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1.
Molecules ; 28(24)2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-38138432

RESUMEN

Peyote (Lophophora williamsii) is a cactus that contains various biologically active alkaloids-such as pellotine, anhalonidine, hordenine and mescaline. Here, mescaline induces the psychoactive effects of peyote through the activation of the serotonin 5-HT2A receptor and the subsequent release of calcium (Ca2+) from the endoplasmic reticulum (ER). Moreover, an evaluation of the therapeutic benefits of mescaline is also currently the subject of research. It is important to consider that the outcome of taking a psychedelic drug strongly depends on the mindset of the recipient and the context (set and setting principle), including ceremonies and culture. This overview serves to summarise the current state of the knowledge of the metabolism, mechanism of action and clinical application studies of peyote and mescaline. Furthermore, the benefits of the potential of peyote and mescaline are presented in a new light, setting an example for combining a form of treatment embedded in nature and ritually enriched with our current highly innovative Western medicine.


Asunto(s)
Alcaloides , Antineoplásicos , Cactaceae , Alucinógenos , Mescalina/farmacología , Alucinógenos/farmacología
2.
Rev Invest Clin ; 75(3): 169-178, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37441761

RESUMEN

Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT2A) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT2A receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use.


Asunto(s)
Alucinógenos , Ketamina , Humanos , Alucinógenos/farmacología , Alucinógenos/química , Ketamina/farmacología , Serotonina , Mescalina/farmacología , N,N-Dimetiltriptamina
3.
J Nat Prod ; 84(8): 2398-2407, 2021 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-34264089

RESUMEN

Commonly, false peyote refers to Lophophora diffusa. However, several other unrelated cacti go by this colloquial name. They either resemble "true" peyote, Lophophora williamsii, or are found in similar habitats. To date, over 40 different alkaloids have been isolated from the Lophophora genus. Of these, only the pharmacological actions of mescaline (1) have been extensively investigated. The major alkaloid in L. diffusa is pellotine (2), a tetrahydroisoquinoline (THIQ), which was briefly marketed as a sleeping aid around the beginning of the 20th century, following reports of its hypnotic properties in humans. Pharmacological experiments with the Lophophora THIQs were performed at the turn of the 20th century, whereas the chemical synthesis was not realized until several decades later. The biosynthetic pathways of the main Lophophora alkaloids were reported at the end of the 1960s. In this review, the relationship of the different "false peyotes" to L. williamsii, in regard to their alkaloid content, the bio- and chemical synthesis of the most relevant alkaloids, and their corresponding pharmacology will be outlined and discussed.


Asunto(s)
Cactaceae/química , Mescalina/química , Alcaloides/química , Alcaloides/farmacología , Animales , Vías Biosintéticas , Cactaceae/clasificación , Alucinógenos , Humanos , Mescalina/farmacología , Estructura Molecular , Fármacos Inductores del Sueño
4.
Transl Psychiatry ; 14(1): 395, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39349427

RESUMEN

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.


Asunto(s)
Presión Sanguínea , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca , Ketanserina , Mescalina , Humanos , Método Doble Ciego , Femenino , Adulto , Masculino , Frecuencia Cardíaca/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Mescalina/administración & dosificación , Mescalina/farmacología , Mescalina/farmacocinética , Ketanserina/farmacología , Ketanserina/farmacocinética , Alucinógenos/administración & dosificación , Alucinógenos/farmacocinética , Alucinógenos/efectos adversos , Alucinógenos/farmacología , Adulto Joven , Voluntarios Sanos , Antagonistas del Receptor de Serotonina 5-HT2/farmacocinética , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Náusea/inducido químicamente
5.
Neuropsychopharmacology ; 48(11): 1659-1667, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37231080

RESUMEN

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756.


