title: The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice.
abstract: BACKGROUND
  Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens.
  
  
  OBJECTIVE
  The present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT).
  
  
  METHODS
  Drug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT.
  
  
  RESULTS
  MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT's effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro.
  
  
  CONCLUSIONS
  The 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.
authors.affiliation: Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Carbonaro
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Eshleman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forster
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gatch
mesh_terms: D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D004130:N,N-Dimethyltryptamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016896:Treatment Outcome; D014363:Tryptamines / Q000494:pharmacology*
chemical_list: D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018094:Receptors, Metabotropic Glutamate; D014363:Tryptamines; C108822:metabotropic glutamate receptor 2; C033695:N,N-diisopropyltryptamine; D004130:N,N-Dimethyltryptamine