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

Hypothalamic Proteoglycan syndecan-3 Is a Novel Cocaine Addiction Resilience Factor

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Free PMC article

Hypothalamic Proteoglycan syndecan-3 Is a Novel Cocaine Addiction Resilience Factor

Jihuan Chen et al. Nat Commun. .
Free PMC article

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.

Figures

Figure 1
Figure 1. LH syndecan-3 is induced by cocaine.
(a) Syndecan-3 is induced by cocaine intake in the LH, but not in the NAc of cocaine-self-administering rats as measured by quantitative real-time PCR (qRT-PCR) with the standard curve method normalizing to β-actin (n=4–5). Units on the y axis represent the ratios of syndecan mRNA levels to that of β-actin in each region (*P<0.05, by one-way ANOVA with Tukey’s post-hoc test). (b) GSEA indicates that genes related to syndecan-3-dependent signaling are enriched in differentially expressed genes in the LH of cocaine-self-administering rats compared with control rats (normalized enrichment score, NES=1.9; P<0.001). The dotted line, also called leading edge, indicates the point at which the running enrichment score reaches its maximum score. (c) Cocaine increases the expression of syndecan-3 mRNA in the LH but not in the NAc of mice after six daily IP administrations of 18 mg kg−1 of cocaine; control mice received isovolemic injections of saline vehicle (n=5; **P<0.01 by t-test). (d) Syndecan-3 mRNA is increased in the LH in cocaine-self-administering macaques (n=4; *P<0.05 by t-test). Data are presented as mean±s.e.m.
Figure 2
Figure 2. Syndecan-3 deficiency increases cocaine intake.
(a) Acquisition of intravenous cocaine self-administration (FR1) in wild-type (WT) and syndecan-3 KO mice. Following acquisition, syndecan-3 KO mice showed a higher level of cocaine intake at the training dose (FR1). Repeated measures (RM) two-way ANOVA: Test session F(11,187)=19.15, P<0.0001; Genotype F(1,187)=2.343, P=0.144; Interaction F(1,187)=2.233, P=0.014. (b) The dose-response curve (FR5) of syndecan-3 KO mice was upward-shifted compared with WT mice. Dose F(6,120)=29.78, P<0.0001; Genotype F(1,120)=4.621, P=0.044; Interaction F(6,120)=3.137, P=0.007. (c) Dose-intake curve (same mice as in middle panel). Syndecan-3 KO mice self-administered greater amounts of cocaine. Dose F(5,85)=59.26, P<0.0001; Genotype F(1,85)=7.793, P=0.013; Interaction F(5,85)=4.958, P<0.001. Data are presented as mean±s.e.m. *P<0.05 compared with wild-type mice (LSD post-hoc test; n=9–10).
Figure 3
Figure 3. Syndecan-3 deficiency does not affect sucrose intake.
Sucrose consumption was not different in syndecan-3 KO and wild-type (WT) mice over a broad range of sucrose concentrations as assessed by a two- bottle choice procedure. Both syndecan-3 KO and wild-type mice showed dose-related increase in sucrose intake (n=12 for each group). Data are presented as mean±s.e.m.
Figure 4
Figure 4. Rescue of syndecan-3 expression in the LH reduces cocaine intake in syndecan-3 KO mice.
