Skip to main content
SpringerLink
Log in

Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor

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

Abstract

Rationale

Prepulse inhibition (PPI) represents a normal sensorimotor gating response that is typically impaired in schizophrenic patients. It is known that cannabinoid CB1 agonists reduce sensorimotor gating in rats, suggesting that the CB1 receptor and the cannabinoid system are involved in sensorimotor gating.

Objective

The objective was to study the effects of AM404, an anandamide reuptake and degradation inhibitor, on PPI and startle response in Swiss mice.

Methods

AM404 was injected either acutely (0, 2.5 and 5 mg/kg i.p.) or chronically (5 mg/kg daily, 7 days). The PPI protocol was based on standard methodologies using acoustic stimuli (pulse 120 dB; prepulses 70 dB and 80 dB). SR141716A, a CB1 antagonist, was employed for further confirmation of the involvement of CB1 receptors.

Results

Acute AM404 (5 mg/kg) disrupted PPI (70-dB prepulse, P<0.05) and enhanced the startle response after the 2.5-mg/kg dose (P<0.01). Chronic AM404 disrupted PPI after both 70-dB (P<0.01) and 80-dB prepulses (P<0.05). These effects were blocked after SR141716A cotreatment.

Conclusions

The data indicate that AM404 (5 mg/kg) acts as a psychodysleptic, altering PPI through stimulation of cannabinoid CB1 receptors, pointing to a possible “psychosis-like” state after enhancement of anandamide bioavailability. The startle response was enhanced only following a lower AM404 dose (2.5 mg/kg), indicating that AM404 induced hyperreactivity at a dose that did not affect PPI, further reinforcing a selective disruption of PPI.

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

  • Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097

    CAS  PubMed  Google Scholar 

  • Beltramo M, Rodriguez de Fonseca F, Navarro M, Calignano A, Gorriti MA et al (2000) Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. J Neurosci 20:3401–3407

    CAS  PubMed  Google Scholar 

  • Braff GL, Geyer MA (1990) Sensorimotor gating and schizophrenia: human and animal model studies. Arch Gen Psychiatry 47:181–188

    CAS  PubMed  Google Scholar 

  • Castle DJ, Ames FR (1996) Cannabis and the brain. Aust N Z J Psychiatry 30:179–183

    CAS  PubMed  Google Scholar 

  • Chan Pk, Chan SC, Yung WH (1998) Presynaptic inhibition of GABAergic inputs to rat substantia nigra pars reticulata neurones by a cannabinoid agonist. Neuroreport 9:671–675

    PubMed  Google Scholar 

  • Emrich HM, Leweke FM, Schneider U (1997) Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 56:803–807

    Article  CAS  PubMed  Google Scholar 

  • French ED, Dillon K, Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmental area and substantia nigra. Neuroreport 8:649–652

    CAS  Google Scholar 

  • Gardner EL, Vorel RH (1998) Cannabinoid transmission and reward-related events. Neurobiol Dis 5:502–533

    CAS  PubMed  Google Scholar 

  • Gardner EL, Paredes W, Smith D, Donner A, Milling C, Cohen D, Morrison D (1988) Facilitation of brain stimulation reward by d9-tetrahydrocannabinol. Psychopharmacology 341:39–44

    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 of review. Psychopharmacology 156:117–154

    CAS  PubMed  Google Scholar 

  • Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053

    Article  CAS  PubMed  Google Scholar 

  • Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (2003) Evidence against the presence of an anandamide transporter. Proc Natl Acad Sci U S A 100:4269–4274

    Article  CAS  PubMed  Google Scholar 

  • Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24

    CAS  PubMed  Google Scholar 

  • Graham FK (1975) The more or less startling effects of weak prestimuli. Psychophysiology 12:238–248

    CAS  PubMed  Google Scholar 

  • Hall W, Solowij N (1997) Long-term cannabis use and mental health. Br J Psychiatry 171:107–108

    CAS  PubMed  Google Scholar 

  • Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle. I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87:175–189

    CAS  PubMed  Google Scholar 

  • Irving AJ, Coutts AA, Harvey J, Rae MG, Mackie K, Bewick GS, Pertwee RG (2000) Functional expression of cell surface cannabinoid CB(1) receptor on presynaptic inhibitory terminals in cultured rat hippocampus neurons. Neuroscience 98:253–262

    Article  CAS  PubMed  Google Scholar 

  • Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 10:1665–1669

    CAS  PubMed  Google Scholar 

  • Liechti ME, Geyer MA, Hell D, Vollenweider FX (2001) Effects of MDMA (ecstasy) on prepulse inhibition and habituation of startle in humans after pretreatment with citalopram, haloperidol, or ketanserin. Neuropsychopharmacology 24:240–252

    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 

  • Martin RS et al (2003) Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat. Psychopharmacology 165:128–135

    CAS  PubMed  Google Scholar 

  • Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weiberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271

    Article  CAS  PubMed  Google Scholar 

  • Ouagazzal AM, Jenck F, Moreau JL (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle in mice: a model for detecting antipsychotic activity? Psychopharmacology 156:273–283

    Google Scholar 

  • Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A, Xiang-Qun X, Makriyannis A (1999) Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci U S A 96:5802–5807

    Article  CAS  PubMed  Google Scholar 

  • Ralph RJ, Paulus MP, Geyer MA (2001) Strain-specific effects of amphetamine on prepulse inhibition and patterns of locomotor behavior in mice. J Pharmacol Exp Ther 298:148–155

    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 

  • Rodríguez de Fonseca F, Del Arco I, Martín-Calderón JL, Gorriti MA, Navarro M (1998) Role of de endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis 5:483–501

    PubMed  Google Scholar 

  • Schneider M, Koch M (2002) The cannabinoid agonist WIN 55,212-2 reduces sensorimotor gating and recognition memory in rats. Behav Pharmacol 13:29–37

    CAS  PubMed  Google Scholar 

  • Stanley-Cary CC, Harris C, Martin-Iverson MT (2002) Differing effects of the cannabinoid agonist CP55,940, in an alcohol or Tween 80 solvent, on prepulse inhibition of the acoustic startle reflex in the rat. Behav Pharmacol 13:15–28

    CAS  PubMed  Google Scholar 

  • Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Study supported by grants to EFE from Fundacio Marato de TV3 (Barcelona, Spain), Plan Nacional sobre drogas, FIS (Red de Trastornos adictivos, G03/05), and Plan Andaluz de Investigacion (CVI-127). The authors thank Sanofi-Synthelabo Recherche (France) for the generous gift of SR141716A.

Author information

Authors and Affiliations

  1. Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, Av. Sanchez Pizjuan 4, 41009, Sevilla, Spain

    Emilio Fernandez-Espejo & Beatriz Galan-Rodriguez

Authors
  1. Emilio Fernandez-Espejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beatriz Galan-Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emilio Fernandez-Espejo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernandez-Espejo, E., Galan-Rodriguez, B. Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor. Psychopharmacology 175, 220–224 (2004). https://doi.org/10.1007/s00213-004-1851-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-1851-5

Keywords

Search

Navigation