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Adam L Halberstadt - One of the best experts on this subject based on the ideXlab platform.
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correlation between the potency of Hallucinogens in the mouse head twitch response assay and their behavioral and subjective effects in other species
Neuropharmacology, 2020Co-Authors: Adam L Halberstadt, Muhammad Chatha, Adam K Klein, Jason Wallach, Simon D BrandtAbstract:Abstract Serotonergic Hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of Hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine Hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported Hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, Hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT2A receptor activation. We present evidence that Hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of Hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of Hallucinogen psychopharmacology and in structure-activity relationship studies of Hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the Hallucinogenic potency of 5-HT2A agonists in humans. “This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.
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return of the lysergamides part i analytical and behavioural characterization of 1 propionyl d lysergic acid diethylamide 1p lsd
Drug Testing and Analysis, 2016Co-Authors: Simon D Brandt, Jason Wallach, Pierce V Kavanagh, Folker Westphal, Alexander Stratford, Simon P Elliott, Khoa Hoang, Adam L HalberstadtAbstract:1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a 'research chemical' in the form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic Hallucinogens is that they produce 5-HT2A -receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P-LSD (0.025-0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50 = 349.6 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P-LSD administration followed pretreatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic Hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated. Copyright © 2015 John Wiley & Sons, Ltd.
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Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the Hallucinogen 5-methoxy-N,N-dimethyltryptamine.
Pharmacology biochemistry and behavior, 2016Co-Authors: Adam L HalberstadtAbstract:Monoamine oxidase inhibitors (MAOIs) are often ingested together with tryptamine Hallucinogens, but relatively little is known about the consequences of their combined use. We have shown previously that monoamine oxidase-A (MAO-A) inhibitors alter the locomotor profile of the Hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats, and enhance its interaction with 5-HT2A receptors. The goal of the present studies was to investigate the mechanism for the interaction between 5-MeO-DMT and MAOIs, and to determine whether other behavioral responses to 5-MeO-DMT are similarly affected. Hallucinogens disrupt prepulse inhibition (PPI) in rats, an effect typically mediated by 5-HT2A activation. 5-MeO-DMT also disrupts PPI but the effect is primarily attributable to 5-HT1A activation. The present studies examined whether an MAOI can alter the respective contributions of 5-HT1A and 5-HT2A receptors to the effects of 5-MeO-DMT on PPI. A series of interaction studies using the 5-HT1A antagonist WAY-100,635 and the 5-HT2A antagonist MDL 11,939 were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in rats pretreated with an MAOI. The effects of MAO-A inhibition on the pharmacokinetics of 5-MeO-DMT and its metabolism to bufotenine were assessed using liquid chromatography-electrospray ionization-selective reaction monitoring-tandem mass spectrometry (LC-ESI-SRM-MS/MS). 5-MeO-DMT (1mg/kg) had no effect on PPI when tested 45-min post-injection but disrupted PPI in animals pretreated with the MAO-A inhibitor clorgyline or the MAO-A/B inhibitor pargyline. The combined effect of 5-MeO-DMT and pargyline on PPI was antagonized by pretreatment with either WAY-100,635 or MDL 11,939. Inhibition of MAO-A increased the level of 5-MeO-DMT in plasma and whole brain, but had no effect on the conversion of 5-MeO-DMT to bufotenine, which was found to be negligible. The present results confirm that 5-MeO-DMT can disrupt PPI by activating 5-HT2A, and indicate that MAOIs alter 5-MeO-DMT pharmacodynamics by increasing its accumulation in the central nervous system.
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recent advances in the neuropsychopharmacology of serotonergic Hallucinogens
Behavioural Brain Research, 2015Co-Authors: Adam L HalberstadtAbstract:Serotonergic Hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of Hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of Hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how Hallucinogens work in the brain. Evidence is also emerging that Hallucinogens may possess therapeutic efficacy.
