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PubMed1991

Behavioural and biochemical evidence of the interaction of the putative antipsychotic agent, BMY 14802 with the 5-HT1A receptor.

The behavioural and biochemical profile of the sigma ligand and putative antipsychotic agent, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol) has been determined in the mouse and rat. In mice, pretreatment with BMY 14802 attenuated both amphetamine-induced hyperactivity and conditioned avoidance responding, consistent with its previously reported antipsychotic potential. In common with 5-HT1A receptor agonists or partial agonists, BMY 14802 induced (a) a dose-dependent hypothermia in mice; (b) aspects of the 5-HT behavioural syndrome in rats, (c) antagonised mescaline-induced head twitches in mice and (d) generalised to the 8-hydroxy-2-(di-n-propylamino)tetralin discriminative stimulus over the dose range of 3-15 mg/kg. BMY 14802 had appreciable affinity for the 5-HT1A receptor (pIC50 = 6.7 compared to 7.3 for sigma binding) and antagonised forskolin-stimulated adenylate cyclase activity with a pEC50 of 6.2, consistent with an agonist action at this receptor. The results support the involvement of 5-HT1A receptors, but not the sigma binding site, in the behavioural profile of BMY 14802.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1982

The late stage following continuous amphetamine administration to rats is correlated with altered dopamine but not serotonin metabolism.

In previous experiments rats pretreated with slow-release d-amphetamine (d-Amp) pellets for 4 1/2 days, given a 12-hr drug-free period, and then injected with d-Amp have been found to show a behavioral syndrome which has similarities to that induced by acute injections of the hallucinogens LSD and mescaline. The present results indicate that rats administered this same drug regimen have large decreases in Dopamine (DA), dihydroxyphenyl acetic acid (Dopac), and homovanillic acid (HVA) in caudate nucleus, smaller decreases in DA with no changes in Dopac and HVA levels in nucleus accumbens, but no alterations in 5-hydroxytryptamine (5HT) and 5-hydroxyindole acetic acid (5HIAA) levels in caudate, accumbens, brainstem and hippocampus. Increased 5HIAA levels are found in rats sacrificed with pellets intact following 3 days of continuous d-Amp administration, while sleep deprived and in motor stereotypies. The late and hallucinatory stage following continuous d-amp is correlated more closely with alterations in dopamine than of 5HT.

Animals↗
PubMed1979

Psychotomimetics potentiate locomotor hyperactivity induced by dopaminergic drugs.

The spontaneous locomotor activity of rats was investigated in an open-field test. Apomorphine and d,1-amphetamine caused a dose dependent increase of locomotor activity. LSD, mescaline, and DMT in low doses were ineffective, when given alone, but caused a strong potentiation of the hypermotility induced by apomorphine and d,1-amphetamine. Cyproheptadine antagonized the potentiating effect of LSD without affecting the hypermotility induced by apomorphine, indicating a causal serotonergic involvement in the potentiation effect.

Amphetamine↗
PubMed1982

Neuropharmacological profile of R 18 503-induced wet-shake behavior in the rat: noradrenergic and opiate components.

R 18 503 (alpha-(p-chlorophenyl)-beta,beta-dimethylimidazole-1-ethanol) 40 mg/kg IP produced a mean of 168 (SEM +/- 4) wet shakes in the 35 min following its administration to 100 g male Wistar rats. No other behavioural abnormalities were seen at this dose. The wet-shakes were not caused by reduced body temperature. However, 20-30 min after R 18 503, body temperature was significantly elevated in comparison with saline treated controls. This supports a role for wet-shakes in thermogenesis in the rat, but suggests that R 18 503-induced wet-shakes are not adapted towards the maintenance temperature homeostasis. R 18 503-induced wet-shakes were potently antagonized by 5 narcotic analgesics, but not by aspirin-like drugs. A further 18 non-narcotic compounds including putative serotonin antagonists, neuroleptics and compounds thought to act on the alpha-adrenergic system, also antagonized R 18 503-induced wet-shakes. Spectral map analysis showed a close link between ED50-values of the non-narcotic R 18 503 wet-shake antagonists and their ED50's to antagonize noradrenaline-induced lethality; this was further confirmed by a highly significant Spearman Rank correlation between the two tests (rs = 0.77, p less than 0.001). However, the spectral mapping and Spearman correlation analysis showed no relationship between antagonism of R 18 503-induced wet-shakes and antagonism of apomorphine-induced stereotypy, tryptamine-induced bilateral forepaw clonus, mescaline-induced head twitches, and 5 HT-induced contractions of rat caudal artery. It is postulated that R 18 503-induced wet-shakes result from an interaction between the opiate system and the alpha-adrenergic system.

