Vagus nerve stimulation modulates synaptic plasticity induced by cocaine- seeking in reward-related circuitry.

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. This study examined how cocaine and VNS affect plasticity in relapse-related pathways. Evoked local field potentials (eLFP) were recorded in the IL, NAc core, and NAc shell following self-administration or reinstatement sessions. In the BLA-IL pathway, cocaine-treated (COC) and sham-VNS (SHAM) groups exhibited the highest baseline eLFP amplitudes and increased long-term potentiation (LTP) induction, which VNS restored to yoked-saline (YS) levels. In the PL-NAc core pathway, high-frequency stimulation (HFS) had no effect on EFPs 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.