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effects of the Hallucinogen 2 5 dimethoxy 4 iodophenethylamine 2c i and superpotent n benzyl derivatives on the head twitch response
Neuropharmacology, 2014Co-Authors: Adam L Halberstadt, Mark A GeyerAbstract:Abstract N-benzyl substitution markedly enhances the affinity of phenethylamine Hallucinogens at the 5-HT2A receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT2A receptor activation in rats and mice, and is widely used as a behavioral proxy for Hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine Hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1–10 mg/kg SC), 25I-NBOMe (0.1–1 mg/kg SC), and 25I-NBMD (1–10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT2A antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine Hallucinogens induce the HTR by activating 5-HT2A receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT2A affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these Hallucinogens will become more widespread in the future.
Roland R Griffiths - One of the best experts on this subject based on the ideXlab platform.
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The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain
Scientific Reports, 2020Co-Authors: Manoj K. Doss, Matthew W. Johnson, Roland R Griffiths, Thomas E Prisinzano, Darrick G. May, John M. Clifton, Sidnee L. Hedrick, Frederick S BarrettAbstract:Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative Hallucinogen found in Salvia divinorum . Despite the resurgence of Hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other Hallucinogens, necessitating studies of direct comparisons.
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double blind comparison of the two Hallucinogens psilocybin and dextromethorphan effects on cognition
Psychopharmacology, 2018Co-Authors: Frederick S Barrett, Matthew W. Johnson, Theresa M Carbonaro, Ethan Hurwitz, Roland R GriffithsAbstract:Classic psychedelics (serotonin 2A receptor agonists) and dissociative Hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative Hallucinogen dextromethorphan (DXM). Twenty Hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered. Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin. This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.
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double blind comparison of the two Hallucinogens psilocybin and dextromethorphan similarities and differences in subjective experiences
Psychopharmacology, 2018Co-Authors: Theresa M Carbonaro, Matthew W. Johnson, Ethan Hurwitz, Roland R GriffithsAbstract:Although psilocybin and dextromethorphan (DXM) are Hallucinogens, they have different receptor mechanisms of action and have not been directly compared. This study compared subjective, behavioral, and physiological effects of psilocybin and dextromethorphan under conditions that minimized expectancy effects. Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of Hallucinogen use. Instructions to participants and staff minimized expectancy effects. Various subjective, behavioral, and physiological effects were assessed after drug administration. High doses of both drugs produced similar increases in participant ratings of peak overall drug effect strength, with similar times to maximal effect and time-course. Psilocybin produced orderly dose-related increases on most participant-rated subjective measures previously shown sensitive to Hallucinogens. DXM produced increases on most of these same measures. However, the high dose of psilocybin produced significantly greater and more diverse visual effects than DXM including greater movement and more frequent, brighter, distinctive, and complex (including textured and kaleidoscopic) images and visions. Compared to DXM, psilocybin also produced significantly greater mystical-type and psychologically insightful experiences and greater absorption in music. In contrast, DXM produced larger effects than psilocybin on measures of disembodiment, nausea/emesis, and light-headedness. Both drugs increased systolic blood pressure, heart rate, and pupil dilation and decreased psychomotor performance and balance. Psilocybin and DXM produced similar profiles of subjective experiences, with psilocybin producing relatively greater visual, mystical-type, insightful, and musical experiences, and DXM producing greater disembodiment.
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use of the classic Hallucinogen psilocybin for treatment of existential distress associated with cancer
2013Co-Authors: Charles S Grob, Anthony P Bossis, Roland R GriffithsAbstract:This chapter reviews the potential of a treatment approach that uses psilocybin, a novel psychoactive drug, to ameliorate the psychospiritual distress and demoralization that often accompany a life-threatening cancer diagnosis. The focus of cutting-edge research beginning in the 1950s, the investigation of classic Hallucinogens had a major impact on the evolving field of psychiatry, contributing to early discoveries of basic neurotransmitter systems and to significant developments in clinical psychopharmacology. While published reports of therapeutic breakthroughs with difficult-to-treat and refractory patient populations were initially met with mainstream professional enthusiasm, by the late 1960s and early 1970s the growing association of Hallucinogens with widespread indiscriminate use led to the temporary abandonment of this promising psychiatric treatment model. After a hiatus lasting several decades, however, regulatory and scientific support has grown for the resumption of clinical research investigations exploring the safety and efficacy of a treatment model utilizing the classic Hallucinogen, psilocybin, in a subject population that had previously demonstrated positive therapeutic response, patients with existential anxiety due to a life-threatening cancer diagnosis.
