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

This study (2016) found that LSD decreased the firing rate of dopamine neurons in the ventral tegmental area (VTA, in the midbrain) in rats at very high doses.

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 (5–20 μg/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 (30–120 μg/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 (50 μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5 mg/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.”

Authors: Danilo De Gregorio, Luca Posa, Rafael Ochoa-Sanchez, Ryan McLaughlin, Sabatino Maione, Stefano Comai & Gabriella Gobbi

Summary

LSD produces psychotic-like symptoms such as visual, tactile, acoustic hallucinations, change in body perception, synaesthesia, thought disorders, time distortions, etc. This study aimed to better characterize the in-vivo contribution of the DA system to the effects of LSD on VTA DA neurons.

In-vivo electrophysiological recording preparation was done in a 12 h light-dark cycle with ad libitum access to food and water.

Rats were placed in a stereotaxic apparatus and a hole was drilled through the skull. Anesthesia was maintained by administering chloral hydrate and monitoring eye blink response to pressure. Single-unit recordings were performed using single-barreled glass micropipettes pulled from 2 mm Stoelting capillary glass on a Narashige PE-21 pipette puller. The recordings were amplified by an AC Differential MDA-3 amplifier, post-amplified and band-pass filtered by a Realistic 10 band frequency equalizer, and digitized by a CED 1401 interface system.

Rats were injected intravenously with VEH, then with sequential doses of LSD, Apo, Halo or 8-OH-DPAT, or with a singular injection of MDL 100 907, WAY, or EPPTB. Only one neuron per rat was tested. Statistical analysis was performed using Student t-test and one-way ANOVA, followed by Bonfer- post hoc comparisons where appropriate.

Cumulative high doses of LSD significantly decreased VTA DA firing activity, while subsequent cumulative injections of the selective D2 antagonist Halo were able to reinstate DA firing activity. This indicates an inhibitory influence of the 5-HT input upon neurons. We found that rats pretreated with PCPA had decreased VTA DA neural activity following 60, 90 and 120 g/kg LSD, but not 30 g/kg LSD. LSD decreased VTA DA burst-firing activity in 5-HT depleted animals, but did not affect firing rate in control animals. After injection of 150 g/kg LSD, VTA DA neurons did not respond to Apo, confirming that haloperidol blocks LSD effects via DA D2 receptors. However, 50 g/kg Halo, prior LSD, increased VTA DA firing activity, but did not affect the number of bursts per 200 s.

Cumulative high doses of LSD did not affect VTA neural activity in neurons pre-treated with WAY-100,635, but reduced DA firing at doses of 30 and 60 – 150 g/kg in non pre-treated neurons. LSD was ineffective at modulating DA neurons in VTA at this dose. We performed electrophysiological recordings of VTA DA neurons with high doses of LSD and found that the D2 antagonist haloperidol prevented the decrease in VTA DA firing rate following cumulative injections of high doses of LSD.

We found that the depletion of 5-HT with PCPA sensitized the animals to the hallucinogenic effects of LSD, and that Halo did not reverse the effects of LSD in 5-HT depleted animals, suggesting that 5-HT depletion can be a factor that influences neuroleptic-resistant psychosis. The dose-dependent electrophysiological effects of LSD on 5-HT and DA neurotransmission are consistent with the biphasic effects of LSD observed in rats and humans. These effects are mediated by the initial activation of 5-HT2A receptors followed by a mediation of D2 receptors in a second phase. The TAAR1 receptor is an important modulator of the dopaminergic and serotoninergic systems, and potentially of the glutamatergic system. It binds trace-amines, including endogenous hallucinogens and exogenous hallucinogens such as LSD. TAAR1 knockout mice have an increased firing activity of DA VTA neurons, are more sensitive to a challenge of amphetamine, and have over-expressed DA D2 receptors. TAAR1 agonists and antagonists can improve performance on an object retrieval task and decrease immobility in the forced swim test.