The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.
Danilo de Gregorio, Luca Posa, Rafael Ochoa-Sanchez, Ryan J Mclaughlin, Sabatino Maione, Stefano Comai, Gabriella Gobbi
Pharmacological Research November 2016 DOI: 10.1016/j.phrs.2016.08.022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In-vivo electrophysiology study in animals Peer reviewed |
|---|---|
| Population | Male adult rats |
| Interventions | LSD p-chlorophenylalanine haloperidol WAY-100 635 EPPTB |
| Dose | LSD 5-20 µg/kg and 30-120 µg/kg i.v.; haloperidol 50 µg/kg i.v.; WAY-100,635 500 µg/kg i.v.; EPPTB 5 mg/kg i.v. |
| Topics | LSD Serotonin |
| Keywords | 8-oh-dpat pubchem cid Apomorphine pubchem cid Dopamine Epptb pubchem cid Haloperidol pubchem cid In-vivo electrophysiology LSD Pubchem Cid Taar1 receptor P-chlorophenylalanine pubchem cid |
| Key points | LSD at low doses (5-20 µg/kg i.v.) reduced dorsal raphe serotonin neuron firing via 5-HT2A and D2 receptors without affecting VTA dopamine neurons, while higher doses (30-120 µg/kg i.v.) dose-dependently decreased VTA dopamine firing. This dopamine inhibition was serotonin-independent and blocked by antagonists of 5-HT1A, D2, and TAAR1 receptors, suggesting a pleiotropic mechanism. |
Abstract
d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 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-HT2A and D2 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 D2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT1A receptor 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, D2 and TAAR1 receptors.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
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