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Pharmacology of Self‐Administration of a Non‐Selective Sigma1/2 Receptor Agonist, 1,3‐di‐o‐tolylguanidine (DTG), and its Induction of Sigma1‐Mediated Reinforcement in Rats

Previous studies showed that sigma1 receptor (σ1R) agonists (e.g. PRE‐084, (+)‐pentazocine) were reinforcing in rats with cocaine or d‐methamphetamine self‐administration (SA) experience, but not in experimentally naïve rats. Further studies demonstrated that the induction of σ1R agonist SA 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 selective σ1R agonists, a recent study showed reinforcing effects of the non‐selective σ1/2R agonist DTG (1.0 mg/kg/inj) in naïve rats. The present study assessed the pharmacology of DTG SA, and whether experience with its SA would induce SA of a selective σ1R agonist, PRE‐084. Responding of rats trained with SA of DTG (0.1‐3.2 mg/kg/inj) under an FR 5‐response schedule of reinforcement was insensitive to antagonism by dopamine (DA) receptor antagonists (SCH 39166, L‐741626) which dose‐dependently right‐shifted cocaine (0.03‐1.0 mg/kg/inj) SA dose‐effect curves in a separate group of rats trained with SA of cocaine. Further, σR antagonists (haloperidol, BD 1063) blocked SA of DTG, but of these only haloperidol, which is also a DA antagonist, blocked cocaine SA. Pretreatments with PRE‐084 and the DAT inhibitor WIN 35,428 dose‐dependently left‐shifted dose‐effect curves for DTG and cocaine SA. The present results suggest that DA‐uptake inhibition while sufficient is not necessary for induction of reinforcement by σ1R agonists, and that once induced σR‐mediated reinforcement is independent of traditional DA receptor mechanisms.