Animals↗
PubMed1986

Hallucinogenic drug research--if so, so what? Symposium summary and commentary.

The conference brought a critical focus both on older findings and new strategies in hallucinogenic drug research as well as on behavioral and electrophysiologic tools that correlate with neurobehavioral and neurochemical events. A number of unsolved problems to be investigated were noted. The sensitizing effects of both mescaline and LSD on other inputs at motor nuclei or at limbic sites, and effects on afferent processes were examples of important new directions as were drug discrimination tests that can determine the relative roles of aminergic systems in drug effect. Fixed ratio operant schedules can differentiate serotonin blocking agents, detect active indole psychotomimetics and demonstrate temporal and tolerance parameters relevant to drug induced neurochemical changes. Data and critique as well as pharmacokinetics no longer support the presynaptic-disinhibition model of LSD effects, nor is LSD induced "slowed turnover" of serotonin seen as an accurate description of neurochemical changes. The distinct nerve ending biochemical changes after LSD are reviewed. Subcellular compartmental analyses require a radical revision of the picture of the ratio in the nerve ending of cytoplasmic and vesicular amine as well as factors normally regulating accessibility of amine to intraneuronal MAO.

Animals↗
PubMedDate not supplied

A behavioral comparison of Nexus, cathinone, BDB, and MDA.

The effects of 4-bromo-2,5-dimethoxyphenethylamine (Nexus), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), and cathinone were studied in the newly hatched chicken and compared to the effects of d-amphetamine and three hallucinogens in the same species. Cathinone, a psychomotor stimulant in man (6), produced effects that were qualitatively similar to effects seen after administration of d-amphetamine (i.e., distress vocalization, wing extension, inability to stand, and loss of righting reflex). BDB, a compound with unknown activity in man, and two known hallucinogens, Nexus (5) and MDA (1), produced effects in the chicken that are common to both stimulants and hallucinogens in this species. For example, both MDA and BDB produced abnormal body posture that was identical to that reported after administration of hallucinogens such as lysergic acid diethylamide (LSD) and harmine (11). Nexus, on the other hand, produced rigid penguin-like posture, an effect seen in the chicken after administration of another hallucinogen, mescaline (12). BDB also produced bursting forward movements, an effect commonly observed after LSD and harmine. Our findings suggest that the young chicken can be used as an alternative, nonmammalian, model for predicting classification of new compounds.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1982

Nerve terminal effects of indoleamine psychotomimetics on 5-hydroxytryptamine.

The mode of action of indoleamine psychotomimetics has been closely linked to 5-HT. Early work showed increases in rat brain levels of 5-HT which were later localized to the nerve-ending fraction. With improved methodology, the 5-HT increment was further detected in the synaptic vesicle fraction. These effects were obtained with several indoleamine hallucinogens but not with mescaline. LSD has been most thoroughly studied and has served as the prototypical compound in ascertaining the mode of action of these drugs. Pretreatment with reserpine abolished the 5-HT effects of LSD in the vesicular fraction. However, a new compartment, termed "juxtavesicular," displayed 5-HT increases following reserpine and LSD. A soluble binding site for 5-HT within the synaptoplasm has been postulated in confirmation of independent results by other groups of investigators. The origin of the 5-HT increment appears to be associated with newly synthesized amine. This was deduced from experiments involving various 5-HT synthesis blockers. To ascertain whether inhibition of raphé neuronal firing is responsible for the accumulation of 5-HT at the nerve terminal, two sets of experiments were performed. Destruction of the raphé cell bodies by radiofrequency lesions failed to abolish the LSD-induced 5-HT increase early after the lesion. Destruction of cortical 5-HT neurons with the neurotoxin 5,7-dihydroxytryptamine completely abolished the 5-HT effect of LSD. It was concluded that an intact nerve terminal is necessary for the expression of the LSD-mediated increases in 5-HT. A LSD "autoreceptor" is postulated, possibly identical to a 5-HT presynaptic receptor inhibiting the release of 5-HT.

