title: The Calpain Inhibitor A-705253 Attenuates Alcohol-Seeking and Relapse with Low Side-Effect Profile.
abstract: Preclinical studies revealed contribution of N-methyl-D-aspartate receptors (NMDARs) to a variety of neuropsychiatric diseases including alcoholism, but development of NMDAR antagonists for therapeutic use has been a challenge, in part due to severe side effects. One of the key intracellular events resulting from stimulation of NMDAR is activation of calpains-calcium-dependent cysteine proteases. Here we studied whether inhibition of calpains would produce therapeutic-like effects of NMDAR antagonists but without their NMDAR-mediated side-effect profile. The calpain inhibitor A-705253 (3-10 mg/kg) was tested in a model of cue-induced reinstatement of alcohol-seeking behavior in post-dependent Wistar rats and in an alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats, two behavioral models for alcohol-seeking and relapse, respectively. We also tested the effect of A-705253 on the saccharine deprivation effect (SDE) as a selectivity measure. Acute treatment with A-705253 dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior. Repeated administration of A-705253 caused significant reductions of relapse-like excessive alcohol intake during the post-abstinence drinking days, an effect that persisted during two more successive drug-free drinking weeks, which was selective for the ADE as the SDE was unaffected. However, A-705253 did not produce psychostimulant, cognition impairing (delayed-matching-to-position), or psychotomimetic effects (specifically, phencyclidine discriminative stimulus effects). Taken together, these results demonstrate the involvement of calpains in alcohol-seeking and relapse and present a rationale for a novel pharmacological intervention that may reduce craving and relapse with minimal side effects in alcohol-dependent patients.
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vengeliene
authors.affiliation: Department of Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Moeller
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Marcus W
authors.identifier: http://orcid.org/0000-0002-5103-0731
authors.initials: MW
authors.lastname: Meinhardt
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Wolfgang H
authors.identifier: http://orcid.org/0000-0002-5903-6521
authors.initials: WH
authors.lastname: Sommer
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Department of Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.|Department of Psychopharmacology, Pavlov Medical University, St Petersburg, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Bespalov
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration
chemical_list: C500488:A-705253; D001549:Benzamides; D000431:Ethanol; D002154:Calpain; D012439:Saccharin