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. Previous studies showed that sigma1 receptor (sigma1R) agonists (e.g. PRE-084, (+)-pentazocine) were reinforcing in rats with cocaine or d-methamphetamine self-administration experience, but not in experimentally nave rats. Further studies demonstrated that the induction of sigma1R agonist self administration specifically occurred with SA of drugs acting at the dopamine transporter (DAT), but not with other abused drugs (e.g. heroin, ketamine). In contrast to effects with sigma1R agonists, a recent report showed self administration of the non-selective sigma1/2R agonist DTG in nave rats. The present study assessed DTG self administration pharmacology, and whether self administration experience would induce PRE-084 self administration. Responding of rats trained with DTG self administration under an FR schedules was subsequently maintained with PRE-084. DTG self administration was insensitive to antagonism by dopamine (DA) receptor antagonists (SCH 39166, L-741626) which dose-dependently blocked cocaine self administration. Further, sigmaR antagonists (BD 1063, haloperidol) blocked DTG self administration, but only haloperidol, which is also a DA antagonist, blocked cocaine self administration. Pretreatments with PRE-084, the DAT inhibitor WIN 35,428, and DA D2R agonists (R(−)-NPA, (−)-quinpirole, which were themselves self administered) dose-dependently potentiated DTG and cocaine self administration. Treatment with DA D1R agonists (R(+)-SKF 81297, ()-SKF 82958, which were also self-administered) dose-dependently decreased maximal self administration of both cocaine and DTG. The results suggest that DA-uptake inhibition while sufficient is not necessary for induction of sigma1R agonist reinforcement, and that once induced, sigma1R-mediated reinforcement is independent of DA receptor antagonism, but is affected by DA agonists in a manner similar to that for cocaine. These results suggest that DA-uptake inhibition is not necessary for induction of reinforcement by sigma1R agonists. Further, positive modulation of DA systems and sigma1R agonism similarly enhance reinforcing effects of both cocaine and DTG. Thus, DA-uptake inhibition while sufficient is not necessary for induction of reinforcement by sigma1R agonists, and that once induced sigmaR-mediated reinforcement is insensitive to DAR antagonism.
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