Asunto(s)
Alucinógenos , Psilocibina , Humanos , Psilocibina/farmacología , Mescalina/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Estudios Cruzados , Voluntarios Sanos , Alucinógenos/farmacología
6.
Neuropharmacology ; 222: 109294, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36252614

RESUMEN

INTRODUCTION: Mescaline (3,4,5-trimethoxyphenethylamine) is one of the oldest hallucinogens, with evidence of use dating back 5700 years. Mescaline is a naturally occurring alkaloid found in cacti, mainly in the peyote cactus (Lophophora williamsii) and in the cacti of the Echinopsis genus. Since the prohibition of psychoactive substances in the early 70s, research on mescaline and other classical psychedelics has been limited. OBJECTIVES: This article aims to review the pharmacology and behavioural effects of mescaline, focusing on preclinical and clinical research. FINDINGS: Mescaline is a serotonin 5HT2A/2C receptor agonist, with its main hallucinogenic effects being mediated via its 5HT2A receptor agonist action. It also exerts effects via agonist binding at α1A/2A noradrenaline and D1/2/3 dopamine receptors. Overall, mescaline has anxiolytic-like effects in animals and increases prosocial behaviour, locomotion, and response reactivity. In humans, mescaline can induce euphoria, hallucinations, improvements in well-being and mental health conditions, and psychotomimetic effects in a naturalistic or religious setting. CONCLUSION: The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, like psilocybin and lysergic acid diethylamide (LSD). Mescaline appears to be safe to consume, with most intoxications being mild and easily treatable. Improvement in mental well-being and its ability to overcome alcoholism render mescaline potentially beneficial in clinical settings. This article is part of the Special Issue on 'Psilocybin Research'.


Asunto(s)
Alucinógenos , Mescalina , Animales , Humanos , Mescalina/farmacología , Alucinógenos/farmacología , Psilocibina/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Trastornos de la Memoria
7.
Naunyn Schmiedebergs Arch Pharmacol ; 396(2): 275-287, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36319858

RESUMEN

The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1-3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium.


Asunto(s)
Fibrilación Atrial , Alucinógenos , N-Metil-3,4-metilenodioxianfetamina , Humanos , Ratones , Animales , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Mescalina/farmacología , Alucinógenos/toxicidad , Efedrina/farmacología , Fenilpropanolamina/farmacología , Atrios Cardíacos , Contracción Miocárdica
8.
Science ; 212(4498): 1051-2, 1981 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-7195070

RESUMEN

Phencyclidine (PCP), lysergic acid diethylamide (LSD), and mescaline produced potent contractile responses on isolated basilar and middle cerebral arteries, where, in terms of potency, LSD greater than mescaline greater than PCP. All three drugs produced cerebrovasospasm in a concentration range which parallels that needed for their psychotomimetic and intoxicating actions. Specific receptors for PCP, which subserve contraction and differ from those for LSD and mescaline, are found in cerebral arteries. Concentrations of PCP that produced near-maximum contractile responses on cerebral arteries were similar to those in the blood and brain of human subjects who had died from PCP overdoses. A specific calcium antagonist, verapamil, readily prevented (and reversed) PCP-induced vasospasm. This study provides direct evidence for PCP receptors in cerebral blood vessels, the biologic action of which can be reversed by a calcium antagonist; the clinical use of the latter could prove invaluable in treating PCP-intoxicated victims.


Asunto(s)
Arterias Cerebrales/fisiología , Alucinaciones/fisiopatología , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Contracción Muscular/efectos de los fármacos , Fenciclidina/farmacología , Animales , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/fisiopatología , Perros , Femenino , Humanos , Masculino
9.
Science ; 192(4241): 801-3, 1976 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-1063447

RESUMEN

At a dose as low as 1 microgram per kilogram of body weight, lysergic acid diethylamide (LSD) significantly decreased the suppressive effect of electric shock on licking behavior of the rat. Attenuation of punishment was also obtained with mescaline, but neither dimethyltryptamine nor delta9-tetrahydrocannabinol was active in this test. Cyproheptadine and alpha-propyldopacetamide, drugs that interfere with the function of neurons that contain serotonin, have a behavioral effect similar to that of LSD and mescaline, which suggests that the attenuation of punishment produced by these hallucinogens may result from decreased activity of such neurons.


