Preclinical efficacy of n-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats

Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, Nbutyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3a-[bis(49-fluorophenyl)methoxy]-tropane dosedependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 mg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((2)-3b-(4-fluorophenyl)-tropan-2-b-carboxylic acid methyl ester tartrate), damphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently leftshifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDAglutamate receptor/channel antagonists [(1)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The m-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of m-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine selfadministration. The m-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and s receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of m-agonists on m-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.