title: Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.
abstract: Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: Karina S
authors.initials: KS
authors.lastname: MacDowell
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: Aline
authors.initials: A
authors.lastname: Sayd
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: José L M
authors.initials: JLM
authors.lastname: Madrigal
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000581:Amidohydrolases / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation; D063388:Endocannabinoids / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000187:drug effects*; D008297:Male; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D013315:Stress, Psychological / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014150:Antipsychotic Agents; D063388:Endocannabinoids; D008071:Lipoprotein Lipase; D000068882:Paliperidone Palmitate; D010714:Phosphatidylethanolamines; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C000609813:N-acylphosphatidylethanolamine
keywords: Endocannabinoid system; antipsychotic; peripheral blood mononuclear cells; prefrontal cortex; stress