Morphine self-administration into the lateral septum depends on dopaminergic mechanisms: Evidence from pharmacology and Fos neuroimaging.

Mice self-administer morphine into the lateral septum (LS), but the neuronal connections underlying this behaviour remain unknown. The present study tested whether the acquisition of intra-LS morphine self-administration depends on dopaminergic mechanisms. Mice were allowed to self-inject morphine (5 or 20ng/50nl) or vehicle directly into the LS using a spatial discrimination Y-maze task. Fos imaging was used to evaluate neuronal activation in cerebral structures directly connected to the LS or belonging to the dopaminergic system. The involvement of dopaminergic and opioidergic mechanisms was assessed by pre-treating naive mice peripherally with the D1 antagonist SCH23390, the D2/D3 antagonist sulpiride or the opiate antagonist naloxone before daily self-administration sessions. Mice acquired self-administration behaviour for intra-LS morphine that was associated with increased Fos expression in the ventral tegmental area (VTA), dorsal and ventral striatum and prefrontal cortex. Pre-treating animals with naloxone, SCH23390 or sulpiride completely prevented them from acquiring intra-LS morphine self-administration. All three antagonists consistently blocked Fos expression in the prefrontal cortex, but not in the VTA and striatum. Taken together, our results show that morphine self-administration into the LS depends on dopaminergic (D1 and D2/D3) and opioidergic mechanisms. Furthermore, they suggest that opioid peptides released in the LS could participate in regulating the activity of mesotegmental dopaminergic neurons.