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Profile of drug effects on temporally spaced responding in rats.

A differential reinforcement of low rate schedule was used with rats to test 15 psychotropic drugs. The computer analysis was based on interresponse time (IRT). Mean IRT, IRT standard deviation, median IRT, IRT midrange, modal IRT, frequency of modal IRT, and an efficiency index, in addition to numbers of responses and reinforcements and the IRT histogram were obtained for each rat in each drug test. An increase in number of responses and a peak shift to shorter IRTs in the histograms were observed with amphetamine, methamphetamine, priradrol and nicotine, as reported by many other investigators. Decrease in IRT midrange and less change in number of responses were observed with diazepam and chlordiazepoxide. Long pauses were found with LSD-25, 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. In a factor analysis, the following main factors were obtained. High values in factor loading a1 were observed with chlorpromazine, chlordiazepoxide, pentobarbital, imipramine, nialamide, LSD-25, DOM and mescaline. With these drugs, mean IRT and IRT standard deviation were also high. Values for a2, were high with amphetamine, methamphetamine, pipradrol and nicotine. High a3 values were observed in some rats with chlorpromazine, diazepam, chlordiazepoxide, pentobarbital, pipradrol and caffeine. The changes in a3 values were correlated with changes in the IRT midrange. These results may be valuable in classifying new compounds in drug screening programs as being of the amphetamine type, nicotine type, diazepam type of LSD-25 type.

Animals↗

Central 5-hydroxytryptamine and the effects of hallucinogens and phenobarbital on operant responding in rats.

The present study was designed to examine the role of 5-hydroxytryptamine (5-HT) neurons in the behavioral effects of d-lysergic acid diethylamide (LSD), an indolealkylamine hallucinogen, 2.5-dimethoxy-4-methylamphetamine (DOM) and mescaline, phenethylamine hallucinogens, and phenobarbital, a non-hallucinogen. Male rats, maintained at 70-80% of their free-feeding weights, were trained to press a lever for food pellet reinforcement on a fixed ratio-40 operant schedule. When trained, these rats responded at a constant, rapid rate (approximately 100 responses/min) during daily 40 min test sessions. Administration of hallucinogens caused an abrupt cessation of responding (a "pause"), for some portion of the session. The duration of this pause was dose-dependent for LSD (12.5-100 micrograms/kg), DOM (0.125-1.0 mg/kg) and mescaline (7.1-14.2 mg/kg). On the other hand, phenobarbital (12.5-50 mg/kg) did not cause pausing, but resulted in slowed, erratic intrasession response rates. When the same tests were repeated in rats that had previously received an intracerebroventricular injection of 5,7-dihydroxyptamine (5,7-DHT) the dose-response curves for the pausing induced by all three hallucinogens were shifted to the left, while the behavioral disruption produced by phenobarbital was unaltered. In these animals the 5-HT but not the norepinephrine concentrations was markedly reduced in all brain regions examined. These results suggest that 5-HT neurons are involved with the behavioral effects of hallucinogens but not of phenobarbital.

5,7-Dihydroxytryptamine↗

Relationship of CNS tryptaminergic processes and the action of LSD-like hallucinogens.

Tryptamine produces pharmacologic effects in man and the chronic spinal dog which are similar to those produced by LSD, mescaline, psilocin, DMT, DOM and DOB. These effects include tachycardia, tachypnea, mydriasis, hyperreflexia, behavioral changes and in man, hallucinations. Chronic spinal dogs treated chronically with LSD became tolerant to its ability to produce mydriasis, tachycardia, tachypnea and hyperreflexia, and were cross tolerant to the ability of tryptamine, psilocin, mescaline, DMT, DOM and DOB to produce these same effects. Further, it was found that the brain and spinal cord contained tryptamine and could release it. Further tryptamine levels were higher in the brainstem and spinal cord above the level of transection in the chronic spinal dog that in intact dogs, and the same in the spinal cord below the level of transection. These observations suggested that there were both ascending and descending tryptaminergic pathways. Supporting this hypothesis were the observations that L-tryptophan also produced hyperreflexia in the acute, but not the chronic, spinal dog and cat, and that L-tryptophan hyperreflexia was antagonized by alpha-methyldopa but not pCPA. These observations and others argue that the spinal cord and brain have tryptaminergic mechanisms which are distinct from serotoninergic mechanisms, and that LSD-like hallucinogens act in part through a tryptaminergic mechanism.

