Place Conditioning and Locomotor Effects of N-Substituted, 4′,4′′-Difluorobenztropine Analogs in Rats

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Abstract
Previous studies demonstrated that analogs of benztropine [3α-(diphenyl-methoxy)tropane (BZT)] bind to the dopamine (DA) transporter with high affinity, inhibit DA uptake, but do not maintain rates of responding in self-administration procedures comparable with those maintained by cocaine. Some BZT analogs have an onset of action that is slower than that for cocaine that may contribute to this decreased effectiveness. In addition, some BZT analogs have affinity for muscarinic-M1 receptors that may interfere with reinforcing effects. The present study assessed effects of BZT analogs in place-conditioning procedures designed to accommodate variations in onset of effect. BZT analogs with variations in relative affinities for the DA transporter over M1 receptors from equal [AHN 1-055 (3α-[bis(4′-fluorophenyl)methoxy]-tropane)] to 16-fold [JHW 007 (N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane)] were compared with cocaine and the muscarinic antagonist, atropine. Cocaine (10–20 mg/kg) but not atropine (1.0–5.6 mg/kg) produced dose-related place conditioning. The N-methyl-substituted BZT analog, AHN 1-055, was without significant effects at doses that ranged from 0.3 to 3.0 mg/kg and when administered up to 90 min before conditioning trials. In contrast, effects of AHN 2-005 (N-allyl-3α-[bis(4′-fluorophenyl)methoxy]-tropane; 0.1–10.0 mg/kg) were significant, and those of JHW 007 approached significance when administered 45 min but not immediately or 90 min before trials. Atropine blocked the effect of AHN 2-005 and approached significant antagonism of cocaine. The present study further supports and extends previous results showing minimal preclinical indications of abuse liability of BZT analogs and suggests that these differences from cocaine are not entirely accounted for by a slower onset of action or muscarinic M1 receptor affinity.