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The Calpain Inhibitor A-705253 Attenuates Alcohol-Seeking and Relapse with Low Side-Effect Profile
- Source :
- Neuropsychopharmacology. 41:979-988
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Side effect
Drug-Seeking Behavior
Self Administration
Stimulation
Craving
Pharmacology
03 medical and health sciences
Saccharin
0302 clinical medicine
Recurrence
medicine
Animals
Rats, Wistar
Psychiatry
Phencyclidine
Ethanol
biology
Calpain
Psychotomimetic
Rats
Psychiatry and Mental health
030104 developmental biology
Benzamides
biology.protein
Conditioning, Operant
NMDA receptor
Original Article
Psychopharmacology
Cues
medicine.symptom
Psychology
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 1740634X and 0893133X
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Neuropsychopharmacology
- Accession number :
- edsair.doi.dedup.....53bf6f345362ee8368d4a99ed5eff97e