The hallucinogen d -lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT 1A , D 2 and TAAR 1 receptors
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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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].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [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.”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [37]
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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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