Reactivity and plasticity in the amygdala nuclei during opiate withdrawal conditioning: differential expression of...

Opiate withdrawal leads to the emergence of an aversive state that can be conditioned to a specific environment. Reactivation of these withdrawal memories has been suggested to be involved in relapse to drug-seeking of abstinent opiate addicts. Among the limbic areas that are likely to mediate these features of opiate dependence, amygdala nuclei represent critical neural substrates. Using a conditioned place aversion paradigm (CPA), we have previously shown specific opposite patterns of reactivity in the basolateral (BLA) and the central (CeA) amygdala, when comparing the experience of acute opiate withdrawal with the re-exposure to a withdrawal-paired environment. These data gave clues about the potential mechanisms by which amygdala nuclei may be involved in withdrawal memories. To extend these results, the present study aimed to assess the cellular reactivity and plasticity of amygdala nuclei during the opiate withdrawal conditioning process. For this, we have quantified c-fos and arc expression using in situ hybridization in rats, following each of the three conditioning sessions during CPA, and after re-exposure to the withdrawal-paired environment. BLA output neurons showed an increase in the expression of the plasticity-related arc gene during conditioning that was also increased by re-exposure to the withdrawal-paired environment. Interestingly, the CeA showed an opposite pattern of responding, and the intercalated cell masses (ITC), a possible inhibitory interface between the BLA and CeA, showed a persistent activation of c-fos and arc mRNA. We report here specific c-fos and arc patterns of reactivity in amygdala nuclei during withdrawal conditioning. These findings improve our understanding of the involvement of the amygdala network in the formation and retrieval of withdrawal memories. Plasticity processes within BLA output neurons during conditioning, may participate in increasing the BLA reactivity to conditioned stimuli, which could in turn (by the control of downstream nuclei) reinforce and drive the motivational properties of withdrawal over drug consumption.