Detection of biochemical intermediates by mass fragmentography: Mescaline and tetrahydroisoquinoline precursors.
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Journal Article↗
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Mescaline-spikes and amino acids in the cortex of cats pretreated with caffeine and pentetrazol.
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Amino Acids↗
[Vegetative and humoral modifications caused by mescalinic shock].
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Autonomic Nervous System↗
Behavioural effects of N-(3,4,5-trimethoxyphenylethyl)aziridine--a mescaline derivative.
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Animals↗
Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline.
The stimulus properties of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and several related compounds were compared to those of (+)-lysergic acid diethylamide (LSD) and mescaline (3,4,5-trimethoxyphenylethylamine) in a two-lever, water-reinforced, drug discrimination task. In animals trained to discriminate LSD (0.08 mg/kg) from saline (n = 8), LSD-like responding occurred during substitution (generalization) tests with sufficiently high doses of (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline, psilocybin and (-)-MDA; saline appropriate responding occurred after (+)-MDA and both (+)- and (+)- and (-)-MDMA. In animals trained to discriminate mescaline (10 mg/kg; n = 8), (-)-MDA, (+)-MDA, (-)-MDMA and (+)-MDMA as well as (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline and psilocybin mimicked the training drug. Neither (+)-amphetamine nor cocaine produced mescaline-like responding; fenfluramine substituted partially for mescaline but not LSD. Because all of the phenylisopropylamine enantiomers mimicked the potent hallucinogen mescaline (10 mg/kg), these results do not support suggestions that similarities in the behavioral effects of "designer" drugs such as MDA and MDMA to those of hallucinogens are limited to (-)-MDA. They also indicate that, although LSD and mescaline may be pharmacologically similar (in other assays), these compounds do not have identical stimulus properties.
3,4-Methylenedioxyamphetamine↗
Autoradiographic studies on the distribution of 3H-2,3,4-trimethoxy-beta-phenylethylamine in the mouse.
The regional distribution of radioactivity was studied in the brain and in other organs of the mouse by light microscopic autoradiography after injection of 3H-2,3,4-trimethoxy-beta-phenylethylamine (2,3,4,-TMPEA), a nonhallucinogenic isomer of mescaline. The distribution patterns were compared with biochemical and autoradiographic results obtained after 3H-mescaline. Although 2,3,4-TMPEA is rapidly deaminated compared to mescaline its distribution pattern in the brain is similar to that of mescaline at 1 h after injection. However, contrary to mescaline the radioactive labeling becomes more and more homogenously distributed in the brain with tiem. The distribution patterns in kidney, pancreas, adrenal, and spinal ganglia were also different from those observed after application of 3H-mescaline.
Animals↗
Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain: regional differences.
The influence of D-lysergic acid diethylamide (LSD) and mescaline on adenylate cyclase activity was studied in homogenates of Cebus and rhesus monkey anterior limbic cortex (ALC), frontal cortex (FC), caudate nucleus and retina. Previous studies have shown these tissues to contain dopamine-stimulated adenylate cyclase (AC). In addition, we are now reporting the presence of a dopamine-sensitive adenylate cyclase in the auditory cortex. AC of ALC and auditory cortex was stimulated by LSD and mescaline, whereas activity of FC, caudate nucleus and retina was not stimulated by the same agents. In contrast to regional specificity for stimulation, LSD was capable of antagonizing dopamine-stimulated activity in all brain regions examined. LSD and mescaline produced similar maximal stimulation (about 70%) of AC of ALC homogenates, but the EC50 for LSD (0.43 micrometer) was about one-tenth that for mescaline (4.5 micrometer). Similar relative potencies were also observed for the auditory cortex enzyme. Although much weaker than LSD, methamphetamine also produced a dose-dependent stimulation of ALC AC. Both agonist and antagonist effects of the hallucinogens appear to involve interaction with dopamine receptors; LSD- or methamphetamine-stimulated activity in ALC was blocked by haloperidol and fluphenazine, which are dopamine antagonists, but not by phentolamine, an alpha-receptor blocker. Antagonism of dopamine by LSD in both ALC and FC was found to be competitive and mescaline was an effective but weaker antagonist than was LSD. In addition, neither histamine--nor Gpp(NH)p--stimulated activity of FC was inhibited by LSD. It is proposed that the occurrence of dopamine agonistic action of hallucinogens in only certain regions of primate brain may provide a basis for at least some of the behavioral effects of LSD, mescaline and methamphetamine in primates.
Adenylyl Cyclases↗
Effect of benzodiazepines on central serotonergic neuron systems.