(a) Immunochemical staining for GFP of a mouse infused with AAV in the LH; Scale bar correspond to 400 μm in the top panel and 200 μm in the bottom ones; (b) Left panel: Intra-LH infusions of AAV-Snd3 downward-shifted the dose-response curve in syndecan-3 KO mice (FR5). Dose F(6,102)=10.55, P<0.0001; AAV-Snd3 F(1,102)=4.596, P=0.047. Right panel: The dose-intake curve was shifted downward in AAV-Snd3-infused syndecan-3 KO mice (same mice as in left panel). Dose F(5,85)=148.4, P<0.0001; AAV-Snd3 F(1,85)=9.135, P=0.008; Interaction F(5,85)=5.443, P<0.001. n=9–10. (c) Left panel: Wild-type mice receiving intra-LH AAV-Snd3 reached lower breakpoints than AAV-GFP mice under a PR schedule. Dose F(6,90)=3.55, P=0.003; AAV-Snd3 F(1,90)=10.51, P=0.006; Interaction F(6,90)=2.311, P=0.04. Middle panel: the dose-response curve of wild-type mice was shifted downward by AAV-Snd3. Dose F(6,90)=3.415, P=0.004; AAV-Snd3 F(1,90)=9.075, P=0.009. Right: dose-intake curve was reduced by AAV-Snd3 in wild-type mice. Dose F(5,75)=60.09, P<0.0001; AAV-Snd3 F(5,75)=7.638, P=0.015; Interaction F(5,75)=2.915, P=0.019. n=8–9. Data are presented as mean±s.e.m. *P<0.05 and **P<0.01, AAV-GFP-infused versus AAV-Snd3-infused mice (LSD post-hoc test).
Figure 5
Figure 5. LH syndecan-3 modulates the effect of GDNF on cocaine intake.
(a) Acquisition of cocaine self-administration before intra-LH infusion of AAV-GDNF: syndecan-3 KO mice showed a higher level of cocaine intake at the training dose (FR1) than wild-type mice (WT). RM two-way ANOVA: Test session F(13,442)=25.39, P<0.0001; Genotype F(1,442)=4.481, P=0.0417. *P<0.05 compared with wild-type mice (n=18 for each genotype). Inset: syndecan-3 KO mice also showed higher lever pressing rates than wild-type mice after switching to FR5 schedule (t=2.36, P=0.021 by t-test). (b) Intra-LH infusion of an AAV vector expressing GDNF (AAV-GDNF) increased cocaine self-administration at the training dose (FR5). Two-way ANOVA showed a significant main effects of AAV-GDNF (F(1,23)=7.206, P=0.013) and genotype (F(1,23)=8.881, P=0.007). *P<0.05 AAV-GFP versus AAV-GDNF of KO mice; #P<0.05 syndecan-3 KO vs wild type mice infused with AAV-GFP (by LSD post hoc test). (c) Intra-LH infusion of AAV-GDNF upward-shifted the dose-response curve (FR5) in wild-type mice (left panel) and syndecan-3 KO mice (right panel). Left panel: Dose F(6,112)=3.573, P=0.003; AAV-GDNF F(1,112)=5.959, P=0.016. Right panel: Dose F(6,77)=3.585, P=0.004; AAV-GDNF F(1,77)=33.01, P<0.0001. *P<0.05 and **P<0.01 AAV-GFP versus AAV-GDNF (n=6–9, by LSD post-hoc test). (d) The c-Ret inhibitor vandetanib (15, 50 and 75 mg kg−1, s.c.) did not modify cocaine intake in wild-type mice infused with either AAV-GFP or AAV-GDNF in the LH (left panel), but selectively reduced cocaine self-administration in syndecan-3 KO mice infused with AAV-GDNF (right panel). Left panel: in wild-type mice, RM two-way ANOVA did not reveal significant main vandetanib effect at any dose of 15 mg kg−1 (F(1,13)=0.165; NS), 50 mg kg−1 (F(1,13)=3.435; NS) and 75 mg kg−1 (F(1,13)=0.095; NS). Right panel: in syndecan-3 KO mice, RM two-way ANOVA showed a significant main effect of vandetanib at 15 mg kg−1 (F(1,11)=5.979; P=0.033), 50 mg kg−1 (F(1,11)=9.694; P<0.01 with significant interaction F(1,11)=5.412; P=0.04), and 75 mg kg−1 (F(1,11)=24.08; P<0.001 with significant interaction F(1,11)=12.65; P=0.005). *P<0.05 AAV-GFP versus AAV-GDNF; #P<0.05 vehicle versus vandetanib group (n=6–7, by LSD post-hoc test). All data are presented as mean±s.e.m.

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