Sigma receptors were initially proposed as opioid, and later phencyclidine receptors, and were finally demonstrated to represent unique binding sites in mammalian brain and peripheral tissues that are expressed throughout the CNS and have been implicated in a variety of physiological functions and disease states. Two subtypes of receptors have been distinguished molecularly and pharmacologically. Although the psychomotor stimulant and reinforcing effects of cocaine are primarily mediated through stimulation of dopamine (DA) neurotransmission by inhibiting dopamine reuptake, cocaine also shows a moderate affinity for Sigma receptors, and it has been suggested that some cocaine-induced effects could be mediated or modulated by its own actions at sigma 1 and/or sigma 2 receptor subtypes. In addition several studies have shown antagonism of various effects of cocaine by sigma receptor antagonists, and chronic exposure to cocaine has neuroplastic effects that are prevented by the sigma receptor antagonists. In a recent study we showed that the sigma receptor antagonist, AC927 (1-(2-phenethyl)piperidine oxalate), significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. In addition, subchronic administration of AC927 attenuated cocaine-induced place conditioning in mice, at doses that alone had no effects. AC927 differed from other receptor antagonists in partially substituting for the discriminative-stimulus effects of cocaine. Further, AC927 was self-administered in non-human primates, though to a lesser extent than was cocaine. The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse. Our previous studies demonstrating reinforcing effects of the σR agonists, DTG and PRE-084 were followed by studies of their actions on dopamine neurotransmission, a major mechanism in the reinforcing effects of drugs of abuse. Results indicated that the non-selective σ1/2R agonist, DTG and the selective σ1R agonist, PRE-084, dose-dependently increased DA levels, to a maximum that was significant, but less than that produced by cocaine. The stimulation of DA levels produced by DTG was antagonized by the nonselective σ1/2R antagonist, BD 1008, and by the preferential σ2R antagonist SN79, but not by the preferential σ1R antagonist, BD 1063. Effects of neither PRE-084 nor cocaine were antagonized by either BD1063 or BD1008. These results indicate that σR agonists can stimulate dopaminergic neurotransmission by acute administration in a brain area involved in the reinforcing effects of cocaine. The effects of DTG appear to be mediated by the σ2R rather than the σ1R subtype. Further, activation of σRs is not likely involved in the mediation of the acute effects on DA transmission by PRE-084 and cocaine. A further study investigated the mechanisms responsible for the reinforcing effects of cocaine agonists with cocaine-discriminating rats to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG) produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (intraperitoneal or subcutaneous) or pretreatment time (5- or 30-min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that overlapping of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects. Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine, but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, SH 3-24 and SH 3-28, dose-dependently decreased the maximal rates of cocaine self administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists (AC927, BD 1008, BD 1047, BD 1063, NE-100) had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors (WIN 35,428, methylphenidate, nomifensine) dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT-inhibitor and σR-antagonists doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. Additionally, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100, AC927) maintained responding above control levels across a wide range of doses. These findings suggest that unique effects of rimcazole analogs are due to dual actions at the DAT and σRs, and that a combined target approach may have utility in development of medical treatments for cocaine abuse.
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