Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor

Nat Commun. 2013;4:1955. doi: 10.1038/ncomms2955.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / metabolism*
  • Feeding Behavior / drug effects
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Hypothalamus / metabolism*
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Knockout
  • Rats
  • Rats, Wistar
  • Sucrose / metabolism
  • Syndecan-3 / deficiency
  • Syndecan-3 / metabolism*


  • Glial Cell Line-Derived Neurotrophic Factor
  • Syndecan-3
  • Sucrose
  • Cocaine