Browsing by Subject "MDMA"
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Item “Ecstasy” to Addiction: Mechanistic and Reinforcing Effects of Synthetic Cathinone Analogs of MDMA(2017-05-01) Dolan, Sean B.; Gatch, Michael B.; Huang, Ren-Qi; Forster, Michael J.Following widespread scheduling, many synthetic cathinone compounds have been diverted from “bath salts” to “Ecstasy” tablets or “Molly” powder formulations in addition to or in lieu of 3,4-methylenedioxymethamphetamine (MDMA). The current study aimed to assess the mechanism and reinforcing effects of three under-researched synthetic cathinone analogs of MDMA frequently used as adulterants in “Ecstasy” formulations: methylone, butylone, and pentylone. To assess the mechanism of these compounds in vitro, we utilized whole-cell patch clamp electrophysiology on HEK293 cells expressing the serotonin transporter (SERT). The abuse-related, in vivo mechanisms were determined using a drug discrimination assay with rats trained to discriminate methamphetamine, the hallucinogenic phenethylamine 2,5-dimethoxy-4-methylamphetamine (DOM), or MDMA from vehicle, and drugs that substituted were tested with the D1-like receptor antagonist SCH23390 to assess relative differences in dopaminergic signaling. The reinforcing effects were assessed in an intravenous self-administration assay using continuous and progressive ratio schedules of reinforcement. Methylone and butylone, like MDMA, produced inward currents at SERT, indicative of a substrate-like mechanism. Each test compound fully substituted for the discriminative stimulus effects of methamphetamine. MDMA, methylone, and butylone substituted partially for DOM, and methylone and butylone substituted fully for MDMA. Pentylone, conversely, substituted partially for MDMA, but failed to substitute for DOM. SCH23390 fully and dose-dependently attenuated methamphetamine-appropriate responding, with pentylone being least sensitive to these antagonistic effects, but failed to attenuate MDMA-like responding against MDMA, methylone, and butylone. Each test compound maintained robust self-administration under a continuous schedule of reinforcement, but pentylone was the most reinforcing test compound under a progressive ratio. These data indicate that methylone and butylone produce complex discriminative stimulus effects, similar to MDMA, that are mediated by both dopamine and serotonin, whereas pentylone is predominately dopaminergic. The underlying differences in relative dopaminergic and serotonergic mechanisms likely influence the relative abuse liability, with pentylone’s predominately dopaminergic mechanism conferring a greater reinforcing efficacy relative to the more serotonergic methylone and butylone. In conclusion, incorporation of these compounds into “Ecstasy” formulations, especially pentylone, may lead to compulsive, uncontrolled use of “Ecstasy”.Item Locomotor and discriminative stimulus effects of three benzofuran compounds in comparison to abused psychostimulants(Elsevier B.V., 2023-08-21) Hill, Rebecca D.; Shetty, Ritu A.; Sumien, Nathalie; Forster, Michael J.; Gatch, Michael B.AIMS: Benzofurans are used recreationally, due their ability to cause psychostimulant and/or entactogenic effects, but unfortunately produce substantial adverse effects, including death. Three benzofurans 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-MAPB) and 6-(2-aminopropyl) benzofuran (6-APB) were tested to determine their behavioral effects in comparison with 2,3-methylenedioxymethamphetamine (MDMA), cocaine, and methamphetamine. METHODS: Locomotor activity was tested in groups of 8 male Swiss-Webster mice in an open-field task to screen for locomotor stimulant or depressant effects and to identify behaviorally active doses and times of peak effect. Discriminative stimulus effects were tested in groups of 6 male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg), cocaine (10 mg/kg), or methamphetamine (1 mg/kg) from saline using a FR 10 for food in a two-lever operant task. RESULTS: In the locomotor activity test, MDMA (ED(50) = 8.34 mg/kg) produced peak stimulant effects 60 to 80 min following injection. 5-MAPB (ED(50) = 0.92 mg/kg) produced modest stimulant effects 50 to 80 min after injection, whereas 6-APB (ED(50) = 1.96 mg/kg) produced a robust stimulant effect 20 to 50 min after injection. 5-APDB produced an early depressant phase (ED(50) = 3.38 mg/kg) followed by a modest stimulant phase (ED(50) = 2.57 mg/kg) 20 to 50 min after injection. In the drug discrimination tests, 5-APDB (ED(50) = 1.02 mg/kg), 5-MAPB (ED(50) = 1.00 mg/kg) and 6-APB (ED(50) = 0.32 mg/kg) fully substituted in MDMA-trained rats, whereas only 5-MAPB fully substituted for cocaine, and no compounds fully substituted for methamphetamine. CONCLUSIONS: The synthetic benzofuran compound 5-APDB and 5-MAPB produced weak locomotor effects, whereas 6-APB produced robust locomotor stimulant effects. All compounds were more potent than MDMA. All three compounds fully substituted in MDMA-trained rats suggesting similar subjective effects. Taken together, these results suggest that these benzofuran compounds may have abuse liability as substitutes for MDMA.