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

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 (σR). The σR 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 σR regulates a variety of cellular functions and possesses neuroprotective activity in the brain. Interestingly, a variety of σR ligands modulate dopamine neurotransmission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σR may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on METH and the σR as well as a literature review regarding the role of σRs in modulating both dopamine neurotransmission and the effects of METH. We aim to highlight the complexities of σR pharmacology and function as well as the therapeutic potential of the σR as a target for the treatment of METH addiction.