The goal of this revised grant proposal is to explore strategies to modulate the activity of the brain proteoglycan syndecan-3 for the therapy of cocaine abuse. Proteoglycans like syndecan-3, while originally identified as components of the extracellular matrix (ECM), also play signaling functions as receptors and co-receptors for growth factors and ECM proteins. We observed that syndecan-3 in the lateral hypothalamus (LH) has an unexpected new role in limiting compulsive cocaine intake. In particular, in Specific Aim 1 we will investigate syndecan-3 ectodomain shedding and signal transduction in the regulation of cocaine intake. The proteolytic cleavage of syndecan-3 ectodomain, also known as "shedding" is induced after ligand interaction and terminates its signaling. To probe the functional consequence of ectodomain shedding, we will use adeno-associated (AAV) viral vectors to deliver modified syndecan-3 constructs including a shedding-resistant syndecan-3, the syndecan-3 ectodomain alone, and the unmodified syndecan-3. The results of these studies will establish the therapeutic potential of inhibiting the proteolytic cleavage of its ligand-binding ectodomain. Studies in Specific Aim 2 will investigate the role of syndecan-3 as an alternative GDNF receptor in the ability of syndecan-3 to reduce cocaine self-administration. To this end we will use AAV to transduce modified GDNF constructs designed to bind selectively either to syndecan-3 or to its canonical high-affinity receptor GFR-?1. The results of Specific Aim 2 will inform future studies aimed at manipulating interactions between syndecan-3 and its two receptor systems and signal transduction partners to boost its signaling activity. Together, the proposed studies will increase our understanding of the functions of the hypothalamic proteoglycan syndecan-3 as a regulator of behavior and will explore innovative therapeutic strategies for the therapy of cocaine abuse.
Proteoglycans like syndecan-3 have complex signaling roles in addition to their function as structural components of the extracellular matrix. We observed that syndecan-3 has an unexpected new role in limiting compulsive cocaine intake by modulating the effect of the neurotrophic factor GDNF on cocaine seeking in mice. Here we propose to test potential strategies to modulate this activity as novel therapeutic approaches for the therapy of cocaine abuse.