Abstract
Addiction to psychoactive substances is a maladaptive learned behaviour. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse-triggering ability. Here, we asked where context and salience might be concurrently represented in the brain during retrieval of drug-context paired associations. For this, we developed a morphine-conditioned place preference protocol that allows contextual stimuli presentation inside a magnetic resonance imaging scanner and investigated differences in activity and connectivity at context recall. We found context-specific responses to stimulus onset in multiple brain regions, namely, limbic, sensory and striatal. Differences in functional interconnectivity were found among amygdala, lateral habenula, and lateral septum. We also investigated alterations to resting-state functional connectivity and found increased centrality of the lateral septum in a proposed limbic network, as well as increased functional connectivity of the lateral habenula and hippocampal 'cornu ammonis' 1 region, after a protocol of associative drug-context. Finally, we found that pre- conditioned place preference resting-state connectivity of the lateral habenula and amygdala was predictive of inter-individual conditioned place preference score differences. Overall, our findings show that drug and saline-paired contexts establish distinct memory traces in overlapping functional brain microcircuits and that intrinsic connectivity of the habenula, septum, and amygdala likely underlies the individual maladaptive contextual learning to opioid exposure. We have identified functional maps of acquisition and retrieval of drug-related memory that may support the relapse-triggering ability of opioid-associated sensory and contextual cues. These findings may clarify the inter-individual sensitivity and vulnerability seen in addiction to opioids found in humans.