Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

The identification of sigma receptor (sigma R) subtypes has been based on radioligand binding and, despite progress with sigma R-1 cellular function, less is known about sigma R subtype functions in vivo. Recent findings that cocaine self administration experience will trigger sigma R agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative sigma R antagonists. Radioligand binding studies determined in vitro sigma R 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 1Rs 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 sigma 2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of sigma R agonist substitution for cocaine self administration as an assay capable of distinguishing sigma R subtype selectivity in vivo. These results further suggest that effectiveness of dual sigma R antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for sigma 1Rs and further support this dual targeting approach to development of cocaine antagonists.