The recreational use of designer drugs, including synthetic cathinones (bath salts), is associated with high levels of abuse and toxicity, and represents a growing threat to public health. 3,4-Methylenedioxypyrovalerone (MDPV) is a cocaine-like monoamine uptake inhibitor, and one of the most widely available and abused synthetic cathinones. The present study used male Sprague-Dawley rats to directly compare: (1) the acquisition of responding for MDPV and cocaine under a fixed ratio (FR) 1 schedule of reinforcement; (2) full dose-response curves for MDPV and cocaine under a FR5 schedule; and (3) progressive ratio (PR) schedules of reinforcement. Self-administration of MDPV and cocaine was acquired at comparable rates, and by a similar percentage of rats. Compared with cocaine, MDPV was ∼10-fold more potent and ∼3-fold more effective at maintaining responding (PR; final ratio completed). Unlike cocaine, for which little variability was observed among rats, the FR5 dose-response curve for MDPV was shifted ∼3-fold upward for a subset of rats (high-responders) relative to other rats with identical histories (low-responders). Compared with low-responding rats, high responders also self-administered more cocaine under the FR5 schedule, and earned significantly more MDPV, cocaine, and methamphetamine under a PR schedule of reinforcement. In addition to functioning as a significantly more effective reinforcer than either cocaine or methamphetamine, MDPV also appears to be unique in its capacity to establish an enduring phenotype in rats, characterized by unusually high levels of drug intake. Although the factors underlying this high-responder phenotype are unclear, they might be related to individual differences in human drug-taking behavior.

Bath salts use is associated with high rates of abuse, toxicity, and death. Bath salt preparations often contain mixtures of drugs including multiple synthetic cathinones (eg, 3,4-methylenedioxypyrovalerone (MDPV) or 3,4-methylenedioxymethcathinone (methylone)) or synthetic cathinones and caffeine; however, little is known about whether interactions among bath salt constituents contribute to the abuse-related effects of bath salts preparations. This study used male Sprague-Dawley rats responding under a progressive ratio schedule to quantify the reinforcing effectiveness of MDPV, methylone, and caffeine, administered alone and as binary mixtures (n=12 per mixture). Each mixture was evaluated at four ratios (10 : 1, 3 : 1, 1 : 1, and 1 : 3) relative to the mean ED for each drug alone. Dose-addition analyses were used to determine the predicted, additive effect for each dose pair within each drug mixture. MDPV, methylone, and caffeine maintained responding in a dose-dependent manner, with MDPV being the most potent and effective, and caffeine being the least potent and effective of the three bath salts constituents. High levels of responding were also maintained by each of the bath salts mixtures. Although the nature of the interactions tended toward additivity for most bath salts mixtures, supra-additive (3 : 1 MDPV : caffeine, and 3 : 1 and 1 : 1 methylone : caffeine) and sub-additive (3 : 1, 1 : 1, and 1 : 3 MDPV : methylone) interactions were also observed. Together, these findings demonstrate that the composition of bath salts preparations can have an impact on both their reinforcing potency and effectiveness, and suggest that such interactions among constituent drugs could contribute to the patterns of use and effects reported by human bath salts users.

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine.

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Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to the behavioral effects of dopaminergic drugs. Specifically, drugs that act on dopamine systems (e.g., quinpirole and cocaine) produce unconditioned behavioral effects (e.g., yawning and locomotion) that are enhanced among rats eating high fat chow. Daily dietary supplementation with fish oil prevents this high fat diet‐induced effect; however, doctors recommend that patients take fish oil only 2–3 times a week for beneficial health effects. To test the hypothesis that intermittent (e.g., 2/7 days per week) dietary supplementation with fish oil prevents high fat diet‐induced effects (e.g., enhanced sensitivity to the behavioral effects of dopaminergic drugs) rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), or standard or high fat chow with 20% (w/w) intermittent (e.g., 2/7 days per week) dietary fish oil supplementation were tested once weekly with quinpirole (0.0032–0.32 mg/kg, i.p.) or cocaine (1–17.8 mg/kg, i.p.) using cumulative dosing procedures. Sensitivity to the behavioral effects of quinpirole was enhanced among rats eating high fat chow as compared to rats eating standard chow, and rats eating high fat chow with intermittent dietary fish oil supplementation were protected against this enhanced sensitivity. Intermittent access to fish oil significantly decreased cocaine‐induced locomotion in some groups, without impacting general locomotor activity (e.g., motor activity following saline injections). Future experiments will focus on understanding the mechanism(s) by which fish oil produces beneficial effects, by examining the specific omega‐3 polyunsaturated fatty acids found in fish oil.Support or Funding InformationNina Beltran is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under the linked award number R25GM069621.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0–17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.

Eating a high fat diet has several negative health consequences, including dysfunction to dopamine systems. It has also been shown to enhance the sensitivity of male rats to methamphetamine‐induced locomotor sensitization. However, it is not known if sensitivity to the other (i.e., rewarding) effects of methamphetamine are similarly enhanced in rats eating a high fat diet. To test the hypothesis that eating high fat chow enhances sensitivity of rats to the rewarding effects of methamphetamine, male Sprague Dawley rats were fed standard (17% kcal from fat) or high fat chow (60% kcal from fat) for 4 weeks prior to conditioned place preference (CPP) training, using a biased design. Before training, rats were given free access to both sides of the chamber to determine a side preference. Rats were then trained on alternating days with saline or methamphetamine (0.1, 0.32 and 1.0 mg/kg, i.p.) with drug conditioned in the initially non‐preferred side. A 2 × 4 between‐subjects ANOVA revealed a significant main effect of methamphetamine dose, but no main effect of diet, and no significant diet × dose interaction effect. Tukey HSD post‐hoc analyses revealed that male rats conditioned with 0.32 mg/kg and 1.0 mg/kg methamphetamine displayed significantly larger preference scores than male rats conditioned with saline, regardless of diet. That is, at the two largest doses, methamphetamine induced a significant CPP. Preference scores for rats conditioned with the smallest dose of methamphetamine (0.1 mg/kg) did not significantly differ from the saline conditioned group nor the two larger doses of methamphetamine. Though no effect of diet was found, in contrast to what might have been predicted based on previous studies with methamphetamine‐induced locomotion, future studies should explore a wider range of doses, as well as other assays (e.g., intravenous self‐administration). Future studies will also examine female rats to investigate potential sex differences.