Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression.
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.
Sarah Ann R
SA
Anderson
Michael
M
Michaelides
Parisa
P
Zarnegar
Yanhua
Y
Ren
Pernilla
P
Fagergren
Panayotis K
PK
Thanos
Gene-Jack
GJ
Wang
Michael
M
Bannon
John F
JF
Neumaier
Eva
E
Keller
Nora D
ND
Volkow
Yasmin L
YL
Hurd
D000328:Adult; D000679:Amygdala / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism*; D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism*; D015198:Designer Drugs / Q000493:pharmacokinetics; D004745:Enkephalins / Q000032:analysis / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology; D006556:Heroin Dependence / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006814:Hungary; D008032:Limbic System / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods; D009474:Neurons / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011498:Protein Precursors / Q000032:analysis / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D019275:Radiopharmaceuticals; D051381:Rats; D020318:Rats, Long-Evans; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014481:United States
D015198:Designer Drugs; D004745:Enkephalins; D005462:Fluorine Radioisotopes; D011498:Protein Precursors; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D019788:Fluorodeoxyglucose F18; C033660:preproenkephalin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003024:Clozapine; C079149:clozapine N-oxide; D003345:Corticosterone