Amines↗
PubMed1982

A screening method for substances potentially active on learning and memory.

A series of substances from different pharmacological classes was examined by two different tests for their activity on learning and memory. A concomitant evaluation was performed by use of a one-trial passive avoidance immediately followed by electroshock in mice and the pole-climbing test in rats. Only doses not producing changes in gross behavior (Irwin's test) were used. A facilitating action on all the considered parameters was observed for d-amphetamine, caffeine, L-glutamine, Mg pemoline, phosphorylserine, piracetam, strychnine, and tricyanoaminopropene. A worsening action was found for atropine, cycloheximide, diazepam, and morphine. Chlorpheniramine, diphenylhydantoin, GABA, imipramine, meclizine, mescaline, metrazol, and testosterone showed no or doubtful activity. Our results suggest that the parallel use of these relatively simple tests supplies information that is satisfactory for screening purposes and that has a high degree of predictability as substantiated by literature data.

Animals↗
PubMed1978

The identification of LSD-like hallucinogens using the chronic spinal dog.

The effects of several indoleamines and phenethylamines were studied in the chronic spinal dog and compared with two standard drugs, LSD and amphetamine. In the nontolerant chronic spinal dog, their effects on a variety of physiologic and behavioral functions were measured in untreated dogs, as well as dogs treated with certain antagonists. The effects of the antagonists phenoxybenzamine and cyproheptadine on the various physiologic effects were studied for all drugs. For some idoleamines and phenethylamines, the effects of chlorpromazine and pimozide were also studied. Indoleamines and phenethylamines in the LSD-tolerant chronic spinal dog and their anorexigenic effects in the intact dog were also studied. The results of these studies indicate that psilocin, mescaline, dimethyltryptamine and tryptamine are LSD-like drugs. DOM, DOB, DMA, and TMA are predominantly LSD-like drugs but do have some amphetamine-like action. PMA and PEA are predominantly amphetamine-like drugs with some LSD-like activity. MMDA and MDA have a more complicated pharmacology showing proerties that resemble LSD and amphetamine, but they have other actions which are not shared by either LSD or amphetamine, which suggests they have yet other modes of action.

Animals↗
PubMed1986

The effects of (+/-)-methylenedioxymethamphetamine and (+/-)-methylenedioxyamphetamine in monkeys trained to discriminate (+)-amphetamine from saline.

Recently, attention has been focused on (+/-)-methylenedioxymethamphetamine (MDMA), a psychotomimetic agent chemically closely related to the psychomotor stimulant methamphetamine, and also to the hallucinogen mescaline. In the present experiment, the effects of MDMA and (+/-)-3,4-methylenedioxyamphetamine (MDA) were determined in rhesus monkeys that were trained to discriminate intravenously administered (+)-amphetamine (AMPH) from saline in a two-lever, food-maintained paradigm or to discriminate intragastrically administered AMPH from saline in a signalled electric shock avoidance paradigm. MDMA produced 100% drug-appropriate responding in all six monkeys, regardless of the procedure and route of administration while MDA substituted completely for AMPH in only two of three monkeys in each paradigm. The results suggest that MDMA has subjective effects that are similar to those of AMPH while MDA is somewhat less like AMPH.

3,4-Methylenedioxyamphetamine↗
PubMed1983

Pharmacologic inhibition of cerebral vasospasm in ischemia, hallucinogen ingestion, and hypomagnesemia: barbiturates, calcium antagonists, and magnesium.

