Cited by 110Neurotransmitter Receptor Influence on BehaviorPsychedelics and Drug StudiesNeuroscience and Neuropharmacology Research

The hallucinogen d -lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT 1A , D 2 and TAAR 1 receptors

De Gregorio, Danilo, Posa, Luca, Ochoa-Sanchez, Rafael, McLaughlin, Ryan, Maione, Sabatino, Comai, Stefano, Gobbi, Gabriella·2016·Pharmacological Research

Abstract

d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT 1 and 5-HT 2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT 2A and D 2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D 2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT 1A, D 2 and TAAR 1 receptors.

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Crossref · 10.1016/j.phrs.2016.08.022

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  • Treatment with the 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.) prevented the inhibitory effect of LSD on the firing rate of dopaminergic ventral tegmental neurons in the rat brain.

    “In electrophysiological studies, treatment with 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.) prevented the inhibitory effect of LSD (1) on the firing rate of dopaminergic ventral tegmental neurons in the rat brain [37].”
  • Treatment with a blocker of the trace amine-associated receptor type 1 also interfered in the effects of LSD on dopamine neuron activity.

    “In the same study, treatment with a blocker of the trace amine-associated receptor (TAAR) type 1 also interfered in the effects of LSD (1) on dopamine neuron activity.”

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Authors
De Gregorio, D., Posa, L., Ochoa-Sanchez, R., McLaughlin, R., Maione, S., Comai, S., & Gobbi, G.
Affiliations
  • McGill University Health Centre (CA)
  • University of Campania "Luigi Vanvitelli" (IT)
Corresponding author
Gobbi, Gabriella
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2016-11
Volume
113
Issue
Pt A
Pages
81-91
ISSN
1043-6618 (ISSN-L)
OpenAlex
W2516564083
Cited by
110
References
73
Citations by year
2026: 6 · 2025: 15 · 2024: 25 · 2023: 16 · 2022: 15 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 11 · 2017: 3 · 2016: 1
FWCI
3.06
Type
journal article
Language
en
Open access
closed
Locations
  • Pharmacological Research (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Consejo Nacional de Ciencia y Tecnología
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
LSD, lysergic acid diethylamide, hallucinogens, dopaminergic neurons, ventral tegmental area, dorsal raphe nucleus, 5-HT1A receptor, dopamine D2 receptor, TAAR1, serotonin, mesolimbic system, haloperidol, WAY-100635, p-chlorophenylalanine, receptor antagonists
MeSH terms
Trace Amine-Associated Receptors, Animals, Benzamides, Dopamine, Hallucinogens, Lysergic Acid Diethylamide, Male, Neurons, Piperazines, Pyridines, Pyrrolidines, Serotonin, Rats, Sprague-Dawley, Receptors, Dopamine D2, Ventral Tegmental Area, Receptors, G-Protein-Coupled, Receptor, Serotonin, 5-HT1A, Rats

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