A role for sigma receptors in stimulant self-administration and addiction

Sigma-1 receptors (sigma 1Rs) are structurally unique intracellular proteins that function as chaperones. sigma 1Rs translocate from the mitochondria-associated membrane to other subcellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to sigma Rs can induce or block the actions of sigma Rs. Studies indicate that stimulant self-administration induces the reinforcing effects of sigma R agonists, because of dopamine transporter actions. Once established, the reinforcing effects of sigma R agonists are independent of dopaminergic mechanisms traditionally thought to be critical to the reinforcing effects of stimulants. Self-administered doses of sigma R agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused drugs. However, self-administration of sigma R agonists is blocked by sigma R antagonists. Several effects of stimulants have been blocked by sigma R antagonists, including the reinforcing effects, assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by sigma R antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing effects. When sigma R antagonists are administered in combination with dopamine uptake inhibitors, an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in sigma R activity and the changes induced potentially create redundant and, once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and sigma R proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.