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N. E. PATERSON, D. BRUNNER, T. HANANIA, J. ZHOU, A. KOZIKOWSKI, B. OLIVIER, B. CALDARONE, A. GHAVAMI

Triple reuptake inhibitors exhibit antidepressant properties, yet inhibition of all three monoamine transporters [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)], similar to cocaine, raises the possibility that these compounds are liable for abuse. DOV 216,303 and JZAD-IV-22 are highly potent triple reuptake inhibitors. In the present experiments, the discriminative stimulus, locomotor stimulant and neurochemical effects of DOV 216,303 and JZAD-IV-22 were evaluated in rodents. The selective DA reuptake inhibitor, GBR12909, produced dose-dependent increases in cocaine-appropriate responding and fully substituted for cocaine, while the preferential NE reuptake inhibitor desipramine exhibited partial substitution for cocaine, unlike the selective 5-HT reuptake inhibitor citalopram that failed to substitute. The mixed DA/NE reuptake inhibitor bupropion fully substituted for cocaine. DOV 216,303 and JZAD-IV-22 partially substituted for cocaine at doses that substantially decreased response rates. Interestingly, despite comparable efficacy in a preclinical test for antidepressants (forced swim), and comparable IC50 values for inhibition of all three monoamine transporters, JZAD-IV-22 (DAT/SERT/NET: 110nM/16nM/150nM) exhibited substantially less substitution for cocaine compared to DOV216,303 (DAT/SERT/NET: 81nM/27nM/49nM). Repeated cocaine or d-amphetamine resulted in locomotor sensitization. Repeated DOV216,303, but not JZAD-IV-22, resulted in locomotor sensitization. Finally, administration of DOV216,303 and JZAD-IV-22 at doses that were similarly effective in the forced swim test, but had distinct discriminative stimulus and locomotor sensitization properties, resulted in similar and significant increases in dopamine, norepinephrine and serotonin overflow in the prefrontal cortex. These results suggest that the abuse liability profiles of different triple reuptake inhibitors might vary substantially. Ongoing studies seek to identify differences in the target occupancies of DOV216,303 and JZAD-IV-22 as an explanation for their different abuse liability profiles.