Arc reactivity in accumbens nucleus, amygdala and hippocampus differentiates cue over context responses during reactivation of opiate withdrawal memory.

Opiate withdrawal induces an early aversive state which can be associated to contexts and/or cues, and re-exposure to either these contexts or cues may participate in craving and relapse. Nucleus accumbens (NAC), hippocampus (HPC) and basolateral amygdala (BLA) are crucial substrates for acute opiate withdrawal, and for withdrawal memory retrieval. Also HPC and BLA interacting with the NAC are suggested to respectively mediate the processing of context and cue representations of drug-related memories. Here we used a paradigm of conditioned suppression of operant food seeking, allowing to differentiate context and cue related responses, to study the influence of withdrawal memories on operant behavior and the underlying neural substrates. catFISH for Arc mRNA expression was used to discriminate cellular responses during context and cue (flashing light) periods in this paradigm. We show that reactivation of the memory of the negative affective state of withdrawal suppresses active lever pressing for food, and this conditioned suppression is generalized to the context. Interestingly the behavioral responses during the context and cue light periods are associated with differential Arc mRNA activations within the NAC, BLA, and HPC. Indeed both periods led to NAC shell activation whereas the NAC core was responsive only following the cue light period. Moreover, BLA and HPC were more responsive during cue-light and context period respectively. These data further support the already reported differential role of these brain structures on cue vs context-induced reinstatement of operant behaviors, and highlight the existence of common mechanisms for the processing of positive and aversive emotional memories.