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Dose-related effects of salvinorin A in humans: dissociative, Hallucinogenic, and memory effects
Psychopharmacology, 2013Co-Authors: Katherine A Maclean, Matthew W. Johnson, Chad J Reissig, Thomas E Prisinzano, Roland R GriffithsAbstract:Rationale Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum , which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A. Objective This double-blind, placebo-controlled study evaluated the dose-related effects of inhaled salvinorin A in individuals with histories of Hallucinogen use. Methods Eight healthy Hallucinogen-using adults inhaled up to 16 doses of salvinorin A (0.375–21 μg/kg) in ascending order. Physiological, behavioral, and subjective effects were assessed every 2 min for 60 min after administration. Qualitative subjective effects were assessed retrospectively via questionnaires at the end of sessions. Persisting effects were assessed 1 month later. Results Orderly dose-related effects peaked at 2 min and then rapidly dissipated, replicating previous findings. Subjective effects were intense, with maximal drug strength ratings or unresponsiveness frequently observed at high doses. Questionnaires assessing qualitative effects (Hallucinogen Rating Scale, Pharmacological Class Questionnaire) suggested some overlap with serotonergically mediated classic Hallucinogens. Salvinorin A also produced dose-related dissociative effects and impairments in recall/recognition memory. At 1-month follow-up, there was no evidence of persisting adverse effects. Participants reported that salvinorin A effects were qualitatively different from other drugs. Conclusions Salvinorin A produces a unique profile of subjective and cognitive effects, including strong dissociative effects and memory impairment, which only partially overlap with classic Hallucinogen effects. Along with nonhuman studies of salvinorin A, these results are important for understanding the neurobiology of the kappa opioid system and may ultimately have important therapeutic applications.
Mark A Geyer - One of the best experts on this subject based on the ideXlab platform.
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effects of the Hallucinogen 2 5 dimethoxy 4 iodophenethylamine 2c i and superpotent n benzyl derivatives on the head twitch response
Neuropharmacology, 2014Co-Authors: Adam L Halberstadt, Mark A GeyerAbstract:Abstract N-benzyl substitution markedly enhances the affinity of phenethylamine Hallucinogens at the 5-HT2A receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT2A receptor activation in rats and mice, and is widely used as a behavioral proxy for Hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine Hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1–10 mg/kg SC), 25I-NBOMe (0.1–1 mg/kg SC), and 25I-NBMD (1–10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT2A antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine Hallucinogens induce the HTR by activating 5-HT2A receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT2A affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these Hallucinogens will become more widespread in the future.
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role of the 5 ht2a receptor in the locomotor hyperactivity produced by phenylalkylamine Hallucinogens in mice
Neuropharmacology, 2013Co-Authors: Adam L Halberstadt, Susan B Powell, Mark A GeyerAbstract:Abstract The 5-HT2A receptor mediates the effects of serotonergic Hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT2A receptor activation. Our previous studies demonstrated that the phenylalkylamine Hallucinogen and 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT2A knockout mice, indicating the effect is a consequence of 5-HT2A receptor activation. Here, we tested a series of phenylalkylamine Hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-Hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1–10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine Hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and Hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT2A activation and Hallucinogenesis.
