Inhibition of fatty-acid amide hydrolase and CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats

Alexandre Seillier, Tushar Advani, TOMMASO Cassano, Julie G. Hensler, Andrea Giuffrida

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The cannabinoid hypothesis of schizophrenia tulates that over-activity of the endocannabinoid system might contribute to the aetiology of schizophrenia. In keeping with this hypothesis, increased expression of CB1 receptors, elevation of the endocannabinoid anandamide (AEA) and cannabinoid-induced cognitive changes have been reported in animal models of schizophrenia and psychotic patients. In this study we measured brain endocannabinoid levels and [35S]GTPS binding stimulated by the CB receptor agonist CP55,940 in rats undergoing withdrawal from subchronic administration of phencyclidine (PCP), a well-established pharmacological model of schizophrenia. We also investigated whether systemic application of the fatty-acid amide hydrolase (FAAH) inhibitor URB597 or CB1 receptor blockade by AM251 affected the following PCP-induced behavioural deficits reminiscent of schizophrenia-like symptoms: (1) working-memory impairment (cognitive deficit), (2) social withdrawal (negative symptom), and (3) hyperactivity in response to d-amphetamine challenge (positive symptoms). PCP-treated rats showed increased endocannabinoid levels in the nucleus accumbens and ventral tegmental area, whereas CB1 receptor expression and CP55,940-stimulated [35S]GTPS binding were unaltered. URB597 reversed the PCP-induced social withdrawal but caused social withdrawal and working-memory deficits in saline-treated rats that were comparable to those observed after PCP treatment. Administration of AM251 ameliorated the working-memory deficit in PCP-treated rats, but impaired working memory in saline-injected controls. Taken together, these results suggest that FAAH inhibition may improve negative symptoms in PCP-treated rats but produce deleterious effects in untreated animals, possibly by disturbing endocannabinoid tone. A similar pattern (beneficial for schizophrenia-related cognitive deficits, but detrimental under normal conditions) accompanies CB1 receptor blockade.

Original languageEnglish (US)
Pages (from-to)373-386
Number of pages14
JournalInternational Journal of Neuropsychopharmacology
Volume13
Issue number3
DOIs
StatePublished - Apr 1 2010

Keywords

  • Cannabinoid
  • Motor activity
  • Schizophrenia
  • Social interaction
  • Working memory

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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