Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

López-Giménez, Juan F.; González-Maeso, Javier

doi:10.1007/7854_2017_478

Cited by 187 publications

(166 citation statements)

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“…Mechanisms that could logically be proposed to explain the findings reported here include effects on G-protein coupled signal transduction and downstream effectors, second messengers, and gene expression ( Halberstadt, 2015 ; Nichols, 2016 ; Lopez-Gimenez and Gonzalez-Maeso, 2018 ; Martin and Nichols, 2018 ), and a systematic exploration of these possibilities is well beyond the scope of this discussion. Classical hallucinogens produce 5-HT 2A R desensitization ( Nichols, 2016 ), and it has been suggested that persistently reduced signaling in downstream pathways linked to the 5-HT 2A R might explain sustained effects observed in clinical studies on substance use ( Bogenschutz and Johnson, 2016 ) or mood and anxiety symptoms ( Vollenweider and Kometer, 2010 ; Ross et al, 2016 ).…”

Section: Discussionmentioning

confidence: 97%

“…Coupling among G proteins, phospholipase effectors and the 5-HT 2A R subsumes a set questions of current interest in research on psychedelics. Although 5-HT 2A Rs classically couple to Gα q/11 , the effects of classical hallucinogens also apparently involve Gα i/o ( Lopez-Gimenez and Gonzalez-Maeso, 2018 ). G i/o signaling interacts with brain region, for example alcohol intake in C57BL/6 mice is decreased by activation of G i/o protein that is regionally expressed in the dorsal striatum ( Robins et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…There is apparently no previously published work on the effects of LSD on the self-administration of alcohol or other abused substances in animals. In view of the elements of possible relevance to addiction in the signaling cascade downstream from the binding sites of LSD ( Lopez-Gimenez and Gonzalez-Maeso, 2018 ), an effect of LSD on the self-administration of alcohol in animals would provide support for the animal model as a possible approach to target identification and drug discovery. This present research focuses on the effect of LSD on alcohol intake in a two-bottle choice drinking paradigm in C57BL/6J mice, an inbred alcohol-preferring strain ( Melo et al, 1996 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

Alper

Dong

Shah³

et al. 2018

Front. Pharmacol.

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There is a substantive clinical literature on classical hallucinogens, most commonly lysergic acid diethylamide (LSD) for the treatment of alcohol use disorder. However, there has been no published research on the effect of LSD on alcohol consumption in animals. This study evaluated the effect of LSD in mice using a two-bottle choice alcohol drinking paradigm. Adult male C57BL/6J mice were exposed to ethanol to develop preference and divided into three groups of equal ethanol consumption, and then treated with single intraperitoneal injection of saline or 25 or 50 μg/kg LSD and offered water and 20% ethanol. The respective LSD-treated groups were compared to the control group utilizing a multilevel model for repeated measures. In mice treated with 50 μg/kg LSD ethanol consumption was reduced relative to controls (p = 0.0035), as was ethanol preference (p = 0.0024), with a group mean reduction of ethanol consumption of 17.9% sustained over an interval of 46 days following LSD administration. No significant effects on ethanol consumption or preference were observed in mice treated with 25 μg/kg LSD. Neither total fluid intake nor locomotor activity in the LSD-treated groups differed significantly from controls. These results suggest that classical hallucinogens in the animal model merit further study as a potential approach to the identification of targets for drug discovery and investigation of the neurobiology of addiction.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

Alper

Dong

Shah³

et al. 2018

Front. Pharmacol.

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“…50,51 The psychopathological features of these patients may be attributable to the agonist properties of oxymetazoline at 5-HT 2A receptor, because several 5-HT 2A receptor agonists such as lysergic acid diethylamide (LSD) are well known to act as a psychotomimetic. 52 In conclusion, the current study indicates that [ 35 been commercially unavailable. 12 Searching for a substitute antibody for sc-393 (E-17) is currently in progress in our laboratory.…”

Section: Discussionmentioning

confidence: 60%

“…In clinical practice, there have been case reports describing patients suffering from paranoid symptoms associated with use of oxymetazoline . The psychopathological features of these patients may be attributable to the agonist properties of oxymetazoline at 5‐HT 2A receptor, because several 5‐HT 2A receptor agonists such as lysergic acid diethylamide (LSD) are well known to act as a psychotomimetic …”

Section: Discussionmentioning

confidence: 99%

Functional activation of Gα_q/11 protein via α₁‐adrenoceptor in rat cerebral cortical membranes

