Dual Diagnosis

Biography

Biography: Hiranita Takato

Abstract

Sigma1 receptors are intracellular chaperones that translocate from their primary endoplasmic reticulum localization to different subcellular compartments upon agonist actions, and regulate ion channels and G-protein-coupled-receptor signaling. Reports have implicated 1Rs in various biological functions. On the other hand, the dopamine (DA) transporter (DAT) is known as a primary target underlying reinforcing effects of stimulants. However, past studies suggest that several atypical DAT inhibitors have low abuse potential, and are prospective leads for cocaine abuse treatments. However, it is unknown about a mechanism underlying the “atypical” property. I characterized the reinforcing effects of 1R agonists and investigated a potential interaction between DAT and 1R using a drug self-administration procedure in rats. Primary findings are as follows: (1) 1R agonists were not reinforcing in naïve rats; however, 1R agonists maintained self-administration responding above saline levels in rats with a reinforcement history of stimulants, but not of heroin or ketamine; (2) the induced reinforcing effects of 1R agonists were DA-independent; (3) several atypical DAT inhibitors functioned as a R antagonist; (4) a dual DAT/1R inhibition resulted in insurmountable antagonism of cocaine self-administration; however, self-administration of heroin or ketamine was insensitive to the dual inhibition. Thus, these results suggest that stimulants function as a specific inducer of DA-independent reinforcement mechanisms mediating 1Rs, which might shed light on understanding the mechanisms underlying the intractability of stimulant abuse to pharmacotherapy. Further, the results indicate a proof of concept that dual DAT/1R inhibition is a target for the discovery of medications specific for stimulant abuse.