σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration

Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects and can block numerous effects of cocaine, including its self-administration. Among these compounds, N-methyl (AHN1055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3 alpha-[bis(4'-fluorophenyl) methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding. The antagonism of cocaine self-administration (0.03-1.0 mg/kg per injection) with the above BZT analogs was reproduced in the present study. Further, the stimulant-antagonist effects resembled previously reported effects of pretreatments with combinations of standard DAT inhibitors and sigma(1)-receptor (sigma R-1) antagonists. Therefore, the present study examined binding of the BZT analogs to sigma Rs, as well as their in vivo sigma R antagonist effects. Each of the BZT analogs displaced radiolabeled sR ligands with nanomolar affinity. Further, self-administration of the sR agonist DTG (0.1-3.2 mg/kg/injection) was dose dependently blocked by AHN2-005 and JHW007 but potentiated by AHN1-055. In contrast, none of the BZT analogs that were active against DTG self-administration was active against the self-administration of agonists at dopamine D-1-like [R(+)-SKF 81297, (+/-)-SKF 82958 (0.00032-0.01 mg/kg per injection each)], D-2-like [R(-)-NPA (0.0001-0.0032 mg/kg per injection), (-)-quinpirole (0.0032-0.1mg/kg per injection)], or mu-opioid (remifentanil, 0.0001-0.0032 mg/kg per injection) receptors. The present results indicate that behavioral antagonist effects of the N-substituted BZT analogs are specific for abused drugs acting at the DAT and further suggest that sR antagonism contributes to those actions.