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Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone.
Neuropharmacology. 2017 06; 119:62-75.N

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.

Authors+Show Affiliations

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, USA. Electronic address: afour1@lsuhsc.edu.Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, USA.Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, USA; Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28396142

Citation

DeLarge, Alyssa F., et al. "Atypical Binding at Dopamine and Serotonin Transporters Contribute to the Discriminative Stimulus Effects of Mephedrone." Neuropharmacology, vol. 119, 2017, pp. 62-75.
DeLarge AF, Erwin LL, Winsauer PJ. Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone. Neuropharmacology. 2017;119:62-75.
DeLarge, A. F., Erwin, L. L., & Winsauer, P. J. (2017). Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone. Neuropharmacology, 119, 62-75. https://doi.org/10.1016/j.neuropharm.2017.04.006
DeLarge AF, Erwin LL, Winsauer PJ. Atypical Binding at Dopamine and Serotonin Transporters Contribute to the Discriminative Stimulus Effects of Mephedrone. Neuropharmacology. 2017;119:62-75. PubMed PMID: 28396142.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone. AU - DeLarge,Alyssa F, AU - Erwin,Laura L, AU - Winsauer,Peter J, Y1 - 2017/04/07/ PY - 2017/01/26/received PY - 2017/03/31/revised PY - 2017/04/05/accepted PY - 2017/4/12/pubmed PY - 2017/9/1/medline PY - 2017/4/12/entrez KW - Bath salts KW - Cathinone KW - Desipramine KW - Drug discrimination KW - Fluoxetine KW - Mephedrone KW - Rimcazole SP - 62 EP - 75 JF - Neuropharmacology JO - Neuropharmacology VL - 119 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28396142/Atypical_binding_at_dopamine_and_serotonin_transporters_contribute_to_the_discriminative_stimulus_effects_of_mephedrone_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30147-8 DB - PRIME DP - Unbound Medicine ER -