Sex-dependent role of the dorsolateral septum in shaping contextual cocaine memory strength

Established memories can be destabilized, updated, and reconsolidated into long-term memory stores. Memory updating and reconsolidation can alter the strength of maladaptive contextual drug memories and consequently context-induced drug craving and relapse. The dorsolateral septum (dlS) is a GABAergic nucleus that receives dense direct input from the cornu ammonis 3 regions of the dorsal hippocampus, a brain region that is critical for the maintenance of contextual cocaine memories. Accordingly, we tested the hypothesis that neuronal activity in the dlS regulates the strength of cocaine-predictive contextual memories prior to reconsolidation. Male and female Sprague-Dawley rats received cocaine self-administration training followed by extinction training in two different environmental contexts. After the last extinction training session, the rats were placed back into the cocaine-predictive context to retrieve and destabilize their cocaine-related contextual memories. Immediately or 6 h after memory retrieval, the rats received intra-dlS vehicle or baclofen/muscimol (B/M; GABA_B/A agonists) infusions to inhibit neuronal activity during or after memory updating/reconsolidation, respectively. Resulting changes in cocaine and extinction memory strength were assessed based on the magnitude of unreinforced lever responding in the two contexts. Intra-dlS B/M infusion immediately after memory retrieval increased subsequent context-induced cocaine seeking behaviors in male rats, but not in female rats, whereas delayed B/M treatment had no effects in male rats. Together these findings suggest that the dlS is selectively engaged during memory updating/reconsolidation to reduce the strength of cocaine memories in males, possibly contributing to sex differences in the progression of cocaine use disorder.