Experiments indicate that several different calcium antagonists have vasodilatory properties which may be expressed selectively on different organ vascular beds. Verapamil was most active as a vasodilator in muscular microvasculature. Cerebral venules are most sensitive to nimodipine. Nisoldipine is inactive in cerebral vascular dilation. We have also studied the vasodilatory effects of several barbiturates. Pentobarbital is the most active cerebrovasodilator in this class of anesthetics. This agent inhibits the vasospastic activity of potassium, serotonin, and prostaglandins, and appears to be a calcium entry antagonist in vasculature. The hallucinogens phencyclidine, mescaline, and LSD all induce cerebral vasospasm. This can be either blocked or reversed with calcium antagonists. Magnesium is a competitive calcium antagonist, and alterations in the extracellular content of this ion have profound effects on cerebral vascular resistance.

Animals↗
PubMedDate not supplied

"Designer drugs"--a current perspective.

Since the late 1970s, in an effort to quench the ever burgeoning appetite for pharmacological substances of abuse and to satiate their own need for profit, unscrupulous chemists have set up clandestine laboratories to produce and market new drugs for street sale. Using fairly common industrial chemicals, they have altered or modified preexisting controlled substances such as fentanyl, meperidine, mescaline, amphetamine, and phencyclidine, producing derivatives of these parent compounds that, up until 1986, were able to temporarily elude the guidelines of the Federal Controlled Substances Act due to their new and unique chemical structures. Unsuspecting users continue to use the drugs recreationally. This article will present a comprehensive review of these "Designer Drugs" looking at historical data, pharmacokinetics, treatment, abuse trends, and some of the more recent additions to the social pharmacopoeia.

Amphetamines↗
PubMed2006

Who is becoming hallucinogen dependent soon after hallucinogen use starts?

This study, based upon epidemiological survey data from the United States (U.S.) National Household Surveys on Drug Abuse (NHSDA) from 2000 to 2001, presents new estimates for the risk of developing a hallucinogen dependence syndrome within 24 months after first use of any hallucinogen (median elapsed time approximately 12 months). Subgroup variations in risk of becoming hallucinogen dependent also are explored. Estimates are derived from the NHSDA representative samples of non-institutionalized U.S. residents ages 12 and older (n=114,241). A total of 2035 respondents had used hallucinogens for the first time within 24 months prior to assessment. An estimated 2-3% of these recent-onset hallucinogen users had become dependent on hallucinogens, according to the NHSDA DSM-IV computerized diagnostic algorithm. Controlling for sociodemographic and other drug use covariates, very early first use of hallucinogens (age 10-11 years) is associated with increased risk of hallucinogen dependence (p<0.01). Excess risk of developing hallucinogen dependence was found in association with recent-onset use of mescaline; excess risk also was found for recent-onset users of ecstasy and of PCP. This study's evidence is consistent with prior evidence on a tangible but quite infrequent dependence syndrome soon after the start of hallucinogen use; it offers leads that can be confirmed or disconfirmed in future investigations.

Adolescent↗
PubMed2005

Methylenedioxymethamphetamine (ecstasy)-related hyperthermia.

MDMA (or 3, 4 methylenedioxymethamphetamine) was first manufactured in the 1920s and found to have structural similarities to both mescaline and amphetamines. Used briefly by some therapists in the 1970s and early 1980s as an adjunct to psychotherapy, it is now primarily abused by teenagers and young adults as an illicit recreational drug known as "ecstasy." As its popularity has increased, so have the number of fatalities and adverse events related to its use. We report six patients suffering fatal or life-threatening hyperthermia after MDMA use. These cases illustrate that hyperthermia associated with MDMA use cannot be solely attributed to rave parties (high ambient temperatures, excessive dancing, dehydration, and overcrowded conditions), drug contaminants, or co-ingestants. A better understanding of the etiology of hyperthermia after MDMA use is needed so that appropriate harm-reduction measures can be developed and instituted.

Adolescent↗
PubMed2004

Hallucinogens and dissociative agents naturally growing in the United States.

