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Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression
Sarah Ann R. Anderson, … , Nora D. Volkow, Yasmin L. Hurd
Sarah Ann R. Anderson, … , Nora D. Volkow, Yasmin L. Hurd
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5334-5341. https://doi.org/10.1172/JCI70395.
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Research Article

Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

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Abstract

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect–related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.

Authors

Sarah Ann R. Anderson, Michael Michaelides, Parisa Zarnegar, Yanhua Ren, Pernilla Fagergren, Panayotis K. Thanos, Gene-Jack Wang, Michael Bannon, John F. Neumaier, Eva Keller, Nora D. Volkow, Yasmin L. Hurd

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Figure 4

Voxel analysis of ExA substructures confirms increase of metabolic activity following PAC-Pdyn inhibition.

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Voxel analysis of ExA substructures confirms increase of metabolic activ...
(A) Representative coronal images of ExA substructures analyzed for voxel analysis (B) Quantitative bar graphs of 3D voxel intensities in the right ExA substructures. Evaluation of each substructure demonstrated that CNO administration enhanced voxel intensity selectively in the right substructures as compared with vehicle administration. BNST, P = 0.002; NAc shell, P = 0.031; MeA, P = 0.008; CeA, P = 0.1, paired t test.
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