title: The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2and TAAR1receptors.
abstract: d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1and 5-HT2receptors. 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-HT2Aand D2receptors. 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 D2receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT1Areceptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) 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-HT1A,D2and TAAR1receptors.
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada; Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: De Gregorio
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada.
authors.forename: Luca
authors.initials: L
authors.lastname: Posa
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ochoa-Sanchez
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: McLaughlin
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Comai
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada. Electronic address: gabriella.gobbi@mcgill.ca.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D006213:Hallucinogens / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D001549:Benzamides; D004298:Dopamine; D006213:Hallucinogens; D008238:Lysergic Acid Diethylamide; D010879:Piperazines; D011725:Pyridines; D011759:Pyrrolidines; D044282:Receptor, Serotonin, 5-HT1A; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin; D000095383:Trace Amine-Associated Receptors; C546333:N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: 8-OH-DPAT (PubChem CID:1220); Apomorphine (PubChem CID: 6005); Dopamine; EPPTB (PubChem CID: 25175634); Haloperidol (PubChem CID: 3559); In-vivo electrophysiology; LSD; LSD (PubChem CID: 5761); MDL 100,907 (PubChem CID:60858); Serotonin; TAAR(1) receptor; WAY 100,635 (PubChem CID: 5684); p-chlorophenylalanine (PubChem CID: 39972)