[Physiological functions of sigma-1 receptors and its relation to psychic dependence]

Sigma-1 receptors had been believed as a one of the opioid receptors. Recent reports have demonstrated that the sigma-1 receptor is a nonopioid receptor that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface and has been shown to be protective against neurodegeneration as an ER chaperone. In this review, we review the molecular mechanism on the cytoprotective effects of sigma-1 receptors. Furthermore, we summarize the effects of sigma-1 receptor ligand on the behavioral effects, especially on the reward-related behaviors induced by psychostimulants. The ER is a major locus for the synthesis of proteins. Under physiological conditions, the overall protein level in the ER is maintained by a balance between the protein synthesis and degradation. When the balance is perturbed, signaling pathways (the unfolded protein response (UPR) caused by ER stress or the ER overload response (EOR)) are activated to regulate the cell survival/death signalings. Sigma-1 receptor could be upregulated by ER stress and EOR, and that upregulated sigma-1 receptors attenuate UPR and EOR by increasing the chaperone activity of sigma-1 receptors and attenuation of prossessed NF-kappaB activity, respectively. On the other hand, even sigma-1 receptor could be upregulated by self-administration of methamphetamine in the ventral tegmental area, exact mechanism how sigma-1 receptor chaperone affect the behavioral effects induced by psychostimulants is not yet cleared. However, the prototypic sigma-1 receptor agonist SKF10,047 induces psychotomimetic effects, and psychotomimetic-like discriminative stimulus effects are at least in part mediated by sigma-1 receptors. Recent research showed that endogenous hallucinogen (N,N-dimethyltryptamine) might be a sigma-1 receptor regulator, indicating that sigma-1 receptor is crosely related to psychotomimetic effects. Furthermore, sigma-1 receptor agonist can enhance the discriminative stimulus effects of psychostimulants, and methamphetamine self-administration could be maintained by sigma-1 receptor agonists. These results suggest that sigma-1 receptors are involved in the psychotomimetic as well as rewarding process inside the cellular signal transduction system.