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behavioral characterization of alpha ethyltryptamine a tryptamine derivative with mdma like properties in rats
Psychopharmacology, 1993Co-Authors: Kirsten M Krebs, Mark A GeyerAbstract:Several reports have speculated that the tryptamine-derived drug alpha-ethyltryptamine (AET) may have effects similar to those of the amphetamine-derived drug 3,4-methylenedioxymethamphetamine (MDMA). Indeed, the US Drug Enforcement Administration has recently placed AET on the Schedule I list because of its putative similarity to MDMA. The Behavioral Pattern Monitor, which quantifies locomotor and investigatory responses of rats, was used to characterize the effects of AET in a paradigm that distinguishes between the effects of traditional Hallucinogens, amphetamine-like stimulants, and MDMA-like drugs. First, a dose-response study revealed that all doses of AET tested (5, 10, 20 mg/kg) significantly increased locomotor activity. Locomotor hyperactivity is produced by MDMA or amphetamine-like stimulants, but not by classical Hallucinogens, such as LSD or mescaline. Additionally, AET significantly decreased measures of investigatory behavior. Similar decreases occur with MDMA or Hallucinogen administration, but not with amphetamine-like stimulant administration. Second, as with MDMA, the locomotor hyperactivity induced by AET was attenuated by pretreatment (10 mg/kg) with the serotonin reuptake inhibitor fluoxetine. Thus, AET, a tryptamine-derived drug, appears to produce an MDMA-like profile of behavioral changes by virtue of releasing presynaptic serotonin.
Pau Celada - One of the best experts on this subject based on the ideXlab platform.
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The serotonin Hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors.
Neuropharmacology, 2017Co-Authors: Maurizio Riga, Laia Lladó-pelfort, Francesc Artigas, Pau CeladaAbstract:5-MeO-DMT is a natural Hallucinogen acting as serotonin 5-HT1A/5-HT2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin Hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5-MeO-DMT alters cortical activity via 5-HT1A and 5-HT2A receptors. Here, we examined 5-MeO-DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely-moving wild-type (WT) and 5-HT2A-R knockout (KO2A) mice. We performed local field potential multi-recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5-MeO-DMT effects by the 5-HT1A-R antagonist WAY-100635. 5-MeO-DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5-MeO-DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5-MeO-DMT effects on oscillatory activity. The present results indicate that hallucinatory activity of 5-MeO-DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY-100635 in KO2A mice supports the potential usefulness of 5-HT1A receptor antagonists to treat visual hallucinations. 5-MeO-DMT effects on PFC theta activity and cortico-thalamic coherence may be related to its antidepressant activity. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
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the serotonergic Hallucinogen 5 methoxy n n dimethyltryptamine disrupts cortical activity in a regionally selective manner via 5 ht1a and 5 ht2a receptors
Neuropharmacology, 2016Co-Authors: Maurizio Riga, Francesc Artigas, Pau Celada, Analia Bortolozzi, Letizia CampaAbstract:5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural Hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic Hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the Hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development.
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disruption of thalamocortical activity in schizophrenia models relevance to antipsychotic drug action
The International Journal of Neuropsychopharmacology, 2013Co-Authors: Pau Celada, Maurizio Riga, Laia Lladopelfort, Noemi Santana, Lucila Kargieman, Eva Troyanorodriguez, Francesc ArtigasAbstract:Non-competitive NMDA receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to evoke the symptoms of the illness. Likewise, serotonergic Hallucinogens, acting on 5-HT2A receptors, induce perceptual and behavioural alterations possibly related to psychotic symptoms. The neurobiological basis of these alterations is not fully elucidated. Data obtained in recent years revealed that the NMDA receptor antagonist phencyclidine (PCP) and the serotonergic Hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane; DOI) produce a series of common actions in rodent prefrontal cortex (PFC) that may underlie psychotomimetic effects. Hence, both agents markedly disrupt PFC function by altering pyramidal neuron discharge (with an overall increase) and reducing the power of low frequency cortical oscillations (LFCO; <4 Hz). In parallel, PCP increased c-fos expression in excitatory neurons of various cortical areas, the thalamus and other subcortical structures, such as the amygdala. Electrophysiological studies revealed that PCP altered similarly the function of the centromedial and mediodorsal nuclei of the thalamus, reciprocally connected with PFC, suggesting that its psychotomimetic properties are mediated by an alteration of thalamocortical activity (the effect of DOI was not examined in the thalamus). Interestingly, the observed effects were prevented or reversed by the antipsychotic drugs clozapine and haloperidol, supporting that the disruption of PFC activity is intimately related to the psychotomimetic activity of these agents. Overall, the present experimental model can be successfully used to elucidate the neurobiological basis of schizophrenia symptoms and to examine the potential antipsychotic activity of new drugs in development.
