Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone.
Alyssa F DeLarge, Laura L Erwin, Peter J Winsauer
Neuropharmacology June 2017 DOI: 10.1016/j.neuropharm.2017.04.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Drug discrimination study in rats Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Mephedrone Cocaine d-Amphetamine Ketamine Heroin R-DOI Δ9-THC MDA Methylphenidate MDPV Rimcazole Desipramine Fluoxetine |
| Dose | Mephedrone 3.2 mg/kg (training dose); mephedrone 0.32-10 mg/kg; cocaine 0.56-32 mg/kg; d-amphetamine 0.18-3.2 mg/kg; ketamine 1.8-18 mg/kg; PCP 1-5.6 mg/kg; heroin 1-10 mg/kg; R-DOI 0.1-1 mg/kg; Δ9-THC 0.56-5.6 mg/kg; MDA 0.32-5.6 mg/kg; methylphenidate 1-10 mg/kg; MDPV 0.56-5.6 mg/kg; rimcazole 0.32-10 mg/kg; desipramine 1.8-18 mg/kg; fluoxetine 1-18 mg/kg |
| Topics | Serotonin |
| Keywords | Bath salts Cathinone Desipramine Drug discrimination Fluoxetine Mephedrone Rimcazole |
| Key points | Only cocaine fully substituted for mephedrone's discriminative stimulus effects without substantially decreasing response rate; other tested drugs did not. Rimcazole, desipramine, and fluoxetine shifted mephedrone's dose-effect curves leftward for drug-lever responding and downward for response rate. The authors conclude mephedrone's effects most resemble cocaine's and require serotonin and dopamine transporter activity. |
Abstract
Mephedrone (4-methylmethcathinone), a constituent of the recreational substances known as "bath salts", is a synthetic cathinone that can produce auditory and visual hallucinations, as well as problematic cardiovascular effects. This study compared the discriminative stimulus effects of mephedrone (0.32-10 mg/kg) with other prototypical drugs of abuse: cocaine (0.56-32 mg/kg), d-amphetamine (0.18-3.2 mg/kg), ketamine (1.8-18 mg/kg), phencyclidine (PCP, 1-5.6 mg/kg), heroin (1-10 mg/kg), 2,5-dimethoxy-4-iodoamphetamine (R-DOI, 0.1-1 mg/kg), Δ9-tetrahydrocannabinol (Δ9-THC 0.56-5.6 mg/kg), 3,4-methylenedioxyamphetamine (MDA, 0.32-5.6 mg/kg), methylphenidate (1-10 mg/kg), and 3,4-methylenedioxypyrovalerone (MDPV, 0.56-5.6 mg/kg). The discriminative stimulus effects of mephedrone were also assessed after administration of the sigma receptor antagonist rimcazole (0.32-10 mg/kg), the relatively selective norepinephrine transporter (NET) inhibitor desipramine (1.8-18 mg/kg), and the selective serotonin transporter (SERT) inhibitor fluoxetine (1-18 mg/kg). Initially, rats were trained to discriminate an intraperitoneal injection of mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 schedule of food presentation. Following training, cumulative doses of mephedrone and the other drugs were administered to test for substitution (80% drug-lever responding). Of the drugs tested, including those that were tested in combination with mephedrone (i.e., rimcazole, desipramine, and fluoxetine), only cocaine fully substituted for mephedrone without substantially decreasing response rate. In addition, the three drugs administered in combination with mephedrone shifted the cumulative dose-effect curves leftward (percent drug-lever responding) and down (response rate), although fluoxetine did so in a dose-dependent manner ranging from antagonism to potentiation. In summary, the discriminative stimulus effects of mephedrone were most similar to those for the central nervous system (CNS) stimulant, cocaine, and SERT and DAT activity were necessary for these effects.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 4
- Methylenedioxymethamphetamine-like discriminative stimulus effects of seven cathinones in rats Behavioural Pharmacology June 1, 2020
- Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats Journal of Psychopharmacology July 1, 2020
- Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans. Neuropharmacology November 2018
- Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4-methylmethcathinone. Psychopharmacology November 2017
Cites 16
- Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions Journal of Neurochemistry 1996
- Intravenous self-administration of mephedrone, methylone and MDMA in female rats Neuropharmacology January 17, 2015
- Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats Drug and Alcohol Dependence June 3, 2012
- Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats British Journal of Pharmacology May 26, 2011
- Mephedrone and 3,4-methylenedioxy-methamphetamine: Comparative psychobiological effects as reported by recreational polydrug users. Journal of Psychopharmacology December 2016
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