Initial exposure to addictive drugs activates polysialylated NCAM-mediated hippocampal memory-associated synaptic plasticity in the rat prior to the emergence of dependence behaviour

The early neural adaptations to addictive substances are crucial to understanding how drug-associated memories form and contribute to later compulsive drug-seeking behaviour. This study investigated whether initial exposures to drugs of abuse engage hippocampal memory mechanisms, specifically through the activation of polysialylated neural cell adhesion molecule (NCAM PSA), a well-established marker of neuroplasticity. Using a rodent model, we assessed hippocampal NCAM PSA expression and synaptic remodelling in response to acute and repeated administration of heroin, cocaine, and amphetamine. We compared these neuroplastic responses with those observed during normal spatial learning. Additionally, we examined changes in hippocampal NCAM PSA levels during heroin self-administration to evaluate the relationship between memory-related hippocampal activation and the emergence of drug-seeking behaviour. Our findings reveal that addictive drugs acutely induce hippocampal neuroplasticity in a manner that parallels normal memory consolidation, including increased NCAM PSA expression and synaptic reorganisation. Following sufficient daily drug exposure, the memory-associated neuroplastic response is lost. Specifically in a setting of drug self-administration, we show that heroin continues to activate molecular memory mechanisms within the hippocampal dentate until the emergence of drug seeking behaviour based on recall of an association between drug reward and lever press. This pattern of hippocampal activity is shown to mirror precisely the molecular events associated with learning a normal explicit memory task, the water maze. Importantly, following chronic exposure to either heroin or cocaine, non-drug-related hippocampal-dependent learning events are no longer processed effectively for long-term storage in the absence of the addictive drug suggesting dependence on the drug for normal memory function. These results identify hippocampal memory machinery as a key early target of addictive drugs and suggest that drug-associated memories may co-opt normal learning processes, contributing to the persistent and intrusive nature of drug cravings. The study provides novel insights into the mechanisms by which early drug experiences shape enduring behavioural vulnerability to addiction.