Abstract
A high rate of relapse is a major clinical problem among drug-addicted individuals. Persistent traces of drug-associated reward memories contribute to intense craving and often trigger relapse. A number of interventions on drug-associated memories have shown significant benefits in relapse prevention. Among them are pre- or post-extinction pharmacological manipulations that facilitate the extinction of drug-associated behavior. Berberine, a bioactive isoquinoline alkaloid, has been recently reported to provide therapeutic benefits for a number of central nervous system (CNS) disorders, including morphine addiction. The present study aimed to investigate whether berberine could serve as a post-extinction pharmacological intervention agent to reduce risks of reinstatement of drug seeking. We found that an intragastric administration of berberine at doses of 25 and 50 mg/kg during the critical time window significantly facilitated the extinction of morphine-reward related behavior in free access and confined conditioned place preference (CPP) extinction paradigms, and subsequently, it prevented reinstatement and spontaneous recovery of morphine-induced CPP in mice. Intriguingly, the berberine treatment with or without extinction training altered expression of plasticity-related proteins such as brain-derived neurotrophic factor (BDNF), AMPA receptors (GluA1 and GluA2) in the nucleus accumbens (NAc). Moreover, the post-extinction berberine treatment significantly reduced reinstatement of cocaine-induced CPP and operant intravenous self-administration (IVSA) memories in rats. Altogether, our findings suggest that extinction training combined with the post-extinction berberine treatment can facilitate extinction of drug-associated behavior making it an attractive therapeutic candidate in relapse prevention.
Highlights
Drug addiction is a serious problem that poses numerous hazards on public health and social welfare worldwide, including China (West et al, 2019)
Our results indicate that extinction training combined with the berberine treatment delivered during the critical time window of memory consolidation facilitates the extinction of morphineand cocaine-induced drug-associated behavior
We demonstrated that the berberine treatment as a post-extinction intervention could significantly prevent reinstatement and spontaneous recovery of original drug-associated memories
Summary
Drug addiction is a serious problem that poses numerous hazards on public health and social welfare worldwide, including China (West et al, 2019). Converging evidence suggests that drug addiction is based on persistent drug reward memory traces that are formed in the brain during drug-induced euphoric effects and exposure to drugassociated cues; both of which play a critical role in relapse (Kelley, 2004; Milton and Everitt, 2012; Tronson and Taylor, 2013). In the ongoing search for novel therapeutics that would facilitate the extinction of drugassociated behavior, recent studies have provided favorable outcomes in various animal models of addiction (Havermans and Jansen, 2003; Kelamangalath et al, 2007; Xue et al, 2012; Luo et al, 2015). A growing number of studies have demonstrated that many pre- or post-extinction pharmacological interventions can facilitate extinction of drugassociated behavior (Zhou and Kalivas, 2008; Ma et al, 2012; Chesworth and Corbit, 2017; Liu et al, 2019); they can reduce the propensity to relapse
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