title: Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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-HT1A, 5-HT2A, 5-HT2C 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-HT1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT2A 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-HT2A and 5-HT2C 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-HT2A and 5-HT2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen-like discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may be important in 2C-I's psychoactive properties.
authors.affiliation: Research Service, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR, USA, eshleman@ohsu.edu.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Eshleman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forster
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Wolfrum
authors.forename: Robert A
authors.initials: RA
authors.lastname: Johnson
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gatch
mesh_terms: D000818:Animals; D004192:Discrimination, Psychological / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D004130:N,N-Dimethyltryptamine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D010627:Phenethylamines; D011619:Psychotropic Drugs; D011985:Receptors, Serotonin; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D004130:N,N-Dimethyltryptamine