The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors

Neuropharmacology. 2016 Feb:101:370-8. doi: 10.1016/j.neuropharm.2015.10.016. Epub 2015 Oct 23.

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development.

Keywords: 5-HT receptors; Hallucinogens; Oscillatory activity; Prefrontal cortex; Sensorial cortical areas; Visual cortex.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Cerebral Cortex / drug effects*
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Hallucinogens / pharmacology*
  • Haloperidol / pharmacology
  • Male
  • Methoxydimethyltryptamines / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Risperidone / pharmacology
  • Serotonin / metabolism
  • Serotonin Agents / pharmacology

Substances

  • Dopamine Antagonists
  • Hallucinogens
  • Methoxydimethyltryptamines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin Agents
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Haloperidol
  • Risperidone