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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 3

DREAMM imaging reveals that neuronal inhibition of Pdyn neurons in the PAC increases metabolic activity in the ExA.

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DREAMM imaging reveals that neuronal inhibition of Pdyn neurons in the P...
(A) Axial and right sagittal views showing that activation of Gi-mediated signaling in Pdyn neurons of the PAC with CNO leads to a profound induction of neuronal activity primarily in the right ExA as compared with vehicle administration in the same animal (red, relative increase; blue, relative decrease). LH, lateral hypothalamus; NAcSh, NAc shell; SI, substantia inominata; VMH, ventral medial hypothalamus; IPAC, interstitial nucleus of posterior limb of anterior commissure; SC/MC, sensory cortex/motor cortex; ON, olfactory nuclei; CeA, central amygdala; MVePC,: medival vestibular nucleus, parvicellular part; VP, ventral pallidum; LEnt, lateral entorhinal cortex; BLA, basolateral amygdala; MPA, medial preoptic area. (B) Schematic diagram of the ExA circuit and its substructures.
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