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Compulsive drug-seeking behavior and its renewal in former drug addicts is promoted by several situations, among which reactivation of drug withdrawal memories plays a crucial role. A neural hypothesis is that such memories reactivate the circuits involved in withdrawal itself and promote a motivational state leading to drug seeking or taking. To test this hypothesis, we have analyzed the neural circuits and cell populations recruited when opiate-dependent rats are reexposed to stimuli previously paired with withdrawal (memory retrieval) and compared them with those underlying acute withdrawal during conditioning (memory formation). Using in situ hybridization for c-fos expression, we report here that reexposure to a withdrawal-paired environment induced conditioned c-fos responses in a specific limbic circuit, which can be partially dissociated from the structures involved in acute withdrawal. At the amygdala level, c-fos responses were doubly dissociated between the central and basolateral (BLA) nuclei, when comparing the two situations. Detailed phenotypical analyses in the amygdala and ventral tegmental area (VTA) show that specific subpopulations in the BLA are differentially involved in the formation and retrieval of withdrawal memories, and strikingly that a population of VTA dopamine neurons is activated in both situations. Together, this indicates that withdrawal memories can drive activity changes in specific neuronal populations of interconnected limbic areas known to be involved in aversive motivational processes. This first study on the neural substrates of withdrawal memories strongly supports an incentive-motivational view of withdrawal in opiate addiction that could be crucial in compulsive drug seeking and relapse.

A Specific Limbic Circuit Underlies Opiate Withdrawal Memories