Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.

TitleVirus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.
Publication TypeJournal Article
Year of Publication2014
AuthorsCohen A, Whitfield TW, Kreifeldt M, Koebel P, Kieffer BL, Contet C, George O, Koob GF
JournalPLoS One
Volume9
Issue5
Paginatione97216
Date Published2014
ISSN1932-6203
KeywordsAnalysis of Variance, Animals, Anxiety, Cocaine, Dependovirus, Depression, Enkephalins, Gene Expression Regulation, Gene Knockdown Techniques, Genetic Vectors, In Situ Hybridization, Locomotion, Maze Learning, Nucleus Accumbens, Protein Precursors, Rats, Rats, Wistar, RNA, Small Interfering
Abstract

Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

DOI10.1371/journal.pone.0097216
Alternate JournalPLoS ONE
PubMed ID24816773
PubMed Central IDPMC4016270
Grant ListAA006420 / AA / NIAAA NIH HHS / United States
DA004398 / DA / NIDA NIH HHS / United States
P60 AA006420 / AA / NIAAA NIH HHS / United States
T32 AA007456 / AA / NIAAA NIH HHS / United States