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The bronchoconstrictor action of bradykinin in the guinea-pig.

Bradykinin was found to be a potent bronchoconstrictor agent in the guinea-pig anaesthetized with urethane. This action was not affected by vagotomy, or by treatment of the animal with mepyramine, atropine, lysergic acid diethylamide, or cortisone. Adrenaline and isoprenaline suppressed the bronchoconstrictor responses to bradykinin and histamine. Small doses of acetylsalicylic acid, however, suppressed only that to bradykinin. Bradykinin also produced bronchoconstriction in the isolated perfused lungs of the guinea-pig. The closely related peptide, wasp kinin, was also a potent bronchoconstrictor.

Animals↗

Determination of common drugs of abuse in body fluids using one isolation procedure and liquid chromatography--atmospheric-pressure chemical-ionization mass spectromery.

A method for determining opiate agonists (morphine, morphine-3-glucuronide, morphine-6-glucuronide, 6-monoacetylmorphine, codeine, codeine-6-glucuronide, dihydrocodeine, dihydromorphine, buprenorphine, methadone, tramadol, and ibogaine), cocaine and its metabolites (benzoylecgonine and ecgonine methyl ester) and lysergic acid diethylamide in serum, blood, urine and other biological matrices is presented. Aliquots (0.5-1.5 mL) of biological fluids were spiked with appropriate deuterated internal standards and extracted using a common solid-phase extraction method (C18 cartridges). The extracts were subjected to liquid chromatographic-atmospheric-pressure chemical-ionization mass spectrometric examination using selected ion monitoring procedures. These procedures were developed after analysis of full-scan mass spectra of examined compounds. The extraction method appeared very universal; the recoveries were high for almost all drugs and the extracts were very clean. The procedure was applied for routine forensic casework.

Body Fluids↗

LSD use and flashbacks in alcoholic patients.

Lysergic Acid Diethylamide (LSD) is a hallucinogenic drug that received considerable attention in the 1960's and early 1970's. It produced a wide variety of psychological phenomena, including a variety of perceptual disturbances which would manifest among some users long after the drug had left the system. These phenomena were commonly referred to as "flashbacks" and may have been largely responsible for the drug falling out of favor among recreational drug users. This report describes histories of LSD use among alcoholism treatment facility inpatients and reports specific characteristics of flashbacks and the degree of subjective distress experienced during flashbacks. Findings indicate a statistically significant relationship between number of doses and incidence of flashbacks.

Adolescent↗

Ascorbic acid antagonizes the behavioural effects of LSD in cats.

Pretreatment with ascorbic acid (500 mg kg-1 i.p.) antagonized the behavioural effects of lysergic acid diethylamide (LSD) and apomorphine, but not 5-methoxy-N,N-dimethyltryptamine, in cats. The data support the hypothesis that these behavioural effects in cats are due to drug action at both 5-HT and dopamine receptors, and that the action of LSD at dopamine receptors is modulated by ascorbic acid.

Animals↗

Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants.

The serotonin syndrome, a behavioral response produced by the activation of serotonin receptors, and 3H-serotonin binding were examined after repeated treatment of rats with different types of antidepressant drugs. The serotonin syndrome was produced by the direct-acting serotonin receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeDMT) or d-lysergic acid diethylamide (LSD). Repeated, but not acute treatment of rats with monoamine oxidase inhibitors (nialamide, pargyline, and phenelzine) prevented the serotonin syndrome in response to either 5-MeDMT or LSD and also reduced 3H-serotonin binding in the brain stem and spinal cord. Pretreatment of rats with p-chlorophenylalanine blocked the ability of nialamide treatment to inhibit the serotonin syndrome caused by 5-MeDMT. By contrast, neither the serotonin syndrome or 3H-serotonin binding was affected significantly by the repeated administration of tricyclic antidepressants (amitriptyline, desmethylimipramine, and chlorimipramine) or iprindole. Repeated monoamine oxidase inhibitor treatments may prevent the serotonin syndrome by causing a reduction of 3H-serotonin receptor binding sites in the brain stem and/or spinal cord.

