Prelimbic cortex and ventral tegmental area modulate synaptic plasticity differentially in nucleus accumbens during cocaine-reinstated drug seeking

Hao Wei Shen, Cassandra D. Gipson, Martijn Huits, Peter W. Kalivas

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Addictive drug use causes long-lasting changes in synaptic strength and dendritic spine morphology in the nucleus accumbens that might underlie the vulnerability to relapse. Although activity in mesocorticolimbic circuitry is required for reinstating cocaine seeking, its role in reinstatement-associated synaptic plasticity is not well characterized. Using rats extinguished from cocaine self-administration, we found potentiated synaptic strength (assessed as the AMPA/NMDA current amplitude ratio) and increased spine head diameter in medium spiny neurons in the accumbens core (NAcore). The basal changes in synaptic strength and morphology in cocaine-extinguished animals were further augmented during cocaine-induced reinstatement. Two NAcore afferents contributing to cocaine reinstatement are glutamatergic inputs from the prelimbic prefrontal cortex (PL) and dopamine from the ventral tegmental area (VTA). Pharmacological inhibition of either PL or VTA prevented cocaine-primed reinstatement. However, inhibiting the PL further potentiated AMPA/NMDA and spine head diameter, while inactivating the VTA or the combined systemic administration of dopamine D1 and D2 antagonists prevented the increase in AMPA/NMDA and spine diameter induced by cocaine priming. These data indicate that neuronal activity in the VTA and associated dopamine receptor stimulation is necessary for the synaptic potentiation in the NAcore during cocaine-induced reinstatement. Although activity in the PL was necessary for reinstatement, it inhibited synaptic potentiation initiated by an acute cocaine injection. Thus, although the PL and VTA differentially regulate the direction of synaptic plasticity induced by a cocaine-priming injection, coordinated synaptic potentiation by both NAcore afferents is necessary for cocaine-induced relapse.

Original languageEnglish
Pages (from-to)1169-1177
Number of pages9
Issue number5
StatePublished - Apr 2014

Bibliographical note

Funding Information:
This work was supported by the DA007288, DA03906, DA012513, and DA015369 grants from the National Institutes of Health.


  • accumbens core
  • cocaine self-administration
  • prefrontal cortex
  • reinstatement
  • synaptic plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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