The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference

Abstract

Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. During periods of abstinence, responding to cocaine cues can time-dependently intensify a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time point compared with the recent time point. This progressive increase was not observed in wild-type mice and it did not generalize to contextualfear memory. Virally mediated overexpression of brevican levels in the hippocampus, but not medial prefrontal cortex, of heterozygous mice prevented the progressive increase in cocaine CPP, but only when overexpression was induced before conditioning. Postconditioning overexpression of brevican did not affect remote cocaine CPP, suggesting that brevican limited the increase in remote CPP by altering neuro-adaptive mechanisms during cocaine conditioning. We provide causal evidence that hippocampal brevican levels control time-dependent enhancement of cocaine CPP during abstinence, pointing to a novel substrate that regulates incubation of responding to cocaine-associated cues.

Dopamine Receptor Activation Modulates the Integrity of the Perisynaptic Extracellular Matrix at Excitatory Synapses

“…Moreover, BC has been shown to be implicated in drug addiction and craving. In heroin-addicted rats, a clear decrease of full length BC in synaptic protein fractions of the PFC has been noted [93], and Lubbers et al (2016) demonstrated that heterozygous BC mice expressing approximately 50% of the BC levels of wild-type mice showed a progressive increase in cocaine-associated context preference over time, which may also involve an interplay between ECM and dopaminergic modulation [94]. Altogether, these findings highlight that fine-tuned and locally controlled proteolytic processing of mature ECM components may also have important functional implications for the diseased or addicted brain, potentially making it an interesting target for new treatment strategies.…”

Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder

“…However, digestion of PNs with ChABC in specific brain regions has been shown to attenuate behaviors related to cocaine, morphine, and heroin reward and drug‐seeking behavior (Slaker et al., ; Xue et al., ). In addition, heterozygous brevican knockout mice exhibit enhanced cocaine‐conditioned place preference, which can be rescued by overexpression of brevican in the dorsal hippocampus (Lubbers et al., ). These studies indicate that manipulations of PN components could feasibly decrease behaviors related to alcohol abuse.…”

Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

“…They are hypothesized to stabilize synapses during memory formation, leading to long-term memory storage, and prevent the formation of new memories (20)(21)(22). Recently, PNNs have gained prominence in the addiction research field through studies demonstrating that they regulate drug-associated memories that contribute to relapse (23)(24)(25)(26)(27).…”