Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.

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Recently, use of the synthetic cathinone (aka "bath salt") eutylone has risen in the United States and globally. Due to its novelty in drug markets, its affective properties remain largely uninvestigated. In this context, drugs of abuse have both rewarding and aversive effects and understanding these effects, their relative balance, and factors that impact each are important to understanding the likelihood of drug use and abuse. This investigation attempted to characterize eutylone's rewarding and aversive effects in a combined conditioned taste avoidance/place preference assay. Female Sprague-Dawley rats were given 20-min access to saccharin, injected with one of five doses of eutylone (0, 3, 10, 18, 32 mg/kg; intraperitoneally; IP), and placed on one side of a place conditioning apparatus. On the following day, subjects were given 20-min access to water, injected IP with vehicle, and placed on the other side of the apparatus. After five conditioning cycles, place preference and saccharin avoidance were assessed. Eutylone induced significant taste avoidance but did not significantly increase time spent on the drug-paired side (relative to controls). Excluding animals with high initial side preference, however, eutylone induced a preference at all doses with the high dose group displaying higher preference than controls. There was no significant correlation between eutylone's aversive and rewarding effects. These data indicate that eutylone (like other synthetic cathinones) induces both rewarding and aversive effects and highlight the need to assess the impact of various factors on its affective properties (and their balance) and on their use and abuse. Public Health SignificanceThis study is the first to demonstrate taste avoidance and place preference induced by the novel synthetic cathinone eutylone. Given that a drug's aversive and rewarding effects are thought in balance to mediate its use and abuse, the present study indicates the potential abuse of eutylone and the importance in assessing various factors that could affect this liability.

The use of both prescription and illicit drugs creates the potential for drug interactions as a function of both pharmacokinetic and pharmacodynamic processes. One such interaction is that of fluoxetine and methylenedioxymethamphetamine (MDMA) in which fluoxetine attenuates the positive-like effects of MDMA. The present work extends the analysis of their interaction by examining the impact of fluoxetine on the aversive effects of MDMA which in balance with its rewarding effects may mediate its abuse potential. Male and female Sprague–Dawley rats were given fluoxetine (10 mg/kg every 4th day for five injections) prior to taste avoidance training with MDMA (3.2 mg/kg). MDMA induced taste avoidance in males and females (faster acquisition in females). Fluoxetine preexposure attenuated this avoidance in males, but not females. For males, the attenuation was partial as MDMA-conditioned animals with fluoxetine preexposure still displayed a significant reduction in fluid intake compared to controls. Consistent with prior work assessing the interaction of fluoxetine and MDMA, fluoxetine preexposure impacted the ability of MDMA to support taste avoidance learning, specifically attenuating the aversive effect of the drug. Prior work has shown that fluoxetine attenuates MDMA’s positive effects which might lead to reduced intake of the drug; however, the concurrent reduction in the drug’s aversive effects may still shift the overall affective balance of these two affective properties toward continued use and abuse. The fact that the attenuation was only evident in males needs further study to investigate the sex-dependent effects of drug history.