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, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently 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 µg/kg/infusion) and
ketamine (0.032-1.0 mg/kg/infusion)
self-administration. Further, standard
dopamine indirect-agonists [WIN35,428 ((-)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate),
d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted
self-administration dose-effect curves for d-
methamphetamine,
heroin, and
ketamine. Noncompetitive
NMDA-
glutamate receptor/channel antagonists [(+)-
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 µ-agonists [dl-
methadone and
morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal
self-administration of µ-agonists (
heroin,
remifentanil) but not d-
methamphetamine or
ketamine self-administration. The µ-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 σ 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 µ-agonists on µ-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.