title: Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaine seeking in mice.
abstract: Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia 3010.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Chen
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia 3010.
authors.forename: Bianca
authors.initials: B
authors.lastname: Jupp
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel, and.
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Sztainberg
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel, and.
authors.forename: Maya
authors.initials: M
authors.lastname: Lebow
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia 3010.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Brown
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia 3010.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel, and Department of Stress Neurobiology and Neurogenetics, Max-Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia 3010, andrew.lawrence@florey.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003216:Conditioning, Operant; D003463:Cues; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000502:physiology; D005508:Food Deprivation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D013315:Stress, Psychological; D017557:Ventral Tegmental Area / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: VTA; cocaine; cue; mouse; relapse; stress