It is usually believed that drugs of abuse are smuggled into the United States or are clandestinely produced for illicit distribution. Less well known is that many hallucinogens and dissociative agents can be obtained from plants and fungi growing wild or in gardens. Some of these botanical sources can be located throughout the United States; others have a more narrow distribution. This article reviews plants containing N,N-dimethyltryptamine, reversible type A monoamine oxidase inhibitors (MAOI), lysergic acid amide, the anticholinergic drugs atropine and scopolamine, or the diterpene salvinorin-A (Salvia divinorum). Also reviewed are mescaline-containing cacti, psilocybin/psilocin-containing mushrooms, and the Amanita muscaria and Amanita pantherina mushrooms that contain muscimol and ibotenic acid. Dangerous misidentification is most common with the mushrooms, but even a novice forager can quickly learn how to properly identify and prepare for ingestion many of these plants. Moreover, through the ever-expanding dissemination of information via the Internet, this knowledge is being obtained and acted upon by more and more individuals. This general overview includes information on the geographical range, drug content, preparation, intoxication, and the special health risks associated with some of these plants. Information is also offered on the unique issue of when bona fide religions use such plants as sacraments in the United States. In addition to the Native American Church's (NAC) longstanding right to peyote, two religions of Brazilian origin, the Santo Daime and the Uniao do Vegetal (UDV), are seeking legal protection in the United States for their use of sacramental dimethyltryptamine-containing "ayahuasca."

Dissociative Disorders↗
PubMed1997

Interactions of amphetamine analogs with human liver CYP2D6.

The interaction of fifteen amphetamine analogs with the genetically polymorphic enzyme CYP2D6 was examined. All fourteen phenylisopropylamines tested were competitive inhibitors of CYP2D6 in human liver microsomes. The presence of a methylenedioxy group in the 3,4-positions of both amphetamine (Ki = 26.5 microM) and methamphetamine (Ki = 25 microM) increased the affinity for CYP2D6 to 1.8 and 0.6 microM, respectively. Addition of a methoxy group to amphetamine in the 2-position also increased the affinity for CYP2D6 (Ki = 11.5 microM). The compound with the highest affinity for CYP2D6 was an amphetamine analog (MMDA-2) having both a methoxy group in the 2-position and a methylenedioxy group (Ki = 0.17 microM). Mescaline did not interact with CYP2D6. O-Demethylation of p-methoxyamphetamine (PMA) by CYP2D6 was characterized (Km = 59.2 +/- 22.4 microM, and Vmax = 29.3 +/- 16.6 nmol/mg/hr, N = 6 livers). This reaction was negligible in CYP2D6-deficient liver microsomes, was inhibited stereoselectively by the quinidine/quinine enantiomer pair, and was cosegregated with dextromethorphan O-demethylation (r = 0.975). The inhibitory effect of methylenedioxymethamphetamine (MDMA) was enhanced by preincubation with microsomes, suggesting that MDMA may produce a metabolite complex with CYP2D6. These findings suggest that phenylisopropylamines as a class interact with CYP2D6 as substrates and/or inhibitors. Their use may cause metabolic interactions with other drugs that are CYP2D6 substrates, and the potential for polymorphic oxidation via CYP2D6 may be a source of interindividual variation in their abuse liability and toxicity.

Amphetamines↗
PubMed2003

Activation of 5-HT2 receptors induces glycogenolysis in the rat brain.

The effect of 5-HT(2) receptor activation on brain glycogen and the extracellular concentration of glucose was investigated in the present study. An injection of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2 mg/kg, i.p.) or mescaline (10 mg/kg, i.p.) at an ambient temperature of 29 degrees C produced a 35-45% decrease in brain glycogen that persisted for at least 2 h. DOI also increased the extracellular concentration of glucose in the striatum by 60%. Maintenance of rats at 22 degrees C significantly attenuated DOI-induced glycogenolysis, as well as DOI-induced hyperthermia, and the increase in the extracellular concentration of glucose in the striatum. DOI-induced hyperthermia, glycogenolysis and increase in the extracellular concentration of glucose also were attenuated in rats treated with the 5-HT(2) receptor antagonist, 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY-53,857) (3 mg/kg, ip). These results support the conclusion that 5-HT(2) receptor activation promotes glycogenolysis and that hyperthermia exerts a prominent role in this process.

Animals↗
PubMed1997

The pharmacology of the novel and selective sigma ligand, PD 144418.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma x glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl-D-aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other sigma ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.

Animals↗