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Pharmacol Res. 2016 Nov;113(Pt A):81-91. doi: 10.1016/j.phrs.2016.08.022. Epub 2016 Aug 17.

The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.

Author information

1
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.
2
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada.
3
Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy.
4
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada. Electronic address: gabriella.gobbi@mcgill.ca.

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.

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)

PMID:
27544651
DOI:
10.1016/j.phrs.2016.08.022
[Indexed for MEDLINE]

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