Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

Abstract

DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive-like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.Triple reuptake inhibitors have been proposed as a novel type of antidepressant drugs that inhibit the reuptake of the three monoamines serotonin, noradrenaline and dopamine via inhibition of their respective transporters SERT, NAT and DAT [1,2]. DOV 216,303 is a prototype of the triple reuptake inhibitors that has shown antidepressant activity in animal models of depression [1,3,4] as well as in a clinical study in depressed patients [5]. However, drugs that block DAT may exert positive reinforcing effects that could lead to addiction [6,7]. Therefore, DOV 216,303 and other triple reuptake inhibitors could possess abuse potential that might seriously limit their use in future treatment of depression. For instance, the highly addictive drug cocaine is a triple reuptake inhibitor that is believed to exert its reinforcing effect via DAT blockade, leading to increase of mesolimbic extracellular dopamine levels [8,9].Several other DAT inhibitors have been found to be reinforcing in animal models of addiction, including GBR 12909, RTI-177, BTCP and AHN 1-005. For instance, GBR 12909 was self-administered in a manner similar to cocaine by rats [6]. RTI-177 maintained self-administration behaviour on a second-o...

Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template

“…19 Interestingly, in a recent study DOV 21,947 (amitifadine), a TRI, has been shown to produce little to no abuse liability. 26 Be that as it may, any novel monoamine transporters blocker which includes dopaminergic activity such as a TRI, should undergo extensive abuse liability testing.…”

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

“…85 While 59 showed acute self-administration in mice similar to 27, it did not induce the place preference associated with cocaine at the same dose. 83 This result, combined with a pharmacokinetic profile of slow clearance, suggested a lower potential of 59 for addiction than 27. Compound 65 was found to show low abuse potential based on a visual analogue scale (VAS) drug-liking score comparable to placebo in a clinical trial with recreational stimulant users, consistent with its pharmacokinetic profile of slow absorption and elimination [t max , 10− 12 h; t 1/2 , 44−77 h].…”

Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters

“…It is hypothesized that an optimal transporter occupancy is important for good efficacy. The concern about abuse liability of TRIs due to increased dopaminergic activity has been alleviated in recent studies demonstrating no such liability [16] , [20] .…”

“…Moreover, both DOV 21,947 and BMS-820836 indicated high level of safety and tolerability in human [18] , [19] . The concern related to dopamine activity in TRIs leading to addiction was alleviated in a recent study indicating that the racemic version of DOV 21,947 has much less addictive-like properties compared to cocaine [20] .…”