Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: Comparison to cocaine

Robinson, J. Elliott; Agoglia, Abigail E.; Fish, Eric W.; Krouse, Michael C.; Malanga, C. J.

doi:10.1016/j.bbr.2012.06.012

Cited by 62 publications

(46 citation statements)

References 34 publications

(50 reference statements)

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“…However, for both drugs, the highest doses tested produces increases (~19% for α-PVP at 5 mg/kg, and ~28% for 4-MEC at 100 mg/kg) in ICSS thresholds, suggesting aversive effects of these high doses. Our ICSS studies confirm reports by other laboratories that synthetic cathinones activate brain reward circuitry [80,81]. …”

Section: Synthetic Cathinones Increase Brain Reward Circuit Functionsupporting

confidence: 91%

Synthetic Cathinones and Their Rewarding and Reinforcing Effects in Rodents

Watterson

2014

Advances in Neuroscience

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Synthetic cathinones, colloquially referred to as “bath salts”, are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000’s, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the “first generation” synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV ≥ methamphetamine > methylone. MDPV and methylone, as well as the “second generation” synthetic cathinones α-pyrrolidinovalerophenone (α-PVP) and 4-methylethcathinone (4-MEC), also dose-dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse.

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Section: Synthetic Cathinones Increase Brain Reward Circuit Functionsupporting

confidence: 91%

Synthetic Cathinones and Their Rewarding and Reinforcing Effects in Rodents

Watterson

2014

Advances in Neuroscience

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“…Acute administration of psychomotor stimulants such as methamphetamine, MDPV, and mephedrone via i.p. injection has been shown to lower ICSS thresholds in rodents (Bauer et al, 2013;Bonano et al, 2014;Harris et al, 2015;Robinson et al, 2012;Watterson et al, 2014). The relative potencies determined by locomotor stimulant effects in this study and our prior work (Aarde et al, 2013a, b;Huang et al, 2012;Wright et al, 2012) were effective in selecting appropriate doses to alter ICSS thresholds.…”

Section: Discussionsupporting

confidence: 57%

“…Further experiments were conducted to determine whether intracranial self-stimulation (ICSS) reward thresholds are reduced by vapor exposure to stimulants, as has been reported following intraperitoneal (i.p.) administration of MA (Bauer et al, 2013), MDPV (Bonano et al, 2014), or mephedrone (Robinson et al, 2012). Finally, the effects of i.p.…”

Section: Introductionmentioning

confidence: 99%

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

Nguyen

Aarde

Cole

et al. 2016

Neuropsychopharmacol

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Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 μg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5-1.0 mg/kg), or MDPV (0.5-1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine.

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“…As expected based on prior studies, methamphetamine, toluene and diazepam all significantly facilitated ICSS responding (Robinson et al 2012; Chan et al 2012; Bauer et al 2013; Tracy et al 2014; Chan et al 2015). Methamphetamine and toluene vapor produced comparably robust ICSS facilitation whereas the effect of diazepam on ICSS was modest relative to previous studies (Straub et al 2010; Tracy et al 2014).…”

Section: Discussionsupporting

confidence: 85%

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

2015

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Rationale There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. Objectives We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Results Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58% decrease in d-methamphetamine stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. Conclusions These results demonstrate that negative modulation of GABAA receptors can produce profound reductions in reward-related effects on a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABAA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.

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Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: Comparison to cocaine

Cited by 62 publications

References 34 publications

Synthetic Cathinones and Their Rewarding and Reinforcing Effects in Rodents

Synthetic Cathinones and Their Rewarding and Reinforcing Effects in Rodents

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

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