A Role for Sigma Receptors in Stimulant Self Administration and Addiction

Sigma(1) receptors (sigma(1)Rs) represent a structurally unique class of intracellular proteins that function as chaperones. sigma(1)Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that sigma R antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by sigma R antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of sigma R agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the sigma R agonists were blocked by sigma R antagonists. Additionally, sigma R agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the sigma R agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential sigma R-2 antagonist but not by a preferential sigma R-1 antagonist. The effects of PRE-084 on dopamine were insensitive to sigma R antagonists. The data suggest that the self administration of sigma R agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by sigma Rs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone sigma Rs, may lead to the pernicious addictive effects of stimulant drugs.