John A Harvey - One of the best experts on this subject based on the ideXlab platform.
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phospholipase c mediates 1 2 5 dimethoxy 4 iodophenyl 2 aminopropane doi but not lysergic acid diethylamide lsd elicited head bobs in rabbit medial prefrontal cortex
Brain Research, 2013Co-Authors: Emmanuelle A D Schindler, John A Harvey, Vincent J AloyoAbstract:The phenethylamine and indoleamine classes of Hallucinogens demonstrate distinct pharmacological properties, although they share a serotonin(2A) (5-HT(2A)) receptor mechanism of action (MOA). The 5-HT(2A) receptor signals through phosphatidylinositol (PI) hydrolysis, which is initiated upon activation of phospholipase C (PLC). The role of PI hydrolysis in the effects of Hallucinogens remains unclear. In order to better understand the role of PI hydrolysis in the MOA of Hallucinogens, the PLC inhibitor, 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U73122), was used to study the effects of two Hallucinogens, the phenethylamine, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and the indoleamine, lysergic acid diethylamide (LSD). PI hydrolysis was quantified through release of [3H]inositol-4-phosphate from living rabbit frontocortical tissue prisms. Head bobs were counted after Hallucinogens were infused into the medial prefrontal cortex (mPFC) of rabbits. Both DOI and LSD stimulated PI hydrolysis in frontocortical tissue through activation of PLC. DOI-stimulated PI hydrolysis was blocked by 5-HT(2A/2C) receptor antagonist, ketanserin, whereas the LSD signal was blocked by 5-HT(2B/2C) receptor antagonist, SB206553. When infused into the mPFC, both DOI- and LSD-elicited head bobs. Pretreatment with U73122 blocked DOI-, but not LSD-elicited head bobs. The two Hallucinogens investigated were distinct in their activation of the PI hydrolysis signaling pathway. The serotonergic receptors involved with DOI and LSD signals in frontocortical tissue were different. Furthermore, PLC activation in mPFC was necessary for DOI-elicited head bobs, whereas LSD-elicited head bobs were independent of this pathway. These novel findings urge closer investigation into the intracellular mechanism of action of these unique compounds.
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serotonergic and dopaminergic distinctions in the behavioral pharmacology of 1 2 5 dimethoxy 4 iodophenyl 2 aminopropane doi and lysergic acid diethylamide lsd
Pharmacology Biochemistry and Behavior, 2012Co-Authors: Emmanuelle A D Schindler, Kuldip D Dave, Elaine M Smolock, Vincent J Aloyo, John A HarveyAbstract:Although the mechanism of action of Hallucinogens is incompletely understood, serotonin (5-HT) and the serotonin2A (5-HT2A) receptor are thought to play a significant role in mediating their effects (Nichols, 2004). There are two major chemical classes fitting this profile—the phenethylamines (e.g. mescaline) and the tryptamines (e.g. lysergic acid diethylamide, psilocybin). Hallucinogens have significant value as pharmacological agents. They have been used to model psychosis and to better understand human cognition and perception (Nichols, 2004). Their role in the discovery of the serotonergic system has also proven invaluable (Nichols, 2004; Passie et al., 2008). These compounds have also demonstrated clinical utility in pain, drug addiction, headache, depression, and anxiety disorders (Griffiths et al., 2006; Griffiths et al., 2008; Grob et al., 2011; Kast and Collins, 1964; Mangini, 1998; Sewell et al., 2006). While the psychedelic effects of Hallucinogens may be essential for some types of therapy, these and other physiologic side effects may preclude widespread clinical use of these drugs. As opposed to other recreational drugs, however, Hallucinogens are not habit-forming in humans, nor are they reinforcing in animals (Chilcoat and Shurtz, 1996; Passie et al., 2008). Deciphering the mechanisms by which