Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone

Abstract

Background: As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone whose affective properties (and abuse potential) are largely unknown. The following experiments begin to characterize these effects and how they may be impacted by drug history (a factor affecting reward/aversion for other drugs of abuse).

Methods: Eutylone was assessed for its ability to induce conditioned taste avoidance (CTA; aversive effect) and conditioned place preference (CPP; rewarding effect) and their relationship (Experiment 1). Following this, the effects of exposure to cocaine or 3,4-methylenedioxymethamphetamine [MDMA] on eutylone's affective properties were investigated (Experiment 2).

Results: Eutylone produced dose-dependent CTA and CPP (Experiment 1), and these endpoints were unrelated. Pre-exposure to cocaine and MDMA differentially impacted taste avoidance induced by eutylone (MDMA > cocaine) and did not impact eutylone-induced place preference.

Conclusions: These data indicate that eutylone, like other synthetic cathinones, has co-occurring, independent rewarding and aversive effects that may contribute to its abuse potential and that these effects are differentially impacted by drug history. Although these studies begin the characterization of eutylone, future studies should examine the impact of other factors on eutylone's affective properties and its eventual reinforcing effects (i.e., intravenous self-administration [IVSA]) to predict its use and abuse liability.

Keywords: MDMA; cocaine; drug history; eutylone; place preference; taste avoidance.

Figure 1

Experimental Timeline for subjects undergoing the combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure. On drug days, animals were given saccharin followed by a drug injection and placed on the drug–paired side (DPS). On saline days, animals were given water access followed by a vehicle (saline) injection and placed on the non–drug–paired side (Non–DPS). Created with BioRender.

Figure 2

(Top): Mean (±SEM) percentage change in saccharin consumption (ml) for subjects injected with vehicle (0) or eutylone at 1, 3.2, 10 or 32 mg/kg. * 10 and 32 mg/kg significantly differed from vehicle and 1 mg/kg; (Middle): Mean (±SEM) percentage saccharin consumed on the two-bottle test for subjects injected with vehicle (0) or 1, 3.2, 10 or 32 mg/kg eutylone. * 10 significantly differed from vehicle. ⁺ 32 mg/kg significantly differed from vehicle, 1, 3.2 and 10 mg/kg; (Bottom): Mean (±SEM) percentage time on the drug-paired side (DPS) on the CPP Post–Test for subjects injected with vehicle (0) or 1, 3.2, 10 or 32 mg/kg eutylone. * 3.2 and 32 mg/kg significantly differed from vehicle.

Figure 3

Scatterplots (with best line of fit), displaying the relationship between percentage of saccharin consumed on the two-bottle test and percentage of time spent on the DPS during the CPP Post–Test for subjects injected with eutylone.

Figure 4

Experimental Timeline for subjects exposed to vehicle, cocaine or MDMA every 4th day (for a total of 5 injections) prior to undergoing a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure. On conditioning days, animals were given saccharin followed by a drug injection and placed on the drug–paired side (DPS). On saline days, animals were given water access followed by a saline injection and placed on the non–drug–paired side (non–DPS). Created with BioRender.

Figure 5

Mean (±SEM) body weight (left) and water consumption (right) on pre-exposure days for animals injected with cocaine or saline (vehicle).

Figure 6

Mean (±SEM) percentage change in saccharin consumption (left) and percentage saccharin (±SEM) consumed (right) for animals pre-exposed to cocaine or vehicle and conditioned with 3.2 (top), 10 (middle) and 32 (bottom) mg/kg of eutylone during CTA acquisition (left) and on the two-bottle test (right). * Subjects injected with 3.2, 10 and 32 mg/kg (collapsed across pre-exposure conditions) significantly differed from controls.

Figure 7

Mean (±SEM) percentage of time spent on the drug-paired side (DPS) for mice pre-exposed to cocaine or vehicle and conditioned with vehicle or 3.2 (top), 10 (middle) or 32 (bottom) mg/kg of eutylone. * Subjects injected with 10 and 32 mg/kg (collapsed across pre-exposure conditions) significantly differed from vehicle.

Figure 8

Mean (±SEM) body weight (left) and water consumption (right) on pre-exposure days for animals injected with MDMA or saline (vehicle).

Figure 9

Mean (±SEM) percentage change in saccharin consumption (left) and percentage saccharin consumed (right) for animals pre-exposed to MDMA or vehicle and conditioned with vehicle or 3.2 (top), 10 (middle) or 32 (bottom) mg/kg of eutylone during CTA acquisition (left) and two-bottle test (right). * Subjects injected with 3.2 and 10 mg/kg (collapsed across pre-exposure conditions) significantly differed from vehicle. ^{^} Subjects in Group V32 significantly differed from Group V0. ⁺ Subjects in Group M32 significantly differed from Group V32.

Figure 10

Mean (±SEM) percentage of time spent on the drug-paired side (DPS) for mice pre-exposed to MDMA or vehicle and conditioned with vehicle or 3.2 (top), 10 (middle) or 32 (bottom) mg/kg of eutylone. * Subjects injected with 10 and 32 mg/kg (collapsed across pre-exposure conditions) significantly differed from vehicle.