Cocaine exposure alters dopaminergic modulation of prefronto-accumbens transmission

• We record NAc field potentials after electrically stimulating the PFC and VTA.
• Stimulation of the VTA is paired at different time intervals to that of the PFC.
• VTA stimulation at − 100 ms before PFC stimulation inhibits PFC–NAc transmission.
• Concurrent VTA stimulation with PFC stimulation potentiates PFC–NAc transmission.
• This process of timing-dependent modulation is blunted by prior cocaine experience.

In the nucleus accumbens (NAc), dopamine transmission modulates glutamatergic input from the prefrontal cortex (PFC). This neuromodulatory action of dopamine can be disrupted by repeated exposure to psychostimulants such as cocaine. However, it is unclear whether this modulation depends on the precise timing of transmission at the same medium spiny neurons (MSNs) and if so, then whether this timing related modulation is also influenced by cocaine experience. Here, combining cocaine self-administration and in vivo extracellular recordings in anesthetized rats, we show that dopamine efflux in the NAc evoked by electrically stimulating the ventral tegmental area (VTA) exerted timing-dependent regulation of the excitatory accumbens response to stimulation of the medial prefrontal cortex (mPFC), and also that this modulation was blunted following prolonged abstinence from cocaine self-administration. These data indicate that dopaminergic timing-dependent dysregulation of mPFC–NAc glutamatergic transmission is implicated in cocaine addiction and might contribute to vulnerability to drug relapse after prolonged abstinence.