5-Hydroxytryptophan↗

Involvement of the central serotoninergic system in the changes of leu-enkephalin level in discrete rat brain areas.

The effects of acute and chronic treatment with LSD and acute treatment with mescaline, m-CPP, citalopram and fenfluramine on leu-enkephalin (LENK) content in rat brain were examined. The acute LSD treatment was found to decrease and chronic treatment to increase the LENK content in the frontal cortex. In the thalamus with hypothalamus the LENK level fell after the administration of LSD, mescaline, citalopram and fenfluramine, while in the striatum it increased significantly, except for fenfluramine treatment. Methergoline and methiothepin prevented the effects of acute and chronic LSD administration. The diminished LENK level was associated with a decrease of 5-HT or 5-HIAA content in the rat brain areas investigated. Therefore, it has been concluded that the serotoninergic system may modulate the LENK pathway.

Animals↗

Interaction of tubulin with single ring analogues of colchicine.

Simple analogues of the tropolone and trimethoxyphenyl moieties of colchicine have been used as probes for the colchicine binding site of purified calf brain tubulin. [3H]Tropolone methyl ether was found to bind to one site per tubulin molecule with equilibrium constant of (2.2 +/- 0.2) x 10(3) M-1 at 0 degree C, with the interaction having delta H0app = -8.3 +/- 1.0 kcal mol-1 and delta S0app = -15.2 +/- 3.6 eu. The binding of tropolone methyl ether and colchicine was inhibited by each other. Both tropolone and its methyl ether inhibited tubulin polymerization into microtubules in vitro. N-[3H]Acetylmescaline bound to tubulin with a K congruent to 4 x 10(2) M-1 at 37 degrees C. This interaction was inhibited by colchicine and at lower temperatures was below the sensitivity of the measuring method employed. [14C]Mescaline interacted with higher affinity site(s) not related to the colchicine site. Both mescaline and N-acetylmescaline inhibited partially the microtubule assembly at 10(-3) M concentrations. No linkage was observed between the binding of tropolone methyl ether and N-acetylmescaline. The relatively weak interactions of both the two separate parts of colchicine can account quantitatively for the much tighter binding of the complete drug to tubulin within a proposed model which takes into account the entropic advantage of colchicine as a bifunctional ligand.

Colchicine↗

Discriminative stimulus effects of the optical isomers of 3,4-methylenedioxyamphetamine (MDA).

The isomers of 3,4-methylenedioxyamphetamine (MDA) functioned as discriminative stimuli in rats trained to discriminate either (-) MDA (1.25mg/kg) or (+) MDA (1.25mg/kg) from saline. Dose- and time-response curves indicated that drug lever selection occurred at doses of at least 1.00mg/kg of (-) MDA and 0.75mg/kg of (+) MDA and that drug-appropriate responding for both isomers was maintained for at least 90min. Cross-substitution was observed between the MDA isomers; both (+) and (-) 3,4-methylenedioxymethamphetamine (MDMA) also substituted completely for (+) and (-) MDA. The hallucinogens (+)-lysergic acid diethylamide (LSD) and (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), substituted for (-) MDA; neither mescaline nor (+) amphetamine or cocaine had (-) MDA-like effects. LSD also substituted for (+) MDA; DOM, mescaline, (+) amphetamine and cocaine failed to have (+) MDA-like effects. The (-) but not the (+) MDA cue was blocked by the 5-HT(2) antagonist pirenpirone; the dopamine (DA) antagonists SCH-23390 and (-) sulpiride had no effect on either the (-) or (+) MDA cues. When animals were trained to discriminate LSD (0.16mg/kg) or (+) amphetamine (1.0mg/kg) from saline, neither (-) MDA nor (+) MDA substituted completely. These results indicate that: (1) the stimulus effects of the isomers of MDA and MDMA are similar; (2) (-) MDA may be more hallucinogenic (or more accurately, LSD- or DOM-like) than (+) MDA; (3) neither (+) nor (-) MDA has potent amphetamine-like effects; and (4) the effects of (-) MDA may be more serotonergic than those of (+) MDA.

Journal Article↗

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA).

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.

Journal Article↗

Effects of d-amphetamine, monomethoxyamphetamines and hallucinogens on schedule-controlled behavior.

