title: Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor.
abstract: Proteoglycans like syndecan-3 have complex signaling roles in addition to their function as structural components of the extracellular matrix. Here, we show that syndecan-3 in the lateral hypothalamus has an unexpected new role in limiting compulsive cocaine intake. In particular, we observe that syndecan-3 null mice self-administer greater amounts of cocaine than wild-type mice. This effect can be rescued by re-expression of syndecan-3 in the lateral hypothalamus with an adeno-associated viral vector. Adeno-associated viral vector delivery of syndecan-3 to the lateral hypothalamus also reduces motivation for cocaine in normal mice. Syndecan-3 limits cocaine intake by modulating the effects of glial-cell-line-derived neurotrophic factor, which uses syndecan-3 as an alternative receptor. Our findings indicate syndecan-3-dependent signaling as a novel therapeutic target for the treatment of cocaine addiction.
authors.affiliation: Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jihuan
authors.initials: J
authors.lastname: Chen
authors.forename: Vez
authors.initials: V
authors.lastname: Repunte-Canonigo
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawamura
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.forename: William
authors.initials: W
authors.lastname: Shin
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Howell
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hemby
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Sanna
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D013395:Sucrose / Q000378:metabolism; D053670:Syndecan-3 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D053670:Syndecan-3; D013395:Sucrose; D003042:Cocaine