title: Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.
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.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Ami
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Whitfield
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Max
authors.initials: M
authors.lastname: Kreifeldt
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational Medicine and Neurogenetic Programme, UdS Université de Strasbourg, INSERM U964, CNRS UMR7104, Illkirch, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Koebel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational Medicine and Neurogenetic Programme, UdS Université de Strasbourg, INSERM U964, CNRS UMR7104, Illkirch, France.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Candice
authors.initials: C
authors.lastname: Contet
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Olivier
authors.initials: O
authors.lastname: George
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D003042:Cocaine / Q000494:pharmacology*; D000229:Dependovirus; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D017403:In Situ Hybridization; D008124:Locomotion / Q000187:drug effects*; D018782:Maze Learning; D009714:Nucleus Accumbens / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; D034741:RNA, Small Interfering; C033660:preproenkephalin; D003042:Cocaine