Animals↗

Pharmacological receptors of the cerebral arteries of the goat.

5-Hydroxytryptamine (5-HT), norepinephrine (NE), histamine (H) and potassium (K+) chloride induce dose-dependent changes in tension of the isolated middle crerbral artery of the goat. Vasopressin produces highly variable responses followed by tachyphylaxis; angiotensin II is ineffective over a wide dose range. The order of potencies of these vasoactive agents is 5-HT greater than NE greater than H greater than K+. With regard to their ability to induce maximal contractile responses, the order is: H greater than 5-HT, K+ greater than NE. Lysergic acid diethylamide (LSD) antagonizes the actions of 5-HT in a manner which progresses from surmountability to unsurmountability of the blockade depending on the concentration of LSD. The blockade exerted by LSD is reversed by washing. Phentolamine and diphenhydramine competitively antagonize the actions of NE and H, respectively. The potency of phentolamine and diphenhydramine in the cerebral arteries of the goat is similar to that determined in different tissues obtained from a variety of animal species. It is concluded that the cerebral arteries of the goat possess receptors for biogenic amines, the most effective of which is 5-HT; receptors for vasoactive peptides are ill defined.?25

Angiotensin II↗

Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.

Animals↗

[Narcotic mushrooms with LSD?].

We tested dried East-Asian mushrooms that have only recently appeared on the German drug "scene". They were impregnated with lysergic acid diethylamide (LSD) but sold as Mexican sacred hallucinogenic mushrooms, containing psilocybine. For the safe identification of psilocybine in mushrooms, TASmethod is proposed. Successful identification of LSD in mushrooms is done by tartaric acid extraction with subsequent TLC of the free base. The modified van Urk reaction in connection with hRf-values is best suited for the detection of psilocybine, psilocine and LSD.

Asia↗

False-positive LSD testing in urine samples from intensive care patients.

Unexpected positive results for lysergic acid diethylamide (LSD) were found in urine samples from 12 patients in an intensive care unit in a routine screening using the CEDIA DAU assay. None of these test results could be confirmed by high-performance liquid chromatography analysis, but all samples contained the mucolytic drug ambroxol. Further studies demonstrated that ambroxol exhibits a significant cross-reactivity in the CEDIA DAU LSD assay. Therefore, positive LSD results obtained with the CEDIA DAU assay have to be critically evaluated, particularly during the cold season, when infections of the respiratory tract often result in more frequent use of mucolytic medications.

Adult↗

Differential changes in 125I-LSD-labeled 5-HT-2 serotonin receptors in discrete regions of brain in the rat model of persistent dyskinesias induced by iminodipropionitrile (IDPN): evidence from autoradiographic studies.

Chronic administration of iminodipropionitrile (IDPN) to rats causes a persistent behavioral syndrome consisting of lateral and vertical twitches, random circling, hyperactivity, and increased startle response. These abnormalities are almost identical to those seen after acute injection of serotonin agonists and hallucinogenic drugs. The results of our quantitative autoradiographic localization studies comparing the distribution of 125I-lysergic acid diethylamide (LSD)-labeled 5-HT-2 serotonin receptors in slide-mounted sections of IDPN- and saline-treated revealed a number of changes in 5-HT-2 receptors in the brain of IDPN-treated animals. There were significant increases in the density of 5-HT-2 receptors in the frontal cortex, the cingulate cortex, and the claustrum in IDPN-treated rats. In contrast, there were significant decreases in the density of 125I-LSD binding sites in the nucleus accumbens and in the ventral region of the striatum. The present data provide further evidence to support the notion that the serotonergic system is involved in the manifestation of the persistent abnormalities induced by IDPN.

Animals↗

Differentiation between the stimulus effects of l-5-hydroxytryptophan and LSD.

