Can the Stereotypy‐Inducing Effects of Atypical Dopamine Uptake Inhibitors Account for Their Blockade of Cocaine Self Administration?

Abstract

Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the stereotypy‐induction produced by Coc. The BZT analogs, however, were inactive alone and did not significantly change the effects of Coc. Thus it appears that the induction of stereotypy does not account for the decreases in Coc SA produced by BZT analogs. The present study further supports the development of N‐substituted BZT analogs as medications to treat Coc abuse. Supported by NIDA IRP.