title: AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents.
abstract: BACKGROUND
  The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia.
  
  
  OBJECTIVE
  These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs).
  
  
  METHODS
  The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential.
  
  
  RESULTS
  AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects.
  
  
  CONCLUSIONS
  These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments.
authors.affiliation: Sanofi-Aventis, Bridgewater, NJ 08807, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Black
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Stevens
authors.forename: Nancy
authors.initials: N
authors.lastname: Rogacki
authors.forename: Robert E
authors.initials: RE
authors.lastname: Featherstone
authors.forename: Yaw
authors.initials: Y
authors.lastname: Senyah
authors.forename: Odessa
authors.initials: O
authors.lastname: Giardino
authors.forename: Beth
authors.initials: B
authors.lastname: Borowsky
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stemmelin
authors.forename: Caroline
authors.initials: C
authors.lastname: Cohen
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.forename: Michal
authors.initials: M
authors.lastname: Arad
authors.forename: Segev
authors.initials: S
authors.lastname: Barak
authors.forename: Amaya
authors.initials: A
authors.lastname: De Levie
authors.forename: Ina
authors.initials: I
authors.lastname: Weiner
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
mesh_terms: D000161:Acoustic Stimulation; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001007:Anxiety / Q000139:chemically induced / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D003071:Cognition / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C523652:AVE1625; D014150:Antipsychotic Agents; D006846:Hydrocarbons, Halogenated; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; D000661:Amphetamine