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Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2013 Dec; Vol. 123 (12), pp. 5334-41. Date of Electronic Publication: 2013 Nov 15. - Publication Year :
- 2013
-
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.
- Subjects :
- Adult
Amygdala chemistry
Amygdala diagnostic imaging
Animals
Clozapine analogs & derivatives
Clozapine pharmacology
Corticosterone blood
Depressive Disorder, Major genetics
Designer Drugs pharmacokinetics
Enkephalins analysis
Enkephalins biosynthesis
Enkephalins deficiency
Enkephalins genetics
Female
Fluorine Radioisotopes
Fluorodeoxyglucose F18
GTP-Binding Protein alpha Subunits, Gi-Go genetics
GTP-Binding Protein alpha Subunits, Gi-Go physiology
Heroin Dependence genetics
Humans
Hungary
Limbic System chemistry
Limbic System diagnostic imaging
Limbic System metabolism
Male
Middle Aged
Neuroimaging methods
Neurons metabolism
Positron-Emission Tomography methods
Protein Precursors analysis
Protein Precursors biosynthesis
Protein Precursors deficiency
Protein Precursors genetics
RNA, Messenger analysis
RNA, Messenger biosynthesis
Radiopharmaceuticals
Rats
Rats, Long-Evans
Recombinant Fusion Proteins metabolism
United States
Amygdala metabolism
Depressive Disorder, Major metabolism
Enkephalins physiology
Heroin Dependence metabolism
Protein Precursors physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 123
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 24231353
- Full Text :
- https://doi.org/10.1172/JCI70395