Asunto(s)
Conducta Animal/efectos de los fármacos , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Castigo , Amidas/farmacología , Animales , Conducta Animal/fisiología , Tronco Encefálico/efectos de los fármacos , Clomipramina/farmacología , Ciproheptadina/farmacología , Dronabinol/farmacología , Electrochoque , Masculino , N,N-Dimetiltriptamina/farmacología , Neuronas/efectos de los fármacos , Ratas , Receptores de Droga/efectos de los fármacos , Serotonina/fisiología
10.
Science ; 158(3801): 669-70, 1967 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-4860952

RESUMEN

We have assessed the effects in normal control volunteers of 2,5-dimethoxy-4-methyl-amphetamine, the chemical present in the hallucinogenic drug STP, in two independent trials. In low doses, this compound produces a mild euphoria. Doses greater than 3 milligrams may cause pronounced hallucinogenic effects lasting about 8 hours and similar to those produced by hallucinogenic doses of lysergic acid diethylamide, mescaline, and psilocybin. 2,5-Dimethoxy-4-methyl-amphetamine, which is chemically related to mescaline and amphetamine, is about 100 times more potent as a hallucinogen than mescaline and only one-thirtieth as potent as lysergic acid diethylamide. Its psychological effects are not accentuated by chlorpromazine.


Asunto(s)
Anfetamina/farmacología , Catecolaminas/farmacología , Alucinógenos/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Clorpromazina/farmacología , Ensayos Clínicos como Asunto , Euforia/inducido químicamente , Alucinaciones/inducido químicamente , Alucinógenos/administración & dosificación , Humanos , Dietilamida del Ácido Lisérgico/farmacología , Masculino , Mescalina/farmacología , Percepción/efectos de los fármacos , Psilocibina/farmacología , Psicofarmacología , Pupila/efectos de los fármacos
11.
Curr Mol Pharmacol ; 12(3): 184-194, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30318013

RESUMEN

BACKGROUND: Mescaline (3,4,5-trimethoxyphenethylamine), mainly found in the Peyote cactus (Lophophora williamsii), is one of the oldest known hallucinogenic agents that influence human and animal behavior, but its psychoactive mechanisms remain poorly understood. OBJECTIVES: This article aims to fully review pharmacokinetics and pharmacodynamics of mescaline, focusing on the in vivo and in vitro metabolic profile of the drug and its implications for the variability of response. METHODS: Mescaline pharmacokinetic and pharmacodynamic aspects were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Biological effects of other compounds found in peyote were also reviewed. RESULTS: Although its illicit administration is less common, in comparison with cocaine and Cannabis, it has been extensively described in adolescents and young adults, and licit consumption often occurs in religious and therapeutic rituals practiced by the Native American Church. Its pharmacodynamic mechanisms of action are primarily attributed to the interaction with the serotonergic 5-HT2A-C receptors, and therefore clinical effects are similar to those elicited by other psychoactive substances, such as lysergic acid diethylamide (LSD) and psilocybin, which include euphoria, hallucinations, depersonalization and psychoses. Moreover, as a phenethylamine derivative, signs and symptoms are consistent with a sympathomimetic effect. Mescaline is mainly metabolized into trimethoxyphenylacetic acid by oxidative deamination but several minor metabolites with possible clinical and forensic repercussions have also been reported. CONCLUSION: Most reports concerning mescaline were presented in a complete absence of exposure confirmation, since toxicological analysis is not widely available. Addiction and dependence are practically absent and it is clear that most intoxications appear to be mild and are unlikely to produce lifethreatening symptoms, which favors the contemporary interest in the therapeutic potential of the drugs of the class.


Asunto(s)
Alucinógenos/farmacocinética , Mescalina/farmacocinética , Animales , Cactaceae/química , Medicina Legal , Alucinógenos/metabolismo , Alucinógenos/farmacología , Alucinógenos/toxicidad , Humanos , Absorción Intestinal , Mescalina/metabolismo , Mescalina/farmacología , Mescalina/toxicidad , Distribución Tisular
12.
J Psychopharmacol ; 33(3): 406-414, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30789291

RESUMEN

BACKGROUND: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models. METHODS: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine). RESULTS: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2. CONCLUSIONS: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.


