Reduced expression of the extracellular matrix protein brevican augments cocaine reward

Vulnerability to drug addiction is thought to depend on genetic and environmental factors. Genetic factors might influence addiction vulnerability by determining the nature and extent of drug-induced adaptations in the brain and may thereby increase sensitivity to environmental stimuli that are associated with drug reward. Recent studies implicate the extracellular matrix (ECM) in a diverse range of neuroadaptive and plasticity-related processes, including experience-dependent plasticity, suggesting that the ECM might also have a role in rendering an individual susceptible to addiction. In support of this, we previously found that reduced expression of the ECM protein brevican in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after heroin self-administration increases vulnerability to cue-induced reinstatement of heroin seeking. To further investigate the relation between brevican expression and addictive behavior, we assessed cocaine-induced associative learning in heterozygous brevican knockout mice (Bcan+/-) that showed reduced brevican levels (60% of wild-type), yet intact perineuronal nets. When conditioned with a low dose of cocaine, we found that Bcan+/mice showed enhanced expression of a cocaine-associated memory, with fear memory being unaffected. Rescue of brevican by viral expression in the dorsal hippocampus (dHC), but not in mPFC and NAc, of Bcan+/mice reduced conditioned cocaine seeking, whereas this effect was absent in contextual fear conditioning. Our data indicate that reduced brevican levels in the dHC augment sensitivity to cocaine reward learning, pointing to a role of ECM mediated plasticity in the development of addictive behavior.