K, Ishikawa M, Hidaka S, Iwakiri M, Sasaki M, Iritani S (2002) Immunohistochemical localization of GABAB receptor in the entorhinal cortex and inferior temporal cortex of schizophrenic brain. Prog Neuropsychopharmacol Biol Psychiatry 26:393–396

    Article  CAS  PubMed  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    CAS  PubMed  Google Scholar 

  • Nevins ME, Nash SA, Beardsley PM (1993) Quantitative grip strength assessment as a means of evaluating muscle relaxation in mice. Psychopharmacology 110:92–96

    CAS  PubMed  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, Clapham 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  CAS  PubMed  Google Scholar 

  • Ralph-Williams RJ, Lehmann-Masten V, Otero-Corchon V, Low MJ, Geyer MA (2002) Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. J Neurosci 22:9604–9611

    PubMed  Google Scholar 

  • Reijmers LG, Vanderheyden PM, Peeters BW (1995) Changes in prepulse inhibition after local administration of NMDA receptor ligands in the core region of the rat nucleus accumbens. Eur J Pharmacol 272:131–138

    CAS  PubMed  Google Scholar 

  • Reynolds GP, Beasley CL, Zhang ZJ (2002) Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. J Neural Transm 109:881–889

    Article  CAS  PubMed  Google Scholar 

  • Schopf J, Hucker H (1977) Baclofen in the treatment of schizophrenia: a pilot study. Pharmakopsychiatr Neuropsychopharmakol 10:89–91

    CAS  PubMed  Google Scholar 

  • Sharkey J, Ritchie IM, Butcher SP, Kelly JS (1996) Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists. Brain Res 735:67–82

    Article  CAS  PubMed  Google Scholar 

  • Steinpresis RE (1996) The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis. Behav Brain Res 74:45–55

    CAS  PubMed  Google Scholar 

  • Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J Pharmacol Exp Ther 256:530–536

    CAS  PubMed  Google Scholar 

  • Swerdlow NR, Caine SB, Geyer MA (1992) Regionally selective effects of intracerebral dopamine infusion on sensorimotor gating of the startle reflex in rats. Psychopharmacology 108:189–195

    Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (2000) Animal models of sensorimotor gating: what we know, what we think we know, and what we hope we know soon. Behav Pharmacol 11:185–204

    CAS  PubMed  Google Scholar 

  • Yamada J, Saitow F, Satake S, Kiyohara T, Konishi S (1999) GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABAergic transmission in the basolateral amygdala. Neuropharmacology 38:1743–1753

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Chiodo LA, Freeman AS (1992) Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons. Brain Res 590:153–163

    PubMed  Google Scholar 

  • Zhang J, Engel JA, Ericson M, Svensson L (1999) Involvement of the medial geniculate body in prepulse inhibition of acoustic startle. Psychopharmacology 141:189–196

    Google Scholar 

  • Zhang WN, Bast T, Feldon J (2000) Microinfusion of the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity. Neuroscience 101:589–599

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Professor Pierfranco Spano, Department of Pharmacology, University of Brescia, for his precious suggestions as well as Mr. Grant C. Luckey, for his assistance with manuscript preparation.

Author information

Authors and Affiliations

  1. Department of Neuroscience "B.B. Brodie", Center of Excellence "Neurobiology of Dependence", University of Cagliari, Cittadella Universitaria, SS 554 Km 4,500, 09042, Monserrato (CA), Italy

    Marco Bortolato, Roberto Frau, Gian Nicola Aru, Marco Orrù & Gian Luigi Gessa

Authors
  1. Marco Bortolato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto Frau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gian Nicola Aru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Orrù
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gian Luigi Gessa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Bortolato.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bortolato, M., Frau, R., Aru, G.N. et al. Baclofen reverses the reduction in prepulse inhibition of the acoustic startle response induced by dizocilpine, but not by apomorphine. Psychopharmacology 171, 322–330 (2004). https://doi.org/10.1007/s00213-003-1589-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1589-5

Keywords

Search

Navigation