Biological And Biochemical Characterization Of Sigma Receptors

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Since my laboratory at the NIDA IRP identified the sigma-1 receptor in 1982, many preclinical studies have shown that sigma-1 receptors and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimer disease, pain, and cocaine addiction. In this fiscal year from Oct 1/2022-Sept 30/2023, we have (1) published a major notion that the sigma-1 receptor is an important innate resilience provider against diverse neurological diseases; (2) published a major article in Autophagy (IF=16.02) that the sigma-1 receptor promotes autophagy for cellular survival; and (3) elucidated via ongoing investigations that the sigma-1 receptor mediates addiction processes induced by cocaine or morphine. They are elaborated as follows. (1) Sigma-1 receptor is an innate resilience provider against multiple neurodegenerative diseases firstly because of its multi-faceted basic molecular actions and secondly because of its diverse existence from the head to the tail of a neuron. More specifically, the sigma-1 receptor can chaperone other functional proteins, can bind and organize signaling lipids, and can absorb toxic RNA repeats. Therefore, the sigma-1 receptor enhances dendritic spine maturation at dendrites, regulates intrinsic excitability of soma, facilitates the extension and myelination of axon, promotes growth cone at nerve ending. Further, the sigma-1 receptor absorbs toxic RNA repeats, promotes autophagy at the nuclear pore; and reorganizes ER-MITO proteins and microdomains, reduces ER stress, and ensures Ca2+ signaling for mitochondrial ATP production. Therefore, we propose and publish it as a short communication that the sigma-1 receptor is a innate resilience factor for neuronal survival and is aa avenue for drug development against multiple neurodegenerative disease. (2) Sigma-1 receptor increases autophagy by chaperoning a nuclear pore protein POM121 that anchors the transport carrier for TEFB transcription factor which initiates the autophagy for neuronal survival. We also found that a drug currently under clinical trials for ALS and Huntington disease enhances this action of sigma-1 receptor. (3) Our ongoing studies indicate that the sigma-1 receptor mediates addiction processes induced by cocaine or morphine. Cocaine. (a) We are discovering that the sigma-1 receptor can directly activate the VTA DA neuron from inside of the neuron. The induction of neuronal excitability in the VTA DA neuron is the hallmark of cocaine reward. We previously showed that the sigma-1 receptor mediates this action of cocaine by two different mechanisms: indirectly decreases the presynaptic GABA input from nuclear accumbens (NAc) by decreasing the intrinsic excitability of NAc D1 GABA neuron; and indirectly as well by decreasing the presynaptic GABA input by increasing the retrograde inhibitory endocannabinoid signaling. Now we are discovering that cocaine utilizes the VTA DA sigma-1 receptor to directly increase the excitability of the neuron by removing the Ca2+-impermeable AMPARs from the plasma membrane so as to strengthen the presynaptic glutamate input onto the neuron. We are now elucidating the exact molecular mechanism whereby the sigma-1 receptor mediates this action of cocaine. (b) We are discovering that the decision-making deficit seen in sensory preconditioning test (SPC) in cocaine withdrawn rats is mediated by sigma-1 receptor at least as evidenced from the electrophysiological study. In the behavioral study, we found that the pretreatment of sigma-1 receptor antagonist BD1063 before each cocaine self-administration potentially blocks the deficit in decision-making in the SPC test. We have added more cohorts of rats and are analyzing data hopefully to gain statistically significant results. Nevertheless, we find from electrophysiological study that the presynsptic glutamate release reduced by cocaine withdrawal is significantly blocked by BD1063! This means that the sigma-1 receptor mediates the dysfunctional decision-making during cocaine withdrawal. We are investigating the exact mechanism whereby the sigma-1 receptor may do so. Morphine. (a) We find that the hyperalgesia induced by sub-chronic use of morphine or after the fentanyl vapor self-administration is mediated by the sigma-1 receptor. In the case of morphine we find that it is in particular the sigma-1 receptor in the central amygdala where sigma-1 receptor co-exists with mu opioid receptor and PKC-delta. We demonstrate this result by using sigma-1 receptor genomic knockout mice as well as by using the regionally conditional knockdown mice. We are elucidating the molecular mechanism whereby sigma-1 receptor participates in this opioid-induced hyperalgesia with a hope to use sigma-1 receptor antagonist to treat the hyperalgesia in clinical setting to reduce opioid craving. (b) We find that the sigma-1 receptor plays a role in the neonatal abstinence syndrome (NAS) in mouse pups whose mothers were treated with morphine during pregnancy. We find that the neuronal hyperexcitability seen in NAS pups are not seen in either sigma-1 receptor knockout pups or pups that receive a single dose of sigma-1 antagonist BD1063. We are investigating the exact molecular underpinning whereby the sigma-1 receptor is doing in the NAS.