Sean B. Dolan

Comparative behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives

Synthetic cathinones, often sold as “bath salts,” are a popular class of recreational drugs used as quasi-legal alternatives to cocaine, methamphetamine, and methylenedioxymethamphetamine. The increased prevalence and health consequences of synthetic cathinone use has prompted regulatory agencies to control a number of these compounds; however, a broad class of analogous compounds known as the second-generation cathinones has been brought to the market to take the place of the banned synthetic cathinone derivatives. The current study aims to characterize the behavioral pharmacology of three pyrrolidinylated second-generation cathinones: 4-methyl-α-pyrrolidinopropiophenone (4ʹ-MePPP), α-pyrrolidinopropiobutiophenone (α-PBP), and α-pyrrolidinopentiophenone (α-PVP). Locomotor activity was tested in mice over an 8-hour period. The discriminative stimulus effects of these compounds were tested in rats trained to discriminate either cocaine or methamphetamine. The rewarding effects of these drugs were assessed in mice using conditioned place preference. Both α-PBP and α-PVP produced long-lasting increases in locomotor activity across a wide range of doses, whereas 4ʹ-MePPP produced locomotor stimulation only at 30 mg/kg. Both α-PBP and α-PVP fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine, whereas 4ʹ-MePPP substituted fully for the discriminative stimulus effects of methamphetamine only. Both α-PBP and α-PVP produced conditioned place preference in an inverted U-shaped dose effect, whereas 4ʹ-MePPP did not produce conditioned place preference. These findings suggest that α-PBP and α-PVP are likely to be recreationally used and have potential for addiction and abuse, but 4ʹ-MePPP may not.

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (−)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50–70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (−)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

Abuse liability of the dietary supplement dimethylamylamine.

BACKGROUND Dimethylamylamine (DMAA) is a component of many dietary supplements and has recently been associated with numerous adverse effects, prompting the US military and World Anti-Doping Agency to ban its use as a supplement. The current study aimed to elucidate the abuse liability profile of DMAA. METHODS Dose-response studies of DMAA were performed with Swiss-Webster mice in locomotor and conditioned place-preference assays. The discriminative stimulus effects of DMAA were investigated in Sprague-Dawley rats trained to discriminate either cocaine or methamphetamine from saline. RESULTS DMAA produced dose-dependent locomotor depression and fully substituted for cocaine and partially substituted for methamphetamine. In the conditioned place-preference assay, DMAA produced an inverted-U-shaped dose-response curve, with intermediate doses producing significant place preference. CONCLUSIONS The cocaine- and methamphetamine-like discriminative stimulus effects and the conditioned place preference produced by DMAA suggest that is has potential for abuse. These findings in combination with reports of substantial adverse effects of DMAA in humans suggest that control of DMAA may warrant further consideration.

“Ecstasy” to addiction: Mechanisms and reinforcing effects of three synthetic cathinone analogs of MDMA

ABSTRACT This study aimed to address the mechanisms and reinforcing effects of three synthetic cathinone analogs of MDMA commonly reported in “Ecstasy” formulations: methylone, butylone, and pentylone. Whole‐cell patch clamp techniques were used to assess the mechanism of each compound at the dopamine and serotonin transporters. Separate groups of rats were trained to discriminate methamphetamine, DOM, or MDMA from vehicle. Substitution studies were performed in each group and antagonism studies with SCH23390 were performed against each compound that produced substitution. Self‐administration of each compound was evaluated under a progressive ratio schedule of reinforcement. Each compound produced an inward current at the serotonin transporter, but little or no current at the dopamine transporter. Each of the test compounds substituted fully for the discriminative stimulus effects of methamphetamine, methylone and butylone substituted partially for DOM and fully for MDMA, whereas pentylone failed to substitute for DOM and substituted only partially for MDMA. SCH23390 fully and dose‐dependently attenuated methamphetamine‐appropriate responding produced by each test compound, but was least potent against pentylone. MDMA‐appropriate responding was minimally affected by SCH23390. Each test compound was robustly self‐administered with pentylone producing the greatest self‐administration at the doses tested. Given the prevalence of synthetic cathinones in “Ecstasy” formulations, these data indicate that adulterated “Ecstasy” formulations may drive more compulsive drug use than those containing only MDMA. HighlightsMDMA, methylone, butylone, and pentylone are serotonin transporter substrates.Each drug produces methamphetamine‐like discriminative stimulus effects.Methylone and butylone produce largely serotonergic discriminative stimulus effects.Pentylone produces predominately dopaminergic discriminative stimulus effects.Pentylone is self‐administered to greater degree than butylone or MDMA.

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents

There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (−)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74–78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

Impure but not inactive: Behavioral pharmacology of dibenzylpiperazine, a common by-product of benzylpiperazine synthesis

Background: Substituted piperazines comprise a substantial proportion of the novel psychoactive substance market. Among the most widely abused piperazine compounds are meta-chlorophenylpiperazine (mCPP), tri-fluoromethylphenylpiperazine (TFMPP), and, especially, benzylpiperazine (BZP), which are commonly incorporated, either alone or in combination, in illicit “party pills” or “ecstasy” formulations. Illicit synthesis of BZP often results in production of an impure by-product dibenzylpiperazine (DBZP), which frequently appears alongside BZP in these formulations; however, despite its ubiquity, little information exists regarding the abuse liability of DBZP. Aims: The current study aimed to evaluate the abuse-related behavioral pharmacology of DBZP. Methods: DBZP, mCPP, and TFMPP were tested in parallel in mice in locomotor activity and conditioned place preference assays, and in a drug discrimination assay with rats trained to discriminate either methamphetamine, cocaine, (±)-3,4-methylenedioxymethamphetamine (MDMA), or -2,5-dimethoxy-4-methylamphetamine(DOM). Results: Each of the compounds tested produced dose-dependent decreases in locomotor activity. DBZP substituted fully for methamphetamine, produced subthreshold drug-appropriate responding for cocaine and MDMA, and failed to substitute for DOM. Conversely, TFMPP and mCPP only produced subthreshold drug-appropriate responding for methamphetamine and MDMA, respectively, and both compounds failed to substitute for cocaine or DOM. None of the compounds tested produced a place preference. DBZP produced convulsions in rats at the highest dose tested. Conclusions: These data indicate that DBZP is more similar to BZP, albeit with lower potency and efficacy, than its serotonergic piperazine counterparts, and is a behaviorally-active compound with some abuse liability and potential for adverse health effects.