Odagaki

Kinoshita

Ota

2019

Clin Exp Pharma Physio

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Summary Although it is recognized that α1‐adrenoceptors are coupled to diverse intracellular signalling pathways, its primary transduction mechanisms are evoked by activating phospholipase C in the cell membrane through Gαq/11, resulting in production of inositol 1,4,5‐trisphosphate and diacylglycerol. However, there have been few studies that indicate directly the involvement of Gαq/11 proteins in this signalling pathway in the central nervous system. In the current study, we tried to pharmacologically characterize (−)‐adrenaline‐stimulated [35S]GTPγS binding to Gαq/11 in rat brain membranes. Functional activation of Gαq/11 coupled to α1‐adrenoceptor was investigated by using [35S]GTPγS binding/immunoprecipitation assay in the membranes prepared from rat cerebral cortex, hippocampus, and striatum. The specific [35S]GTPγS binding to Gαq/11 was stimulated by (−)‐adrenaline in a concentration‐dependent and saturable manner in rat cerebral cortical membranes. In hippocampal or striatal membranes, the stimulatory effects of (−)‐adrenaline were scarce. The effect of (−)‐adrenaline was potently inhibited by prazosin, a potent and selective α1‐adrenoceptor antagonist, but not by yohimbine, a selective α2‐adrenoceptor antagonist. The response was mimicked by cirazoline, but not by R(−)‐phenylephrine. Although oxymetazoline also stimulated the specific [35S]GTPγS binding to Gαq/11 as an apparent “super‐agonist”, detailed pharmacological characterization revealed that its agonistic properties in this experimental system were derived from off‐target effects on 5‐HT2A receptors, but not via α1‐adrenoceptors. In conclusion, functional coupling of α1‐adrenoceptors to Gαq/11 proteins are detectable in rat brain membranes by means of [35S]GTPγS binding/immunoprecipitation assay. It is necessary to interpret the experimental data with caution when oxymetazoline is included as an agonist at α1‐adrenoceptors.

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Use of Lysergic Acid Diethylamide by Major Depression Status

Walsh,

Gorfinkel,

Shmulewitz

et al. 2024

JAMA Psychiatry

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ImportanceRenewed interest in the clinical potential of hallucinogens may lead people with depression to a generally more positive view of the use of lysergic acid diethylamide (LSD). Therefore, past-year LSD use among people with depression may be increasing in prevalence.ObjectiveTo assess time trends in the prevalence of past-year nonmedical LSD use by past-year major depression status and the variation in this association by sociodemographic characteristics.Design, Setting, and ParticipantsThis survey study used pooled publicly available data from 478 492 adults aged 18 years or older who were administered the National Survey on Drug Use and Health from 2008 through 2019. Statistical analysis was conducted from December 2022 to June 2023.Main Outcome and MeasuresPast-year major depression diagnoses per criteria from the DSM-IV were analyzed. Logistic regression models examined whether time trends in past-year nonmedical LSD use differed between adults with vs without past-year depression, adjusting for sociodemographic characteristics. Secondary analyses examined whether the trends in LSD use by depression status differed between sociodemographic subgroups.ResultsThe analytic sample included 478 492 adults, of whom 51.8% were female, 56.1% were younger than 50 years, 11.7% were Black, 15.1% were Hispanic, 65.8% were White, and 7.5% were another race. Weighted interview response rates ranged from 64.9% to 75.6% during the study time frame. From 2008 to 2019, past-year use of LSD increased significantly more among adults with major depression (2008 prevalence, 0.5%; 2019 prevalence, 1.8%; prevalence difference [PD], 1.3% [95% CI, 1.0%-1.6%]) compared with adults without major depression (2008 prevalence, 0.2%; 2019 prevalence, 0.8%; PD, 0.6% [95% CI, 0.5%-0.7%]) (difference in difference, 0.8% [95% CI, 0.5%-1.1%]). This difference was particularly pronounced among young adults aged 34 years or younger (PD among those aged 18-25 years with depression, 3.3% [95% CI, 2.5%-4.2%]; PD among those aged 26-34 years with depression, 2.7% [95% CI, 1.6%-3.8%]) and individuals with incomes less than $75 000 per year (PD among those with income &lt;$20 000, 1.9% [95% CI, 1.3%-2.6%]; PD among those with income $20 000-$49 999, 1.5% [95% CI, 1.0%-2.1%]; PD among those with income $50 000-$74 999, 1.3% [95% CI, 0.7%-2.0%]).Conclusions and RelevanceThis study suggests that, from 2008 to 2019, there was a disproportionate increase in the prevalence of past-year LSD use among US adults with past-year depression. Among those with depression, this increase was particularly strong among younger adults and those with lower household incomes. Among individuals with depression who also report LSD use, clinicians should discuss potential strategies for mitigating harm and maximizing benefits in medically unsupervised settings.

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Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

Cited by 187 publications

References 142 publications

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

Functional activation of Gα_q/11 protein via α₁‐adrenoceptor in rat cerebral cortical membranes

Use of Lysergic Acid Diethylamide by Major Depression Status

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Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

Cited by 187 publications

References 142 publications

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

Functional activation of Gαq/11 protein via α1‐adrenoceptor in rat cerebral cortical membranes

Use of Lysergic Acid Diethylamide by Major Depression Status

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Product

Resources

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Functional activation of Gα_q/11 protein via α₁‐adrenoceptor in rat cerebral cortical membranes