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Psychopharmacology

, Volume 232, Issue 1, pp 275–284 | Cite as

The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

  • Theresa M. Carbonaro
  • Amy J. Eshleman
  • Michael J. Forster
  • Kejun Cheng
  • Kenner C. Rice
  • Michael B. Gatch
Original Investigation

Abstract

Rationale

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.

Keywords

N,N-diisopropyltryptamine N,N-dimethyltryptamine Hallucinogens Drug discrimination 5-HT2A 5-HT2C mGluR2 Rat 

Notes

Funding

Funding was provided by the Addiction Treatment Discovery Program of the National Institute on Drug Abuse (NIH N01DA-7-8872) and by T32 AG020494. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. There are no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Theresa M. Carbonaro
    • 1
  • Amy J. Eshleman
    • 2
    • 3
  • Michael J. Forster
    • 1
  • Kejun Cheng
    • 4
  • Kenner C. Rice
    • 4
  • Michael B. Gatch
    • 1
  1. 1.Department of Pharmacology & NeuroscienceUniversity of North Texas Health Science CenterFort WorthUSA
  2. 2.Research ServicePortland Veterans Affairs Medical CenterPortlandUSA
  3. 3.Department of Psychiatry and Behavioral NeuroscienceOregon Health and Science UniversityPortlandUSA
  4. 4.Chemical Biology Research BranchNational Institute on Drug Abuse and National Institute on Alcohol Abuse and AlcoholismBethesdaUSA

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