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 the sigma1 receptor agonists were reinforcing in rats with a history of stimulant self-administration, but not in experimentally naive rats. Further studies demonstrated that the induction of sigma1 receptor agonist self administration specifically occurred with self administration of drugs acting at the dopamine transporter (DAT), but not with other abused drugs (e.g. heroin, ketamine). In contrast to effects with sigma1 receptor agonists, a recent report showed self administration of the non-selective sigma agonist DTG in naive rats. The identification of sigma receptor subtypes has been based on radioligand binding and, despite progress with sigma1 receptor cellular function, less is known about sigma receptor subtype functions in vivo. Recent findings that stimulant self-administration experience will trigger sigma receptor agonist self-administration were used in the present study to assess the in vivo receptor subtype specificity of the agonists, (+)-pentazocine, PRE-084 and DTG, and several novel putative sigma receptor antagonists. Radioligand binding studies determined in vitro sigma receptor selectivity of the novel compounds which were subsequently studied for self-administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self-administration. Across the dose ranges studied, none of the novel compounds were self-administered, nor did they alter cocaine self-administration. All compounds blocked DTG self-administration, with a subset also blocking (+)-pentazocine and PRE-084 self-administration. The most selective of the compounds in binding sigma receptors blocked cocaine self-administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast the most selective of the compounds in binding sigma2 receptors had no effect on cocaine self-administration in combination with either dopamine transport inhibitor. Thus the present results identify subtype-specific in vivo antagonists, and the utility of sigma receptor-agonist substitution for cocaine self-administration as an assay capable of distinguishing sigma receptor subtype selectivity in vivo. The present results further suggest that effectiveness of dual sigma receptor antagonism and dopamine transport inhibition in blocking cocaine self-administration is specific for sigma1 receptors and further support this dual targeting approach to development of cocaine antagonists.
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