Search

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 (5–20 μg/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 (30–120 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 D 2 receptor antagonist haloperidol (50 μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1 ) 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-HT 1A, D 2 and TAAR 1 receptors. [ABSTRACT FROM AUTHOR]

Melatonin (MLT), a neuromodulator mainly acting through two G-protein coupled receptors MT 1 and MT 2 , regulates many brain functions, including circadian rhythms, mood, pain and sleep. MLT and non-selective MT 1 /MT 2 receptor agonists are clinically used in neuropsychiatric and/or sleep disorders. However, the selective roles of the MT 1 and MT 2 receptors need to be clarified. Here, we review the role of the MT 1 receptor in neuropsychopharmacology, describe the anatomical localization of MT 1 receptors in the brain, discuss the medicinal chemistry, biochemistry and molecular aspects of the receptor, and explore the findings linking MT 1 receptors to psychiatric and neurological disorders. MT 1 receptors are localized in brain regions which regulate circadian rhythms, sleep, and mood, such as the suprachiasmatic nucleus, cortex, hippocampus, dorsal raphe nucleus and lateral hypothalamus. Their activation modulates intracellular signaling pathways also targeted by psychoactive drugs, including antidepressants and mood stabilizers. MT 1 receptor knockout mice display increased anxiety, a depressive-like phenotype, increased propensity to reward and addiction, and reduced Rapid-Eye-Movement sleep. These behavioral dysfunctions are associated with altered serotonergic and noradrenergic neurotransmissions. Several studies indicate that the MT 1 , rather than MT 2 , receptor is implicated in circadian rhythm regulation. The involvement of MT 1 receptors in Alzheimer's and Huntington diseases has also been proposed. Postmortem studies in depressed patients have further confirmed the possible involvement of MT 1 receptors in depression. Overall, there is substantial evidence indicating a role for MT 1 receptor in modulating brain function and mood. Consequently, this MLT receptor subtype deserves to be further examined as a novel target for neuropsychopharmacological drug development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)