Relationship between apparent in vivo occupancy at the dopamine transporter and cocaine‐like discriminative stimulus effects of N‐substituted benztropine analogs in mice (803.4)

Abstract

Standard inhibitors of the dopamine transporter (DAT) have cocaine‐like subjective effects; however, several atypical DAT inhibitors that bind the DAT with high affinity, such as benztropine (BZT) analogs, do not fully substitute for cocaine in animals trained to discriminate cocaine injections.The lack of cocaine‐like effects may be related to a slow rate of association to the DAT. Several N‐substituted BZT analogs (R‐2‐amino‐3‐methyl‐n‐butyl; 2‐aminoethyl; 2‐ethyl‐3‐indole; and methylcyclopropyl) were reported to have a relatively fast onset of behavioral effects, but it is unclear if these effects were related to DAT activity. Therefore, the present study examined the in vivo binding to DAT of the above BZT analogs and their cocaine‐like discriminative stimulus effects in mice. None of the BZT analogs fully substituted for cocaine discriminative effects despite the testing of doses that produced in vivo DAT occupancy greater than the ~13% occupancy produced by 10 mg/kg training dose of cocaine. The BZT analogs produced displacement of [I125]RTI‐121 from striatum at maximal rates from 0.86 to 1.28 %/min compared to 1.23%/min for cocaine, indicating a relatively fast apparent rate of DAT association. The results of the present study suggest that DAT occupancy, or rate of association, alone cannot account for the lack of cocaine‐like discriminative effects found with these N‐substituted BZT analogs.Grant Funding Source: NIH Intramural Research Program