Browsing by Author "Dolan, Sean B."

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Abuse liability of the novel benzofuran 6-APDB
(2015-03) Dolan, Sean B.; Gatch, Michael B.
Benzofurans, sold online as “benzo-fury,” represent a class of designer drugs that have gained popularity on the ever-expanding market of “legal highs.” Users report that these compounds produce entactogen-like effects similar to MDMA. The current study aims to investigate the behavioral effects and abuse liability of the novel benzofuran 6-APDB. The locomotor effects of 6-APDB were tested in male Swiss-Webster mice over an 8-hour period in an open-field assay of locomotor activity. The discriminative stimulus effects of 6-APDB were tested in separate groups of male Sprague-Dawley rats trained to discriminate cocaine, methamphetamine, or MDMA from vehicle. The rewarding effects of 6-APDB were tested in male Swiss-Webster mice using a conditioned place preference assay. 6-APDB produced locomotor stimulation at 5 and 10 mg/kg starting 30-minutes post-injection and lasting approximately 3 hours. 6-APDB fully substituted for the discriminative stimulus effects of MDMA at 1 mg/kg, but produced low levels of drug-appropriate responding for cocaine- and methamphetamine-trained rats at the same dose. 6-APDB produced conditioned place preference. Our results indicate that 6-APDB produces hyperlocomotion, conditioned place preference, and discriminative stimulus effects similar to MDMA, suggesting that 6-APDB may have potential for abuse. The substitution of 6-APDB for MDMA, but not cocaine or methamphetamine, suggests that this compound may be used as a substitute for MDMA in a club or rave setting, especially as MDMA becomes more difficult to obtain.
DOSE-RESPONSE PATTERN OF REWARD OF THREE SUBSTITUTED CATHINONES
(2014-03) Dolan, Sean B.; Gatch, Michael B.
Synthetic cathinones, sold online and in head shops as “bath salts,” have seen a tremendous increase in popularity since 2007. Consequently, the number of cathinone-related hospitalizations has increased, hitting a peak in 2011. Unfortunately, there has been very little research done regarding the behavioral effects of these drugs. The current study aimed to examine the rewarding effect of three cathinones: MDAI, flephedrone (4-FMC), and butylone. The rewarding effects were measured in a conditioned place preference test. In conditioned place preference, mice, animals regularly used as models for human behavior, are placed in one environment while under the influence of a drug, and in another while not. Before being exposed to the drug, animals are given free access to both environments, the time spent in either environment is recorded, and the environment in which less time is spent is designated the drug-paired environment. After multiple drug/nondrug environment pairings, the mice are, once again, given access to both environments and the time spent in the drug-paired environment is measured. If the time in the drug environment increases after drug exposure, the drug is said to have rewarding effects. Each of the cathinones tested produced an increase in time spent in the drug-paired environment. MDAI produced a plateau effect. Butylone produced a dose-dependent increase in time spent on the drug-paired floor. Flephedrone produced an inverted-U dose-response curve These results suggest that MDAI, flephedrone, and butylone produce rewarding effects. Given earlier findings that these compounds produced cocaine- and methamphetamine-like discriminative stimulus effects, they have a strong potential to be abused. Purpose (a): Synthetic cathinones, sold online and in head shops as “bath salts,” have seen a tremendous increase in popularity since 2007. Consequently, the number of cathinone-related hospitalizations has increased, hitting a peak in 2011. Although cathinone usage and hospitalization has decreased since the Synthetic Drug Prevention Act was passed in 2012, the drugs remain popular amongst young people and dance club frequenters. While the literature on synthetic cathinones has been steadily accumulating, behavioral data still remains sparse, especially in regards to abuse liability. The current study examined the dose-dependent rewarding effects of three substituted cathinones: MDAI (0.1, 0.3, 1, 3, 10 mg/kg), flephedrone (4-FMC, 3, 10, 30 mg/kg), and butylone (1, 3, 10 mg/kg). Methods (b): A biased conditioned place preference model of drug reward was utilized. For each drug, doses between 0.1-30 mg/kg were administered to generate a dose-response curve. Results (c): MDAI resulted in increased time on the drug-paired floor from 0.3-10 mg/kg, with 3 mg/kg yielding the largest increase. Flephedrone produced an inverted U-shaped dose-response curve with 10 mg/kg resulting in an increase in drug-paired floor time, but not 3 or 30 mg/kg. Butylone produced a dose-dependent increase in drug-paired floor time from 1 to 10 mg/kg. Conclusions (d): These results suggest that MDAI, flephedrone, and butylone produce rewarding effects. Given earlier findings that these compounds produced cocaine- and methamphetamine-like discriminative stimulus effects, they have a strong potential to be abused. Potency, efficacy, and dose-response pattern differed among the three drugs, with MDAI being the most potent, followed by butylone, then flephedrone.
