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Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action

  • Clinton E. CanalEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 252)

Abstract

Recent, well-controlled – albeit small-scale – clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

Keywords

α-Adrenergic 5-HT2A 5-HT2C Cingulate cortex Head-twitch Ketanserin Psychedelic mechanisms Receptor binding Receptor conformations Receptor dimers Receptor function Serotonin Signal transduction 

Abbreviations

1P-LSD

1-Propionyl-lysergic acid diethylamide

25C-NBOMe

N-(2-Methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine

25CN-NBOH

N-(2-Hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine

25I-NBOMe

N-(2-Methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine

2C-B

4-Bromo-2,5-dimethoxyphenethylamine

2C-I

4-Iodo-2,5-dimethoxyphenethylamine

2C-T-7

2,5-Dimethoxy-4-propylthiophenethylamine

5-APB

5-(2-Aminopropyl)benzofuran

5-HT

5-Hydroxytryptamine (serotonin)

5-MeO-DALT

5-Methoxy-N,N-diallyltryptamine

5-MeO-DIPT

5-Methoxy-N,N-diisopropyltryptamine

5-MeO-DMT

5-Methoxy-N,N-dimethyltryptamine

6-APB

6-(2-Aminopropyl)benzofuran

AL-LAD

N6-allyl-6-norlysergic acid diethylamide

AMPA

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

bk-2C-B

β-Keto-2,5-dimethoxy-4-bromophenethylamine

BOL-148

2-Bromo-lysergic acid diethylamide

CB1

Cannabinoid 1 receptor

DA

Dopamine

DIPT

N,N-Diisopropyltryptamine

DMT

N,N-Dimethyltryptamine

DOB

2,5-Dimethoxy-4-bromoamphetamine

DOI

2,5-Dimethoxy-4-iodoamphetamine

DOM

2,5-Dimethoxy-4-methylamphetamine

DOPAC

3,4-Dihydroxyphenylacetic acid

DPT

N,N-Dipropyltryptamine

IP3

Inositol 1,4,5-trisphosphate

LSA

Lysergamide

LSD

Lysergic acid diethylamide

LSM-775

Lysergic acid morpholide

LSZ

Lysergic acid 2,4-dimethylazetidide

mCPP

meta-Chlorophenylpiperazine

MDMA

3,4-Methylenedioxymethamphetamine

mGluR2

Metabotropic glutamate receptor 2

NMDA

N-Methyl-D-aspartate

PARGY-LAD

N6-Propynyl-6-norlysergic acid diethylamide

PET

Positron emission tomography

SERT

Serotonin transporter

TAAR1

Trace amine-associated receptor 1

TCB-2

1-(3-Bromo-2,5-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine

THC

Δ9-Tetrahydrocannabinol

THH

Tetrahydroharmine

Notes

Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse (R21DA040907) and the Department of Defense (W81XWH-17-1-0329). I express my sincere gratitude to Dr. Nader Moniri and Austen Casey for critically reading and providing feedback on an early draft of this manuscript.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesCollege of Pharmacy, Mercer UniversityAtlantaUSA

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