Intracerebral (i.c.) injection of serotonin (5-HT) into mice induced head twitches in a dose-dependent manner at 10 min after injection. The head twitches induced by 5-HT (i.c.) were potentiated by the pretreatment of isocarboxazid (3 mg/kg i.p.), and inhibited by cyproheptadine (0.3 mg/kg i.p.), a 5-HT antagonist. Benzodiazepines such as fludiazepam and diazepam potentiated the head twitches induced by 5-HT (i.c.) in a dose-dependent manner. Mescaline (50 mg/kg i.p.) also induced head twitches in mice at 15 and 30 min after injection. Benzodiazepines potentiated the head twitches induced by mescaline in a dose-dependent manner. Cyproheptadine blocked the potentiating effect of benzodiazepines on the head twitches induced by both 5-HT (i.c.) and mescaline. By repeated administration of fludiazepam or diazepam for 5 days, the potentiating effect of both drugs on the head twitches induced by mescaline was unchanged and their anticonvulsant effects were not modified. In contrast, the potency of both drugs on muscle relaxation was significantly decreased by repeated administration. Benzodiazepines failed to change the uptake of 5-HT into the synaptosomal fractions from the rat brain. These results suggest that the pharmacological action of benzodiazepines is derived at least in part from their activating effect on 5-HT receptors.
Animals↗
Differences in the stimulus properties of barbital and hallucinogens.
The present investigation sought to determine whether drugs which produce markedly different perceptual effects in man, barbital and mescaline or LSD produce different stimuli in rats. In a standard 2 lever operant test chamber, rats received sweetened milk for correct responses according to a variable interval schedule. All sessions were preceded by 1 of 2 treatments; following Treatment A, only responses on Lever A were reinforced and, in a similar fashion, Lever B was correct following Treatment B. No responses were reinforced during the first 5 min of a daily 30 min session. It was found that barbital can serve as a discriminative stimulus when this drug is paired with saline. Previously, we had demonstrated that mescaline or LSD can serve as discriminative stimuli. When barbital was administered to animals trained to discriminate mescaline or LSD and saline, they made either random responses or responses appropriate to saline treatment. This observation suggests that the stimulus properties of barbital are difference from those of the hallucinogens. A subsequent demonstration of discriminated responding when barbital and mescaline or LSD were paired as discriminative stimuli supports this conclusion. The present results extend previous findings which suggest that the degree of similarity or difference of drug stimuli in rats is congruent with the degree of similarity or difference of perceptual drug effects in man.
Animals↗
Assessment of the MDA and MDMA optical isomers in a stimulant-hallucinogen discrimination.
The phenylisopropylamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) have been compared to both psychostimulants and hallucinogens in drug discrimination investigations. The stereoisomers of these compounds, in particular those of MDA, appear to produce differential effects. Previous studies have demonstrated that animals trained to discriminate amphetamine from vehicle generalize to the S(+)-isomers but not the R(-)-isomers of MDA and MDMA while animals trained to discriminate LSD from saline generalize to R(-)-MDA and neither isomer of MDMA. However, animals trained to discriminate mescaline from vehicle generalize to both stereoisomers of these phenylisopropylamine derivatives. The present study consisted of two experiments in which a three-choice drug discrimination procedure was employed to compare the stereoisomers of MDA and MDMA to both amphetamine and either mescaline (experiment one) or LSD (experiment two). Sixteen male Sprague-Dawley rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and mescaline (12.5 mg/kg) and eight rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and LSD (0.08 mg/kg) from saline in three-choice, food reinforced drug discrimination procedures. Substitution tests were administered with the isomers of MDA and MDMA. In the second experiment, substitution tests were also administered with lower doses of each training compound and with the stimulant cocaine and the hallucinogen 2,5-dimethoxy-4-methylphenylisopropylamine (DOM). In both experiments, all of the isomers produced very few responses on the S(+)-amphetamine lever. In the first experiment, R(-)-MDA and R(-)-MDMA produced nearly complete substitution for mescaline. The results of the second experiment revealed partial substitution for LSD with both isomers of MDMA and S(+)-MDA, and nearly complete substitution with R(-)MDA for LSD. The present findings do not support previous reports that S(+)-MDMA and S(+)-MDMA substitute for S(+)-amphetamine. The three-lever drug discrimination procedure may provide a more sensitive behavioral assay in which to examine the discriminative stimulus effects of drugs with compound stimulus properties.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rats and mice.
The characteristics of the behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM or STP) were compared with those of mescaline and methamphetamine in rats and mice. DOM significantly increased locomotor activity in an open-field situation at 0.5-1.0 mg/kg i.p., but at doses above 5 mg/kg i.p. caused biphasic changes, i.e. an initial decrease followed by an increase in motility and exploratory behavior. This hyperactivity was not accompanied by simultaneous increase in rearing. Besides, DOM induced head twitches in rats as well as in mice at doses above 0.1 mg/kg i.p., and marked backward locomotion only in rats at doses larger than 5 mg/kg i.p. The occurrence of backward locomotion might be attributable to the initial decrease in general activity. Behavioral effects of DOM were different from those of either mescaline or methamphetamine although they resembled those of mescaline in some respects.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Neurotransmitter basis of the behavioral effects of hallucinogens.
