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.

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

“…On the behavioral level, alcohol-dependent rats in protracted abstinence show enhanced motor activity, enhanced alcohol consumption (24,25,27,49,50), and augmented reinstatement of cue-induced alcohol seeking, a finding that has been replicated consistently in several studies (51)(52)(53). A similar phenotype is observed in DAT N157K mutant rats.…”

Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse

“…In the present study we applied three different treatment schedules with psychedelics in order to investigate the effect of psilocybin and LSD on relapse-like drinking in the ADE rat model. The chosen drug administration schemes were (i) a repeated subchronic dosing scheme (i.e., five doses across 3 days) based on a well-established paradigm used in our previous ADE studies to test relapse behavior [e.g., [27,33]. (ii) two high dose applications Fig.…”

“…1). The chosen drug administration schemes were (i) a repeated dosing scheme (i.e., five doses across three days, starting Monday night, followed by administration twice daily on Tuesday and Wednesday) based on an established paradigm used in our previous ADE studies to test alcohol relapse behavior [27,32,33]. (ii) Two high dose applications 1 week apart as to resemble the administration scheme of human clinical trials [e.g., [17]].…”

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

“…In brain, chronic alcohol intake increases calpain activity in rats’ cerebral cortex and cerebellum ( Rajgopal and Vemuri, 2002 ), and hippocampus Dwivedi et al (2018) . Furthermore, administration of calpain inhibitor A-705253 reduced alcohol-seeking and relapse in chronic alcohol-fed rats ( Vengeliene et al, 2016 ), suggesting the important role of caplain, not only in alcohol-induced cellular damage, but also in behavioral changes. Activated Calpain I, cleaves BH3-interacting domain death agonist (Bid) causing its activation and forming BAX pores on the mitochondrial membrane, which releases cytochrome C to cytosol and initiates apoptotic cell death via caspase cascade ( Fricker et al, 2018 ; Figure 2 ).…”