A specific limbic circuit underlies opiate withdrawal memories
J Neurosci.. 2005-02-09; 25(6): 1366-74
DOI: 10.1523/jneurosci-3090-04.2005
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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.