The stimulus properties of the serotonin precursor 1-5-hydroxytryptophan (5-HTP) and the hallucinogen d-lysergic acid diethylamide (LSD) were compared in a two-lever, water-reinforced drug discrimination task. 5-HTP (in combination with the peripheral decarboxylase inhibitor Ro 4-4602) elicited no more than 50% drug-lever responding in rats trained to discriminate LSD (0.08 mg/kg) from saline while LSD substituted completely in animals trained to discriminate 5-HTP (50 mg/kg) from saline. Combination tests indicated that, while the 5-HTP cue was unaffected by pretreatment with various serotonin antagonists, the substitution of LSD for 5-HTP was abolished by the putative serotonin-2 antagonist ketanserin. It was concluded that LSD mimics 5-HTP by stimulating a subset of serotonin receptors activated by 5-HTP which are sensitive to ketanserin (serotonin-2?).

5-Hydroxytryptophan↗

The modification of lumbar motoneurone excitability by stimulation of a putative 5-hydroxytryptamine pathway.

1 Changes in lumbar motoneurone excitability were monitored by recording spinal reflex activity from the ventral roots of rats anaesthetized with fluothane.2 Electrical stimulation of nucleus raphes medianus increased the amplitude of the monosynaptic reflex via a pathway having a slow conduction velocity. Stimulation elsewhere in the lower brain stem was less effective. This increase in motoneurone excitability was potentiated by the intravenous injection of L-tryptophan and reduced by intravenous injections of lysergic acid diethylamide (LSD), methysergide or Cinanserin.3 Extracellular field potential responses to stimulation of dorsal or ventral roots were recorded with six barrelled microiontophoresis electrodes. Stimulation of nucleus raphes medianus and iontophoretic application of 5-hydroxytryptamine (5-HT) both increased the excitability of lumbar motoneurones as reflected by an increase in field potential amplitude.4 Responses to both stimulation of raphe nuclei and iontophoretic application of 5-HT were reduced by iontophoretic application of Cinanserin and methysergide.5 The similarities of the responses of lumbar motoneurones to applied 5-HT and activity within the raphe-spinal pathway are discussed. It is suggested that activity within the raphe-spinal pathway can increase lumbar motoneurone excitability via the release of 5-HT in the ventral horn of the spinal cord.

Animals↗

The effect of drugs on the acquisition of stimulus control in a conditioned suppression procedure.

Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may "overshadow" other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.

Animals↗

Drug-induced ataxia in opponents elicits "pathological" fighting in undrugged rats exposed to footshock.

One member of a pair of rats was administered either mescaline, lysergic acid diethylamide (LSD), pentobarbital, or ethanol intraperitoneally twenty minutes prior to exposure to footshock in the presence of an undrugged opponent. At high doses, all drugs elicited biting from the undrugged rat of sufficient intensity to produce injury to its drugged opponent. Low doses produced species-typical fighting behavior which consisted of striking each other with their forepaws while upright and failed to elicit biting. Biting attacks by the undrugged rat were highly correlated with ataxic behavior by the drugged rat. Conversely, species-typical aggressive behavior was highly correlated with behaviors such as boxing or upright threat posture. These results suggest that drug-induced ataxic behavior may disinhibit mechanisms that regulate intra-species behavior, thus producing behavior that is more typical of inter-species aggression.

Aggression↗

Vasoactive intestinal polypeptide, 5-hydroxytryptamine and reflex hyperaemia in the small intestine of the cat.

