Vagus nerve stimulation modulates cocaine seeking induced synaptic plasticity in reward related brain circuits.

Cocaine use alters brain networks and connections, impairing inhibitory control over drug-seeking. Cortical-limbic circuits, including the infralimbic (IL), prelimbic (PL) cortices, and basolateral amygdala (BLA), regulate extinction learning and drug-seeking via projections to the nucleus accumbens (NAc). Vagus nerve stimulation (VNS) paired with extinction enhances learning and reduces reinstatement, but its effects on extinction-related networks remain unclear. We recorded evoked local field potentials (eLFP) in the IL, NAc core, and NAc shell across four experimental groups. The first two groups-cocaine (COC) and yoked-saline controls (YS)-were used to assess the direct effects of the drug immediately following the final self-administration session. The other two groups underwent eLFP recording after a cue-induced reinstatement session to evaluate how combining extinction with either VNS or SHAM stimulation modified plasticity in these pathways and subsequently reduced reinstatement. In the BLA-IL pathway, COC and SHAM groups exhibited the highest baseline eLFP amplitudes and increased long-term potentiation (LTP) induction, which VNS restored to YS levels. In the PL-NAc core pathway, high-frequency stimulation (HFS) had no effect on eLFP in VNS-treated animals, significantly differing from the long-term depression (LTD) observed in COC and SHAM groups, which had the highest baseline eLFP amplitudes. In the IL-NAc shell pathway, VNS-treated rats displayed the largest baseline amplitudes, and unlike YS, COC, and SHAM groups, HFS in the IL induced persistent LTP in the NAc shell. These findings suggest cocaine use and craving induce maladaptive neuroplasticity within cortical-limbic circuits, and VNS may modulate these changes, contributing its beneficial effects in preventing reinstatement.