d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

Gregorio, Danilo De; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

doi:10.3390/ijms17111953

Cited by 98 publications

(72 citation statements)

References 145 publications

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“…Although hallucinogenic drugs seem to mimic some symptoms present in schizophrenia ( Gouzoulis-Mayfrank et al, 1998 ; Carhart-Harris et al, 2016a ; Liechti, 2017 ), there are presumably also important differences. Firstly, negative symptoms as commonly seen in schizophrenia are probably not present to this extent with hallucinogens, which mainly induce effects similar to positive symptoms ( De Gregorio et al, 2016 ). Secondly, there are also important differences among the positive symptoms, such as the predominance of visual hallucinations in hallucinogens compared to mainly auditory hallucinations in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Altered network hub connectivity after acute LSD administration

Müller

Dolder

Schmidt

et al. 2018

NeuroImage: Clinical

130

116

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LSD is an ambiguous substance, said to mimic psychosis and to improve mental health in people suffering from anxiety and depression. Little is known about the neuronal correlates of altered states of consciousness induced by this substance. Limited previous studies indicated profound changes in functional connectivity of resting state networks after the administration of LSD. The current investigation attempts to replicate and extend those findings in an independent sample. In a double-blind, randomized, cross-over study, 100 μg LSD and placebo were orally administered to 20 healthy participants. Resting state brain activity was assessed by functional magnetic resonance imaging. Within-network and between-network connectivity measures of ten established resting state networks were compared between drug conditions. Complementary analysis were conducted using resting state networks as sources in seed-to-voxel analyses. Acute LSD administration significantly decreased functional connectivity within visual, sensorimotor and auditory networks and the default mode network. While between-network connectivity was widely increased and all investigated networks were affected to some extent, seed-to-voxel analyses consistently indicated increased connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These latter observations are consistent with findings on the importance of hubs in psychopathological states, especially in psychosis, and could underlay therapeutic effects of hallucinogens as proposed by a recent model.

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Section: Discussionmentioning

confidence: 99%

Altered network hub connectivity after acute LSD administration

Müller

Dolder

Schmidt

et al. 2018

NeuroImage: Clinical

130

116

View full text Add to dashboard Cite

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“…Both investigated compounds also reversed DOI-induced head twitches. DOI, similar to the other 5-HT 2A activating agents (i.e., d-lysergic diethylamide acid, LSD), has hallucinogenic potential in humans ( Jacobs and Trulson, 1979 ; Geyer and Vollenweider, 2008 ; Vollenweider and Kometer, 2010 ), and in animals, it induces characteristic head twitches ( González-Maeso et al, 2008 ; De Gregorio et al, 2016a ), that are reversed by the administration of both typical and atypical neuroleptics ( Marona-Lewicka et al, 2005 ; De Gregorio et al, 2016b ). The activity of ADX71743 was observed in lower doses than that observed after MMPIP administration.…”

Section: Discussionmentioning

confidence: 99%

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

Cieślik

Woźniak

Kaczorowska

et al. 2018

Front. Mol. Neurosci.

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The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

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“…Similar to other hallucinogens, the effects of lysergic acid diethylamide (LSD) are primarily mediated by the serotonin 5-HT 2A receptor (De Gregorio et al, 2016), although LSD binds to most serotonin receptors and some other GPCRs (Kroeze et al, 2015). A few studies have used the 5-HT 2B b-Arrestin 2 and Drug Addiction receptor, which is very similar to the 5-HT 2A receptor, to study the molecular effects of LSD.…”

Section: B-arrestin 2 and Drug Addictionmentioning

confidence: 99%

Arresting the Development of Addiction: The Role ofβ-Arrestin 2 in Drug Abuse

Porter-Stransky

2017

J Pharmacol Exp Ther

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The protein -arrestin (arr) 2 directly interacts with receptors and signaling pathways that mediate the behavioral effects of drugs of abuse, making it a prime candidate for therapeutic interventions. arr2 drives desensitization and internalization of G protein-coupled receptors, including dopamine, opioid, and cannabinoid receptors, and it can also trigger G protein-independent intracellular signaling.arr2 mediates several drug-induced behaviors, but the relationship is complex and dependent on the type of behavior (e.g., psychomotor versus reward), the class of drug (e.g., psychostimulant versus opioid), and the circuit being interrogated (e.g., brain region, cell type, and specific receptor ligand). Here we discuss the current state of research concerning the contribution of arr2 to the psychomotor and rewarding effects of addictive drugs. Next we identify key knowledge gaps and suggest new tools and approaches needed to further elucidate the neuroanatomical substrates and neurobiological mechanisms to explain howarr2 modulates behavioral responses to drugs of abuse, as well as its potential as a therapeutic target.

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d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

Cited by 98 publications

References 145 publications

Altered network hub connectivity after acute LSD administration

Altered network hub connectivity after acute LSD administration

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

Arresting the Development of Addiction: The Role ofβ-Arrestin 2 in Drug Abuse

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