Asunto(s)
Conducta Animal/efectos de los fármacos , Alucinógenos/farmacología , Mescalina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Alucinógenos/química , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Mescalina/análogos & derivados , Mescalina/química , Ratones , Ratones Endogámicos C57BL , Agonistas de Receptores de Serotonina/química , Relación Estructura-Actividad
13.
ACS Chem Neurosci ; 9(10): 2448-2458, 2018 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-29847089

RESUMEN

Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti "diabolic", leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or "mescal buttons" was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2A serotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.


Asunto(s)
Alucinógenos/química , Alucinógenos/farmacología , Mescalina/química , Mescalina/farmacología , Alucinógenos/historia , Alucinógenos/uso terapéutico , Historia del Siglo XVI , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Historia Antigua , Humanos , Mescalina/historia , Mescalina/uso terapéutico , Relación Estructura-Actividad
15.
J Med Chem ; 49(14): 4269-74, 2006 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-16821786

RESUMEN

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor.


Asunto(s)
Alucinógenos/síntesis química , Indanos/síntesis química , Mescalina/análogos & derivados , Mescalina/síntesis química , Metilaminas/síntesis química , Receptor de Serotonina 5-HT2A/química , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Sitios de Unión , Células Cultivadas , Simulación por Computador , Cristalografía por Rayos X , Aprendizaje Discriminativo/efectos de los fármacos , Alucinógenos/farmacología , Indanos/farmacología , Fosfatos de Inositol/biosíntesis , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Metilaminas/farmacología , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Homología de Secuencia de Aminoácido , Estereoisomerismo , Relación Estructura-Actividad
17.
Neurosci Biobehav Rev ; 6(4): 521-7, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-6817241

RESUMEN

Indole and phenethylamine-type hallucinogenic drugs were studied in an FR-40 operant behavioral procedure programmed to quantify "pausing,"-a behavioral disruption somewhat specific to hallucinatory drug effects. LSD, DOM, DMT and mescaline showed a potency ratio to produce pausing that is well correlated with the hallucinatory potencies of these agents in man. Furthermore, combinations of the hallucinogens interact with potentiation to cause FR-40 pausing, whereas a variety of non-hallucinogenic psychoactive drugs failed to shift the dose-response patterns of pausing for DOM or LSD. Depletion of brain catecholamines by pretreatment with intraventricular 6-OHDA reduced baseline FR-40 rates and attenuated the disruptive effects of d-amphetamine, but failed to modify the dose-response patterns of indole and phenethylamine hallucinogens. On the other hand, pretreatment with intraventricular 5,7-DHT to deplete brain 5-HT potentiated the pause-producing effects of the hallucinogens, although the disruptive effects of phenobarbital were not altered by this pretreatment. Injection of 5,7-DHT into the medial forebrain bundle at the hypothalamic level slightly potentiated LSD, attenuated DOM, and did not affect the pausing produced by mescaline. Metergoline pretreatment shifted the LSD and DMT dose-response curves for pausing to the right by a factor of 2--3, but shifted the DOM and mescaline dose-response patterns to a much greater extent. Metergoline alone slightly increased FR-40 response rates and decreased pausing from baseline levels. The patterns of imparied FR-40 performance induced by d-amphetamine and phenobarbital were unaltered by pretreatment with metergoline. The indole and phenethylamine classes of hallucinogens appear to disrupt this behavior by an agonistic effect at central 5-HT receptors. However, the two classes of drugs may interact with brain 5-HT systems by somewhat different mechanisms.


Asunto(s)
Encéfalo/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Alucinógenos/farmacología , Serotonina/fisiología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Condicionamiento Operante/fisiología , Relación Dosis-Respuesta a Droga , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Metergolina/farmacología , N,N-Dimetiltriptamina/farmacología , Ratas , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Esquema de Refuerzo
18.
Neurosci Biobehav Rev ; 6(4): 509-14, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-7177511

