title: Sustained AAV-mediated overexpression of CRF in the central amygdala diminishes the depressive-like state associated with nicotine withdrawal.
abstract: Smoking cessation leads to a dysphoric state and this increases the risk for relapse. Animal studies indicate that the dysphoric state associated with nicotine withdrawal is at least partly mediated by an increase in corticotropin-releasing factor (CRF) release in the central nucleus of the amygdala (CeA). In the present study, we investigated whether a sustained overexpression of CRF in the CeA affects the dysphoric-like state associated with nicotine withdrawal. To study brain reward function, rats were prepared with intracranial self-stimulation (ICSS) electrodes in the medial forebrain bundle. An adeno-associated virus (AAV, pseudotype 2/5) was used to overexpress CRF or green fluorescent protein (GFP, control) in the CeA and minipumps were used to induce nicotine dependence. The AAV2/5-CRF vector induced a 40% increase in CRF protein and mRNA levels in the CeA. Administration of the nicotinic receptor antagonist mecamylamine (precipitated withdrawal) or nicotine pump removal (spontaneous withdrawal) led to elevations in ICSS thresholds. Elevations in ICSS thresholds are indicative of a dysphoric-like state. The overexpression of CRF did not affect baseline ICSS thresholds but diminished the elevations in ICSS thresholds associated with precipitated and spontaneous nicotine withdrawal. The real-time reverse transcriptase (RT)-PCR analysis showed that the overexpression of CRF led to a decrease in CRF1 mRNA levels and an increase in CRF2 mRNA levels in the CeA. In conclusion, the overexpression of CRF in the CeA diminishes the dysphoric-like state associated with nicotine withdrawal and this might be driven by neuroadaptive changes in CRF1 and CRF2 receptor gene expression.
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Shan
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Guerra
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Alexander
authors.affiliation: J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Ormerod
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Bruijnzeel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D066274:Central Amygdaloid Nucleus / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*; D000229:Dependovirus / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014029:Tobacco Use Disorder / Q000378:metabolism*
chemical_list: D018733:Nicotinic Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; D009538:Nicotine; D003346:Corticotropin-Releasing Hormone
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