Hallucinogens exert their various effects will significantly benefit areas of basic and clinical science (Vollenweider and Kometer, 2010). Drug-elicited head movement is a widely used behavioral model with which to investigate Hallucinogens and there is a strong correlation between the dose of Hallucinogens used to elicit mouse head twitch behavior and that used recreationally in humans (Corne and Pickering, 1967). Serotonin2A receptors have been implicated in head movements elicited by the phenethylamine Hallucinogen, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; Darmani et al., 1990; Dave et al., 2002; Dave et al., 2007; Schreiber et al., 1995; Willins and Meltzer, 1997), but a role for this receptor in the action of the indoleamine Hallucinogen, lysergic acid diethylamine (LSD), which also elicits head movements, is not as clear. Serotonergic antagonists such as cyproheptadine (Vetulani et al., 1980), methysergide (Yamamoto and Ueki, 1981), and bromo-LSD (Sloviter et al., 1980) block LSD-elicited rodent head movements, but these antagonists are relatively non-selective for the 5-HT2A receptor. The report of the absence of head twitch behavior elicited by LSD in mice lacking 5-HT2A receptors suggests that the 5-HT2A receptor is necessary for LSD mediation of this behavior in this species (Gonzalez-Maeso et al., 2007). The pharmacology that characterizes the head movement response in mice may be more complex than that for other animals, however. For example, 5-HT2C receptors were not implicated in either DOI-elicited head shakes in rat (Schreiber et al., 1995) or head bobs in rabbit (Dave et al., 2002). In contrast, 5-HT2C receptors contributed significantly to DOI-elicited head twitch behavior in mice (Canal et al., 2010). More precisely, Fantegrossi and associates (2010) demonstrated that 5-HT2C receptor antagonism right shifted the descending limb of the DOI dose response curve in mice. These findings support an inhibitory role of 5-HT2C activation at high doses of DOI (Fantegrossi et al., 2010). Further investigation with non-DOI Hallucinogens, such as LSD, may help further explain the contribution of 5-HT2C receptors in Hallucinogen-elicited behavior. Although 5-HT2A receptors are found in many brain regions, direct infusion of the Hallucinogen, DOI, into the frontal cortex of rats (Willins and Meltzer, 1997) or rabbits (Dave et al., 2007) has been shown to elicit head shakes and head bobs, respectively. Previous studies have also demonstrated that repeated systemic administration of DOI or LSD robustly down-regulates frontocortical 5-HT2A receptors in both rats and rabbits (Aloyo et al., 2001; Smith et al., 1999). Thus, the frontocortical area is an appropriate brain region in which to investigate the role of 5-HT2A receptors in mediating the effects of Hallucinogens. The dopaminergic system is believed to play a major role in human psychosis, a condition that Hallucinogens have been shown to mimic (Nichols, 2004). Hallucinogens differ in their dopaminergic pharmacology, however. For example, LSD binds dopamine receptors, but DOI does not (Burt et al., 1976; Watts et al., 1995). Investigating the role of dopaminergic receptors in the animal head movement model would not only improve our understanding of Hallucinogen pharmacology, but might also offer new insight into human psychosis. Presently, dopamine1 (D1) receptor antagonists are known to block DOI-elicited head shakes in rats (Schreiber et al., 1995), but the role of D1 receptors in LSD-elicited head movement behavior has not been studied. The present study compares and contrasts the 5-HT2A and D1 receptor actions of Hallucinogens, represented by two chemical classes, the phenethylamines (DOI) and the indoleamines (LSD). The experiments include receptor binding properties and behavioral actions. The goal of these experiments is to identify the essential pharmacological components shared among Hallucinogenic agents.
