Biomaterial Database

Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone. 2017

Alyssa F DeLarge, and Laura L Erwin, and Peter J Winsauer

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

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.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008694	Methamphetamine	A central nervous system stimulant and sympathomimetic with actions and uses similar to DEXTROAMPHETAMINE. The smokable form is a drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed.	Deoxyephedrine,Desoxyephedrine,Desoxyn,Madrine,Metamfetamine,Methamphetamine Hydrochloride,Methylamphetamine,N-Methylamphetamine,Hydrochloride, Methamphetamine,N Methylamphetamine
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D012054	Reinforcement, Psychology	The strengthening of a conditioned response.	Negative Reinforcement,Positive Reinforcement,Psychological Reinforcement,Reinforcement (Psychology),Negative Reinforcements,Positive Reinforcements,Psychological Reinforcements,Psychology Reinforcement,Psychology Reinforcements,Reinforcement, Negative,Reinforcement, Positive,Reinforcement, Psychological,Reinforcements (Psychology),Reinforcements, Negative,Reinforcements, Positive,Reinforcements, Psychological,Reinforcements, Psychology
D003216	Conditioning, Operant	Learning situations in which the sequence responses of the subject are instrumental in producing reinforcement. When the correct response occurs, which involves the selection from among a repertoire of responses, the subject is immediately reinforced.	Instrumental Learning,Learning, Instrumental,Operant Conditioning,Conditionings, Operant,Instrumental Learnings,Learnings, Instrumental,Operant Conditionings
D004192	Discrimination, Psychological	Differential response to different stimuli.	Discrimination, Psychology,Psychological Discrimination
D004298	Dopamine	One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action.	Hydroxytyramine,3,4-Dihydroxyphenethylamine,4-(2-Aminoethyl)-1,2-benzenediol,Dopamine Hydrochloride,Intropin,3,4 Dihydroxyphenethylamine,Hydrochloride, Dopamine
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004338	Drug Combinations	Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture.	Drug Combination,Combination, Drug,Combinations, Drug
D000697	Central Nervous System Stimulants	A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here.	Analeptic,Analeptic Agent,Analeptic Drug,Analeptics,CNS Stimulant,CNS Stimulants,Central Nervous System Stimulant,Central Stimulant,Analeptic Agents,Analeptic Drugs,Central Stimulants,Agent, Analeptic,Agents, Analeptic,Drug, Analeptic,Drugs, Analeptic,Stimulant, CNS,Stimulant, Central,Stimulants, CNS,Stimulants, Central