Lack of cocaine-like discriminative-stimulus effects of σ-receptor agonists in rats

Previous studies demonstrated the effectiveness of selective sigma-receptor (sigma R) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by sigma Rs. In addition, sigma R antagonists blocked self-administration of sigma R agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of sigma R agonists and cocaine. This study further examined the cocaine-like effects of sigma R agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35 428, methylphenidate), but neither sigma R agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of sigma R agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective sigma R agonists, indicating that an overlap of subjective effects is not necessary for sigma R agonist self-administration. The previously found differences in neurochemical effects of cocaine and sigma R agonists may contribute to their different subjective effects. Behavioural Pharmacology 22:525-530 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.