ahn-1055 and vanoxerine

The present studies compared the acute effects of benztropine analogs (4-Cl-BZT, JHW 007, AHN 1-055), which are atypical dopamine uptake inhibitors, with those of the standard dopamine uptake inhibitors GBR 12909 and cocaine, on the reinforcing efficacy of food and food intake in male Sprague-Dawley rats. Repeated drug effects of JHW 007 on food intake were also determined. The number of ratios completed under a progressive-ratio schedule of food delivery was used as an index of reinforcing efficacy. Food intake was determined by measuring powdered laboratory-chow consumption during daily 40 min food-availability time periods. Under the progressive-ratio schedule, cocaine and GBR 12909 dose-dependently increased the number of ratios completed. JHW 007 decreased ratios completed, whereas neither 4-Cl-BZT nor AHN 1-055 increased ratios completed with a magnitude that approximated any of the increases produced by cocaine or GBR 12909. Acute administration of each drug dose-dependently decreased food intake; however, the benztropine analogs were more potent than cocaine and GBR 12909. A reduction in food intake emerged after repeated administration of a low dose of JHW 007. Future studies that compare JHW 007 with standard anorectic drugs (e.g. phentermine) and continue investigation of the repeated drug effects under similar experimental procedures are clearly warranted.

Topics: Animals; Behavior, Animal; Benztropine; Cocaine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Male; Piperazines; Rats; Rats, Sprague-Dawley; Reinforcement Schedule

Analogs of benztropine (BZT) bind to the dopamine (DA) transporter and inhibit DA uptake but often have behavioral effects that differ from those of cocaine and other DA-uptake inhibitors. To better understand these differences, we examined the relationship between locomotor-stimulant effects of cocaine, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)-piperazine (GBR 12909), and BZT analogs [(3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (AHN 1-055) and (N-allyl-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (AHN 2-005)] and their in vivo displacement of the DA transporter ligand [125I]3beta-(4-iodophenyl)-tropan-2beta-carboxylic acid isopropyl ester hydrochloride (RTI-121) in striatum. Cocaine, GBR 12909, and BZT analogs each displaced [125I]RTI-121 and stimulated locomotor activity in a dose- and time-dependent manner. The time course revealed a slower onset of both effects for AHN 1-055 and AHN 2-005 compared with cocaine and GBR 12909. The BZT analogs were less effective than cocaine and GBR 12909 in stimulating locomotor activity. Locomotor stimulant effects of cocaine were generally greater than predicted by the regression of displacement of [125I]RTI-121 and effect at short times after injection and less than predicted at longer times after injection. This result suggests that the apparent rate of occupancy of the DA transporter, in addition to percentage of sites occupied, contributes to the behavioral effects of cocaine. The present results suggest that among drugs that act at the DA transporter, the slower apparent rates of occupancy with the DA transporter by the BZT analogs may contribute in an important way to differences in their effectiveness.

Topics: Animals; Benztropine; Cocaine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Piperazines