<p>Addictive drugs engage molecular pathways of associative learning and memory. Drug craving triggered by cues that were once associated with drug intoxication contributes to continued drug-seeking behaviors. Reactivated memories are vulnerable to disruption by interference with the process of reconsolidation, hence targeting reconsolidation could be beneficial in reducing cue-induced drug craving and relapse. Here, we sought to identify the neuronal pathways and neuroplasticity involved in cocaine contextual memory reconsolidation. Mice expressing inhibitory DREADDs in either nucleus accumbens (NAc) neurons or neurons in the ventral hippocampus (vHPC) projecting to NAc underwent cocaine place conditioning to establish cocaine contextual memories. Clozapine-N-oxide (CNO) administered after memory reactivation was used to inhibit NAc neurons or vHPC neurons projecting to the NAc during the reconsolidation period. Inhibition of either neuronal population abolished the previously established preference for the cocaine context. FosTRAP2-Ai14 mice were used to identify and characterize neurons in the NAc and vHPC activated during reconsolidation of cocaine memory. Results demonstrate NAc medium spiny neurons activated by cocaine contextual memory recall had greater dendritic spine density, length and complexity than without memory recall. vHPC pyramidal neurons also showed higher dendritic spine density after cocaine contextual memory recall. The neuroplastic changes induced by cocaine memory reactivation suggest synaptic strengthening and eventual maturation of synapses. The results of this work reveal a critical role for a circuit involving glutamatergic projections from the vHPC onto NAc neurons in the reconsolidation of cocaine memories; disruption of the activity of this circuit abolishes previously established cocaine contextual memories.</p>