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.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Therapeutic usefulness of hallucinogenic drugs as a function of their chemical structure.
D-lysergic acid diethylamide (LSD) displays (1) the phenylethylamine pattern present in mescaline, cyclazocine and catecholamines and (2) the 4-substituted tryptamine structure of psilocybin which is a serotonin analog. Hence (a) Naloxone--a blocker of the LSD-like side effects of cyclazocine--should (and does) block effects of LSD, and (b) cross-tolerance may be present between LSD and cyclazocine but not between mescaline and psilocybin. Even though LSD binds subcortically, its effect on regional perfusion of the brain and, presumably, function is primarily cortical and, since the perfusion shifts evoked by psilocybin are confined to subcortical regions, we assume that other compounds with the phenylethylamine structure such as mescaline, also may selectively affect cortical activity.
Binding Sites↗
2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug.
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.
Adult↗
Studies on the mechanisms of learning. IV. Ontogeny of calcium channels in the rat's cortex.
The sensitivity of some electrocortical potentials of rats to topically applied tetrodotoxin (TTX), manganese, lanthanum, calcium, mescaline and strychnine was followed from the age of 6 to 20 days and compared with that of adult animals. Sensitivity to TTX was relatively greater in the younger rats. In contrast, the blocking effect of Mn2+ or La3+ was small initially but increased with age. Similarly, the ability of mescaline or strychnine to give rise to giant spikes (dendritic action potentials) increased with maturation of the brain cortex. Finally, an increase in external calcium concentration depressed cortical potentials in the younger animals and had the usual increase of the mescaline or strychnine spikes in the older rats. It is concluded that the formation of calcium channels in dendritic membranes is part of the maturation process of cortical neurons and possibly related to the learning mechanisms. The depressant action of high external calcium during the first days of life was ascribed to an unspecific reduction in membrane permeability.
Age Factors↗
Synthesis and 5-HT2A radioligand receptor binding assays of DOMCl and DOMOM, two novel 5-HT2A receptor ligands.
A synthesis of two new active substances, DOMCl (1-(4-chloromethyl-2, 5-dimethoxyphenyl)-2-propanamine; 2) and DOMOM (1-(2, 5-dimethoxy-4-methoxymethylphenyl)-2-propanamine; 3), was developed. Unexpectedly, the Blanc reaction permitted successful synthesis of 2, 5-dimethoxyphenylpropylamine derivatives having a substituted methyl group in position 4 since solvation of the reactant occurs during the reaction. Afterwards, their affinities towards the 5-HT(2A) receptor were examined in 5-HT(2A) radioligand receptor binding assays. The study of these substances is of considerable interest because they were predicted, by preliminary molecular modeling studies based on mescalin units, to be potential new hallucinogens that should be added to the list of substances prohibited by law. It was assumed that DOMCl would be 82 times more potent as a hallucinogen than mescalin, and DOMOM would be 94 times more potent. The 5-HT(2A) radioligand receptor binding studies showed that the affinities of DOMCl and DOMOM for the 5-HT(2A) receptor are less than expected but are nevertheless 1.6 and 8.7 times higher, respectively, than that of mescalin. Therefore, scheduling these substances as potential drugs of abuse might be considered.
Animals↗
The behavioral effects of hallucinogens in rats following 5,7-dihydroxytryptamine administration into the medial forebrain bundle.
The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 micrograms/2 microliter) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratio-40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.
5,7-Dihydroxytryptamine↗
[REVIEW OF PSYCHODYSLEPTICS: I. CLASSIFICATION OF PSYCHODYSLEPTICS].
The discovery of new dysleptic drugs has prompted the present review of these substances which influence neuropsychic activity. It is possible to divide dysleptics into two categories: under the first heading fall mescaline, LSD-25, psilocybine, adrenochrome, bufotenine and dimethyltryptamin; the other group includes Ditran, Butoxamine, WH-4849, and AHR-379. The place of Sernyl could not be ascertained and it might well constitute a class by itself. The mescaline type of reaction is mainly characterized by the induction of perceptual distortions without alteration of the state of consciousness, whereas the Ditran type reaction is one of confusion with postexperimental amnesia. Electroencephalographic recordings support this classification: lowering of amplitude, acceleration of rhythm and desynchronization were noted with the first group; and slowing of rhythm and slow waves similar to those seen during the onset of sleep, with the other group.
Adrenochrome↗