The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction

Abstract

Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal activity in the reward centers of the brain. One promising therapeutic target for the treatment of METH addiction is the sigma-1 receptor (σ₁R). The σ₁R is an endoplasmic reticulum-localized chaperone protein that is activated by cellular stress, and, unique to this chaperone, its function can also be induced or inhibited by different ligands. Upon activation of this unique "chaperone receptor", the σ₁R regulates a variety of cellular functions and possesses neuroprotective activity in the brain. Interestingly, a variety of σ₁R ligands modulate dopamine neurotransmission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σ₁R may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on METH and the σ₁R as well as a literature review regarding the role of σ₁Rs in modulating both dopamine neurotransmission and the effects of METH. We aim to highlight the complexities of σ₁R pharmacology and function as well as the therapeutic potential of the σ₁R as a target for the treatment of METH addiction.

Keywords: Dopamine; Dopamine transporter; Methamphetamine; Sigma-1 receptor.