The effects of 16 drugs were studied in rats responding under fixed-ratio (FR 30) and fixed-interval (FI 2 minute) schedules of food presentation. The drugs tested included lysergic acid diethylamide (LSD), dimethyltryptamine, mescaline, d-amphetamine and 12 methoxylated amphetamines. All of the drugs decreased the average rates of responding under both schedules, but their potencies varied widely. For example, with LSD, the most potent drug tested, doses of 0.1 to 0.3 mg/kg were sufficient to reduce responding while with dimethyltryptamine and mescaline, doses of 10 to 30 mg/kg were required to clearly reduce responding. For the 12 drugs which are known to produce hallucinogenic effects, their potencies in reducing responding were positively correlated with their reported potencies in producing these subjective effects in humans. Although all of the drugs decreased the average rates of responding, alterations in the patterns of responding under the FR and FI schedules varied among the drugs. Analysis of responding under the FI schedule indicated that d-amphetamine, m-methoxyamphetamine, p-methoxyamphetamine, LSD and 3,4-methylenedioxyamphetamine generally increased the low rates of responding occurring at the beginning of each interval and decreased the high rates of responding occurring later in each interval (rate-dependent effects). The other drugs generally decreased responding throughout the interval. These results are discussed in terms of the known neurochemical effects of these drugs.

Amphetamines↗

[PSYCHODYSLEPTIC DRUGS. II. SOME PROBLEMS RELATED TO THEIR USE].

In the first part of this paper, a classification was proposed which divided dysleptic drugs into two categories. Further evidence in support of this classification is drawn from the variability of the clinical picture in schizophrenics elicited by mescaline or allied substances, whereas dysleptics with potent anticholinergic properties always induce the same symptomatology. If the therapeutic usefulness of LSD-25 for instance still may be argued, dysleptics belonging to the second group seem to have no therapeutic usefulness. The dysleptics of the first group include in their chemical formula an aromatic or an indole nucleus; the second group is characterized by a phenylglycolate group. The classification proposed here may be compared with Henri Ey's ideas: in this Jacksonian perspective, dysleptics like LSD would impair the superior strata of the psycho-organic structure whereas Ditran (in the second group) would act at a lower level.

Cerebral Cortex↗

Sequential patterns of multiple-drug use among high school students.

Only recently have multiple-drug use studies involving more than heroin and marijuana begun to be reported in the literature. Four of these studies have found evidence that multiple-drug use is a progressive phenomenon, although the particular pattern of multiple-drug use reported in different populations varies somewhat. This study examines the patterns of multiple-drug use reported by a random sample of 1,094 high school students living in greater New Haven, Conn in the 1972-1973 academic school year. Scalogram analysis reveals a progressive relationship for nine drugs: alcohol, marijuana, hashish, barbiturates, amphetamines, LSD, mescaline, cocaine, and heroin. Cigarettes and glue were not found to play a part in this pattern. The temporal order in which respondents reported that they had begun using each drug supports the results of scalogram analysis only in part.

Adolescent↗

The role of hallucinogenic drugs and sensory stimuli in Peruvian ritual healing.

On Peru's north coast, curanderos perform night-long curing ceremonies in which the mescaline-bearing cactus San Pedro is used. The concept of autonomic nervous system tuning is presented as the best explanation for the overall physiological effect of the ritual. An assessment of the possible therapeutic impact of this condition is provided. Organic response and symbolic message are seen to resonate in the purificatory connotations of the ritual.

Arousal↗

Following several days of continuous administration d-amphetamine acquires hallucinogenlike properties.

Rats injected with LSD or mescaline show the behavioral syndrome which has been previously reported following injections of hallucinogens in higher mammals: limb flicks and whole body shakes. Although these behaviors are not elicited by acute injections of amphetamine, they are present in rats which have been pretreated for 108 h with a slow-release amphetamine pellet, given a 12 h rest period, and then injected with d-amphetamine. Such pellet-pretreated animals also groom their body surface excessively. We propose that this novel syndrome which follows continuous amphetamine administration can serve as an animal model of the type of amphetamine psychosis that is produced by a similar drug regimen in humans.

Animals↗

Psilocybin as a discriminative stimulus: lack of specificity in an animal behavior model for 'hallucinogens'.

Fifteen rats were trained to discriminate between the tryptamine hallucinogen psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine; 1.0 mg/kg) and saline in a two-lever choice task. Dose-response and time-response curves were obtained. The psilocybin cue generalized to psilocin (the dephosphorylated congener of psilocybin) and to the prototypical indoleamine hallucinogen LSD, but not to the phenylethylamine hallucinogen mescaline. These results indicate that the hallucinogenic effects of these drugs in humans may not be identical with their discriminative stimulus functions in animals, and that these four compounds may not be members of a single drug class. The term 'hallucinogen' may thus be a misnomer in the context of drug discrimination studies in nonhumans.