“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”.
Increased side-chain length confers a greater dopaminergic phenotype and increased reinforcing efficacy to cathinone analogs of MDMA
(2016-03-23) Gatch, Michael B.; Dolan, Sean B.
In recent years, synthetic cathinone compounds have been utilized in “Ecstasy” formulations in lieu of MDMA, some of which are congeners of MDMA. The current study aimed to assess structure-activity relations of the discriminative stimulus and reinforcing effects among three synthetic cathinone analogs of MDMA: methylone, butylone, and pentylone. Rats were trained to discriminate methamphetamine from vehicle. Dose-response studies were performed with each of the test compounds and the lowest substituting dose was then tested in the presence of a range of doses of the D1-selective antagonist SCH23390. A separate group of rats was trained to self-administer methamphetamine under a FR10 schedule of reinforcement. Rats then self-administered methamphetamine, MDMA, and the test compounds under a progressive ratio schedule of reinforcement. Each of the test compounds fully substituted for the discriminative stimulus effects of methamphetamine. SCH23390 fully and dose-dependently antagonized the methamphetamine-appropriate responding produced by these compounds with methylone being the most sensitive to the effects of SCH23390, followed by butylone, then pentylone. In the self-administration studies, breakpoints increased concurrently with side-chain length. Methylone’s breakpoint was higher than saline, but the same as MDMA. The breakpoints for butylone and pentylone were both greater than saline or MDMA, but only pentylone produced responding comparable to methamphetamine. These data indicate that as side-chain length increases, the sensitivity to SCH23390 decreases and self-administration increases, suggesting that side-chain length is positively associated with dopaminergic phenotype and reinforcing efficacy. Furthermore, these synthetic cathinones may drive compulsive use of “Ecstasy” given their presence in “Ecstasy” formulations and increased reinforcing efficacy relative to MDMA.
Methylone: "Ecstasy" by another name
(2017-03-14) Gatch, Michael B.; Dolan, Sean B.
Purpose: Following increased governmental intervention regarding the sale of novel psychoactive substances, the synthetic cathinone derivative methylone has been diverted from “bath salts” into “Ecstasy” formulations in lieu of MDMA; however, it is unknown what effects substitution with methylone may have on “Ecstasy” use. In the current study, we evaluated the pharmacology of methylone in parallel with MDMA using in vitro and in vivo techniques in order to assess its potential for compulsive abuse. Methods: We assessed the activity of methylone and MDMA at SERT using whole-cell patch clamp electrophysiology. We determined the dopaminergic and serotonergic contributions to the discriminative stimulus effects of both compounds in rats trained to discriminate methamphetamine, DOM, or MDMA from vehicle and utilized the D1-selective antagonist SCH23390 and the 5-HT2A/2C antagonist pirenperone to further probe mechanistic differences. Furthermore, we tested for substitution of methylone and MDMA in rats trained to self-administer methamphetamine under continuous and progressive ratio schedules of reinforcement. Results: Methylone, like MDMA, produced an inward current at SERT, indicative of an amphetamine-like substrate mechanism. Both methylone and MDMA fully substituted for the discriminative stimulus effects of methamphetamine and MDMA, but only partially for DOM. In methamphetamine-trained rats, SCH2330 fully and dose-dependently attenuated methamphetamine-appropriate responding by methylone and MDMA with similar potencies. SCH23390 and pirenperone both partially attenuated MDMA-appropriate responding by methylone and MDMA, but both antagonists were less efficacious against methylone than MDMA. Methylone and MDMA were both readily self-administered, but there were no significant differences in reinforcing efficacy between the two drugs under either schedule of reinforcement. Conclusions: These data indicate that methylone possesses similar mechanistic and reinforcing effects as MDMA, and its inclusion in “Ecstasy” formulations is unlikely to produce different subjective effects or increased compulsive use.