Role of Sigma-1 Receptor in Cocaine Abuse and Neurodegenerative Disease

Sigma-1 receptors (Sig-1R) are recognized as a unique class of non-G protein-coupled intracellular protein. Sig-1R binds to its ligand such as cocaine, resulting in dissociation of Sig-1R from mitochondrion--associated ER membrane (MAM) to the endoplasmic reticulum (ER), plasma membrane, and nuclear membrane, regulating function of various proteins. Sig-1R has diverse roles in both physiological as well as in pathogenic processes. The disruption of Sig-1R pathways has been implicated as causative mechanism(s) in the development of both neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington Disease (HD). Additionally, the interaction of cocaine and Sig-1R has more recently been implicated in potentiating the pathogenesis of HIV-associated neurocognitive disorders (HAND) through impairment of blood-brain barrier (BBB), microglial activation and astrogliosis. On the other hand, restoration of Sig-1R homeostasis has been shown to exert neuroprotective effects. In this review, we provide an overview of how Sig-1R plays a role in the pathogenesis of neurodegenerative disorders and cocaine and implications for future development of therapeutic strategies.