RESUMEN

Low intravenous doses of the hallucinogen d-lysergic acid diethylamide (LSD) markedly suppress the discharge of serotonin (5-HT)-containing neurons in the dorsal raphe nucleus of the rat. Microiontophoretically applied LSD also inhibits the firing of 5-HT neurons, indicating that the inhibitory effect is mediated directing on 5-HT neurons. Forebrain neurons receiving a major serotonergic input are relatively insensitive to LSD. Other indole hallucinogens (i.e., psilocin, dimethyltryptamine, and 5-methoxydimethyltryptamine) also preferentially inhibit raphe firing as compared to postsynaptic forebrain neurons. These observations led to the hypothesis that hallucinogens produce their psychoactive effects by acting preferentially upon 5-HT autoreceptors in the dorsal raphe allowing postsynaptic neurons to escape from the tonic inhibitory action of 5-HT neurons. However, problems exist with the concept that hallucinogens produce their psychoactive effects by disinhibiting postsynaptic neurons. First, the time course of the behavioral and neuronal effects of LSD do not correlate. Second, 5-HT neurons do not become tolerant to the inhibitory actions of LSD. Third, the hallucinogen mescaline fails to directly inhibit 5-HT neurons. Finally, the nonhallucinogen lisuride markedly suppresses the discharges of 5-HT neurons. These observations suggest that postsynaptic actions of hallucinogens may be of prime importance in producing their psychedelic effects. Evidence is presented to suggest that the hallucinogens may act postsynaptically to sensitize both serotonergic and noradrenergic receptors. It is suggested that a mechanism of receptor sensitization, in distinction to disinhibition, might account for the altered perceptual reactivity produced by these drugs.


Asunto(s)
Alucinógenos/farmacología , Neuronas/efectos de los fármacos , Serotonina/fisiología , Animales , Encéfalo/metabolismo , Gatos , Relación Dosis-Respuesta a Droga , Cuerpos Geniculados/efectos de los fármacos , Cuerpos Geniculados/fisiología , Lisurida/farmacología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Norepinefrina/fisiología , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/fisiología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Serotonina/metabolismo
19.
Biol Psychiatry ; 10(5): 561-73, 1975 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-241433

RESUMEN

Mescaline (25 mg/kg; 66 muc/kg) was injected (ip) in mice 45 min before chlorpromazine (CPZ, 2.5, 5, 15 mg/kg), thioridazine (10, 30, 45 mg/kg), or chlorpromazine-sulfoxide (CPZ-SO, 15 mg/kg). Excitement, agitation, slight increase in ventilation and occasional head-shaking were seen 30 min after mescaline and continued for 30-45 min thereafter; locomotor activity and the number of scratching events were significantly increased during this period. CPZ (2.5, 5, 15 mg/kg) and thioridazine (10, 30, 45 mg/kg) partially or completely blocked mescaline-induced gross behavior; CPZ-SO (15 mg/kg) was not effective. Increased scratching responses and locomotor activity induced by mescaline were antagonized by all doses of CPZ and thioridazine; at higher doses, both CPZ (7.5, 15 mg/kg) and thioridazine (45 mg/kg) induced cataleptic-like condition and marked hypothermia. Tissue levels of mescaline, examined 3 hr after its administration, were increased by all doses of CPZ and a higher dose of thioridazine (45 mg/kg); CPZ-SO and lower doses of thioridazine had no effect.


Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Mescalina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Antagonismo de Drogas , Interacciones Farmacológicas , Mescalina/metabolismo , Ratones , Actividad Motora/efectos de los fármacos , Fenotiazinas
20.
Biol Psychiatry ; 15(1): 95-102, 1980 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7357060

RESUMEN

Male hooded rats were observed for 6 days following implantation with slow-release subcutaneous pellets containing LSD, mescaline, or control vehicle solution. In animals housed in isolation cages, continuous hallucinogen administration resulted in a gradual increase in head twitches and catatonic postures which peaked 3--4 days after pellet implantation and then declined. In animals housed in social colonies, there were also delayed increases in behavior following hallucinogen-pellet implantation, but these principally involved social behaviors such as fighting by mescaline-treated animals and social grooming by LSD-treated animals. This finding of gradual and cumulative effects of continuous hallucinogen administration contrasts with the usual finding of a rapid tolerance to hallucinogens following repeated injections.


Asunto(s)
Conducta Animal/efectos de los fármacos , Dietilamida del Ácido Lisérgico/farmacología , Mescalina/farmacología , Animales , Preparaciones de Acción Retardada , Tolerancia a Medicamentos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Aislamiento Social
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