Drinking Levels and Profiles of Alcohol Addicted Rats Predict Response to Nalmefene

Abstract

Background: Pharmacotherapeutic options supporting the treatment of alcohol dependence are recommended and available but underutilized, partly due to questions about efficacy. Nalmefene, a μ-opioid receptor antagonist and partial kappa receptor agonist, is recommended for reduction of alcohol consumption, but evidence about its effectiveness has been equivocal; identifying factors which predict response will help optimize treatment. Methods: The alcohol deprivation effect paradigm is a tightly controlled procedure comprising repeated deprivation and reintroduction phases, leading to increased preference for alcohol; reintroduction approximates relapse. Using a digital drinkometer system measuring high-resolution drinking behavior, we examined the effects of nalmefene on relapse drinking behavior in alcohol addicted rats. We also tested whether drinking behavior in the relapse phase prior to nalmefene administration predicted treatment response. We further examined whether longitudinal drinking behavior and locomotor activity predicted treatment response. Results: Our results showed that nalmefene (0.3 mg/kg) reduced relapse-like consumption significantly (∼20%) compared to vehicle on the first 2 days of alcohol reintroduction. Examining the first 6 h of a preceded treatment-free relapse episode revealed drinking patterns clustering the rats into responders (reduction of >40%, n = 17) and non-responders (reduction of <40%, n = 7) to subsequent nalmefene treatment. During the first 6 h of the preceding relapse phase, responders consumed more alcohol than non-responders; the amount of alcohol consumed during each drinking approach was larger but frequency of drinking did not differ. Longitudinal drinking behavior and locomotor activity did not significantly predict response. Conclusion: Our results suggest that nalmefene reduces alcohol intake during a relapse-like situation but effectiveness can differ greatly at the individual level. However, who responds may be informed by examining drinking profiles and rats that show high drinking levels prior to treatment are more likely to respond to nalmefene.

Nalmefene alleviates the neuroimmune response to repeated binge‐like ethanol exposure: A TSPO PET imaging study in adolescent rats

“…The selected dose of nalmefene used in our study (0.4 mg/kg = 28 mg/70 kg) could be safely administered to patients to reduce ethanol consumption 48 . Similar dose (0.3 mg/kg) was shown to reduce ethanol intake in rats 49 and lower doses (0.1 mg/kg) were shown to reduce ethanol‐induced neuroinflammation in mice 29 . Altogether, our results and a large body of translational studies support the assumption that nalmefene may offer a double‐line of protection by (i) reducing ethanol craving and the risk for repeated binge‐like ethanol exposure and (ii) protecting against the pro‐inflammatory response to binge drinking within the CNS while preventing the deleterious or even lethal effects of ethanol poisoning.…”

Melatonin Reduces Alcohol Drinking in Rats with Disrupted Function of the Serotonergic System

“…These findings are in line with previous studies showing that individual differences may have a considerable impact on the treatment outcome. For instance, our earlier study demonstrated that nalmefene was most effective in rats that consumed greater amounts of highly concentrated alcohol per drinking approach [ 22 ]. The impact of individual differences has also been demonstrated in human studies.…”

Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder

“…However, this effect was transient and drinking levels returned to normal after a few days. The ADE has been proposed as a relevant model to study relapse-like drinking with good predictive validity as it has been pharmacologically validated using the clinically approved compounds acamprosate ( Spanagel et al ., 1996 , 2014 ), naltrexone ( Holter and Spanagel, 1999 ) and nalmefene ( Foo et al ., 2019 ). The novel GABA B PAM CMPPE (2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol) was found to potently and dose-dependently (10 and 30 mg/kg, i.p.)…”