TY - JOUR T1 - Stimulants as specific inducers of dopamine-independent sigma agonist self-administration in rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.113.207522 SP - jpet.113.207522 AU - Takato Hiranita AU - Paul L. Soto AU - Gianluigi Tanda AU - Theresa A. Kopajtic AU - Jonathan L. Katz Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/08/28/jpet.113.207522.abstract N2 - A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of selective agonists mediated by their actions at sigma1 receptors (σ1Rs), which are intracellularly-mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg/injection), the mu-opioid receptor agonist, heroin (0.001-0.032 mg/kg/injection), and the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel antagonist ketamine (0.032-1.0 mg/kg/injection). As with cocaine, self-administration of d-methamphetamine induced the reinforcing effects of the selective σ1R agonists, PRE-084 and (+)-pentazocine (0.032-1.0 mg/kg/injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg/injection, each) self-administration. Though the σ1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g. remifentanil, 0.1-3.2 µg/kg/injection, for heroin and (+)-MK 801, 0.32-10.0 µg/kg/injection, for ketamine). The σR antagonist BD 1008 (1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was not affected by the dopamine receptor antagonist, (+)-butaclamol (10-100 μg/kg), nor the opioid antagonist, (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induce reinforcing effects of previously inactive σ1R agonists. It is further suggested that induced σ1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. ER -