Journal Article

Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function

Gatch, Michael B., Eshleman, Amy J., Forster, Michael J., Wolfrum, Katherine M., Johnson, Robert A., Janowsky, Aaron

2014

Overview

Rationale Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C-I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4-chloroamphetamine (DOC) are used recreationally and may have deleterious side effects. Objectives This study compares the behavioral effects and the mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant. Methods The effects of these compounds on mouse locomotor activity and in rats trained to discriminate dimethyltryptamine, (−)-DOM, (+)-LSD, (±)-MDMA, and S (+)-methamphetamine were assessed. Binding and functional activity of the phenethylamines at 5-HT 1A , 5-HT 2A , 5-HT 2C receptors and monoamine transporters were assessed using cells heterologously expressing these proteins. Results The phenethylamines depressed mouse locomotor activity, although 2C-D and 2C-E stimulated activity at low doses. The phenethylamines except 2C-T-2 fully substituted for at least one hallucinogenic training compound, but none fully substituted for (+)-methamphetamine. At 5-HT 1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT 2A arachidonic acid release assays, the phenethylamines were partial to full agonists except 2C-I which was an antagonist. All compounds were full agonists at 5-HT 2A and 5-HT 2C receptor inositol phosphate assays. Only 2C-I had moderate affinity for, and very low potency at, the serotonin transporter. Conclusions The discriminative stimulus effects of 2C-C, 2C-D, 2C-E, 2C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine. Additionally, the substituted phenethylamines were full agonists at 5-HT 2A and 5-HT 2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen-like discriminative stimulus effects. Additionally, the 5-HT 2A inositol phosphate pathway may be important in 2C-I's psychoactive properties.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Analysis / Animal behavior / Animals / Biomedical and Life Sciences / Biomedicine / Discrimination (Psychology) - drug effects / Drug abuse / LSD / Lysergic acid diethylamide / Male / Methamphetamine - pharmacology / Mice / Motor Activity - drug effects / N,N-Dimethyltryptamine - pharmacology / Neurosciences / Original Investigation / Pharmacology/Toxicology / Phenethylamines / Phenethylamines - pharmacology / Physiological aspects / Psychiatry / Psychopharmacology / Psychotropic Drugs - pharmacology / Rats / Rats, Sprague-Dawley / Receptors, Serotonin - metabolism / Serotonin / Vesicular Monoamine Transport Proteins - metabolism