Animals↗

Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists.

As previously reported, systemic administration of the hallucinogens D-lysergic acid diethylamide (LSD) (5-10 micrograms/kg) and mescaline (2 mg/kg) in the anesthetized rat produced a decrease in spontaneous activity but, paradoxically, facilitated activation of locus coeruleus (LC) neurons by sciatic nerve stimulation. In the present study, the hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) (20-80 micrograms/kg) was found to have similar effects. Systemic administration of the selective 5-HT2 antagonists LY 53857 (0.02-0.8 mg/kg) and ritanserin (0.1-0.3 mg/kg) completely reversed both actions of the hallucinogens on the LC. In contrast, LY 53857 did not reverse the effects of (+)-amphetamine (0.5 mg/kg) on the spontaneous or sensory-evoked activity of the LC. These results suggest that the common actions of indoleamine and phenethylamine hallucinogens displayed in the LC are mediated via 5-HT2 receptors; however, these receptors appear to be located outside the LC itself.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

Disordered recognition and perception of human faces in acute schizophrenia and experimental psychosis.

Three disorders of facial recognition and perception in acute schizophrenia and mescaline-induced psychosis are described and illustrated using original clinical and experimental material: "affective prosopagnosia" or stress-related dysfunctional face recognition; "physiognomization" of the environment or persistent illusions and hallucinations of nonspecific faces; and the "mirror phenomenon" or the experience of inner alienation from one's reflected face, which is perceived as independently alive, sinister, and generally physically distorted. It is proposed that neuropsychology suggests relationships between these phenomena that might otherwise be less apparent. No final neurobiological solution to the problem of dysfunctional facial perception and recognition in psychosis is presented, but various insights and suggestive models from the neurosciences are discussed. Attention is also paid to the conditions under which one might need to combine neuropsychological approaches with hermeneutically oriented analyses.

Acute Disease↗

Transcallosally evoked potentials and the EEG in the decerebrate dog: actions of tryptaminergic, dopaminergic and adrenergic agonists.

The midpontine decerebrate dog, immobilized with gallamine, was used to determine the changes in the transcallosally evoked potential (TEP) produced by intravenous infusions of various drugs. A total of 50 TEPs, recorded from the g. ectolateralis, was computer analyzed before, during and after administration of the drugs. Changes in the TEP were also correlated with changes in the EEG recorded from the g. ectolateralis. The EEG was analyzed by inspection and amplitude integration (electrogenesis). LSD (30 microng/kg) significantly depressed the TEP, and the effect persisted for at least 80 min. DMT (1 mg/kg) caused a significant and reversible increase in the amplitude of the TEP. LSD and DMT reduced the alpha activity of the EEG and enhanced the amplitude of the low-frequency waves. DMT produced a significant and LSD a marginal increase in electrogenesis. Tryptamine (10 and 20 mg/kg), mescaline (6 mg/kg), methoxamine (0.88 mg/kg) and apomorphine (5 mg/kg) had no significant effect on the TEP or EEG. These results suggest that depression of the TEP is not related to spinal reflex facilitation in the dog or hallucinogenic activity in man.

Adrenergic Agonists↗

Effects of various psychoative drugs on the metabolism of delta-tetrahydrocannabinol by rats in vitro and in vivo.

Metabolism of 14C-tetrahydrocannabinol (14C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoative drugs. Disappearance of 14C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media. In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary 14C-excretion or metabolite pattern, or on final tissue levels of 14C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total 14C and alter the pattern of THC metabolities in the bile, and increased the final tissue 14C levels. It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.

Animals↗

In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists.

Using a food-reinforced two-lever operant method, rats (n = 9) were trained to discriminate 0.16 mg/kg LSD from saline. Tests for stimulus generalization in rats so trained indicated that the purported 5-HT antagonists cyproheptadine (1.25 and 10 mg/kg), methysergide (0.16 to 10 mg/kg) and mianserin (2.5 to 40 mg/kg) produced partial generalization with LSD. The hallucinogens mescaline (5 to 40 mg/kg) and quipazine (1.25 to 5 mg/kg) were also generalized with LSD. The data suggest that cyproheptadine, methysergide and mianserin may produce partial agonist effects in addition to their antagonist action at central 5-HT receptor sites.

Animals↗