1. The release of vasoactive intestinal polypeptide (VIP) into venous blood from the small intestine of the cat was studied when mechanically stimulating the intestinal mucosa and during close intra-arterial infusions of 5-hydroxytryptamine (5-HT) or isopropylnoradrenaline. The studies were performed on anaesthetized cats given atropine.2. Mechanical stimulation of the intestinal mucosa induced a vasodilatation and a release of VIP into the intestinal venous blood. Intra-arterial administration of tetrodotoxin was given in doses that blocked the vasoconstrictor effect of the regional sympathetic nerve fibres. This also abolished the vascular response and the release of VIP into blood upon mechanical stimulation.3. Close intra-arterial administration of 2-bromo-lysergic acid diethylamide reduced the VIP release and the intestinal vasodilatation upon mucosal stimulation to largely the same extent.4. Close intra-arterial infusions of 5-HT produced a marked release of VIP from the intestine and a moderate vasodilatation. Close intra-arterial infusions of isopropylnoradrenaline, which caused a pronounced intestinal vasodilatation, evoked only a small release of VIP.5. The results are compatible with the hypothesis that the vasodilatation in the gut, induced by mechanical mucosal stimulation, is mediated via an intramural nervous reflex containing a neurone capable of releasing VIP. It is proposed that the nervous reflex is activated by the release of 5-HT from the enterochromaffin cells evoked by mechanical stimulation of the mucosa.

Animals↗

The determination of lysergide (LSD) in urine by high-performance liquid chromatography-isotope dilution mass spectrometry (IDMS).

The use of isotope dilution mass spectrometry (IDMS) has been investigated for the forensic confirmation of lysergic acid diethylamide (LSD) in urine by LC-MS. The advantages of using a deuterated analog of LSD as an internal standard over methysergide are discussed. This study includes a comparison of the electrospray mass spectra of LSD, LSD-d3 and methysergide, and discusses the choice of suitable ions for use in selected ion monitoring (SIM) mode. An IDMS method is presented for the LC-MS confirmation of LSD in urine, with a limit of quantification (LOQ) of 0.5 ng/mL, reflecting the forensic requirement at this laboratory. Under some circumstances the LOQ can be improved to 0.1 ng/mL. This method is linear in the range tested (up to 10 ng/mL LSD in urine) and has been validated in terms of accuracy and precision.

Chromatography, High Pressure Liquid↗

Dissociations between the behavioral effects of LSD and tolerance development during ontogeny in cats: a novel approach to the study of tolerance mechanisms.

The characteristic behavioral effects of d-lysergic acid diethylamide (LSD) in cats first appeared at approximately 25 days of age and increased rapidly in magnitude over the next 10 days. However, 25 day old kittens showed no tolerance to the repeated administration of the drug. While the behavioral response to the initial dose of LSD remained relatively constant between 35 and 112 days of age, the tolerance gradually became more pronounced throughout this time period, reaching an adult level of virtually complete tolerance at 112 days. These findings provide new insight into the nature of the relationship between the primary drug action and the development of tolerance, and suggest a new strategy for investigating the neural bases of tolerance, i.e., examining the neurochemical effects of repeated LSD administration in kittens during various stages of tolerance development.

Animals↗

Platelet serotonin 2A (5-HT2A) receptor characteristics and parenting factors for boys at risk for delinquency: a preliminary report.

OBJECTIVE: This study examined the cross-sectional association between platelet membrane serotonin 2A (5-HT2A) receptor variables in children and characteristics of their parents that place these children at risk for antisocial behavior. METHOD: As part of a larger prospective study investigating predictors of antisocial behavior, 38 younger brothers of convicted delinquents provided platelet samples; samples from 34 boys (mean age=8.3 years) were usable. The authors determined the density (Bmax) and affinity (Kd) of platelet membrane 5-HT2A receptors by using [3H]lysergic acid diethylamide. They also measured parental characteristics related to serotonergic dysfunction in prior studies, the quality of parent-child interactions, and psychiatric profiles of the boys who provided platelets. RESULTS: Bmax was significantly lower in boys whose parents had histories of substance abuse or incarceration. Bmax was also inversely related to harsh parenting; boys raised in environments characterized by frequent parental physical punishment and anger had a significantly lower Bmax. Bmax was not related to boys' disruptive behavior. CONCLUSIONS: In boys at risk for antisocial behavior, the density of 5-HT2A receptors on platelets is inversely related to parental factors known to place youth at risk for antisocial behavior.

Antisocial Personality Disorder↗