In vitro effect of d-lysergic acid diethylamide on immunoglobulin synthesis.
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Amino Acids↗
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Lysergic acid diethylamide: dissociation of its behavioral and hyperthermic actions by DL-alpha-methyl-p-tyrosine.
Rabbits treated with LSD 25 exhibit characteristic signs of hyper-excitability, increased peripheral sympathetic activity, and hyperthermia. When the rabbits received prior treatment with DL-(alpha)-methyl-p-tyrosine, the excitation and sympathetic actions of LSD 25 were abolished or attenuated, but the hyperthermia was unchanged from that of the controls. Concentrations of norepinephrine in brain stems of treated rabbits were greatly decreased. The excitation of central nervous system and sympathomimetic actions of LSD 25 in the rabbit are apparently mediated by norepinephrine, whereas the hyperthermic action functions. through a nonadrenergic mechanism.
Animals↗
Synaptosomal uptake and release of dopamine and 5-hydroxy-tryptamine in the nucleus accumbens in vitro following in vivo administration of lysergic acid diethylamide in rats.
The uptake and the depolarisation-induced release of dopamine (DA) and serotonin (5-HT) were investigated after systemic application of LSD on synaptosomes of the nucleus accumbens of rats. For the release experiments synaptosomes were prelabelled with [14C]-DA and [3H]-5-HT, respectively, and superfused with physiological and potassium-enriched (50 mM) solutions. Low doses of LSD (0.1 and 0.5 mg/kg i. p.) induced a dose-dependent inhibition of the DA-release and an increase of the DA-uptake, respectively. LSD inhibited both the release and the uptake of 5-HT significantly. The results are discussed with respect to a reliable characterization of the in vivo induced effects of LSD on the isolated synaptosomes.
Animals↗
Adverse consequences of lysergic acid diethylamide.
The continued endemic use of hallucinogenic drugs, and of LSD in particular, raises concern regarding their short and long term adverse consequences. The epidemiology of LSD abuse is reviewed suggesting an increase in LSD use among the young as the prevalence rates for other substances continues to fall. Evidence supports the association of LSD use with panic reactions, prolonged schizoaffective psychoses and post-hallucinogen perceptual disorder, the latter being present continually for as long as 5 years. Evidence does not support claims of genetic disorders arising from hallucinogens. In light of the foregoing, current data confirm earlier findings of long lasting psychopathology arising in vulnerable individuals from the use of LSD. A hypothetical long term molecular mechanism of adverse effects is proposed.
Adolescent↗
[High affinity binding of 5-hydroxytryptamine to some membrane preparations from cattle brain. Relationship to lysergic acid diethylamide (LSD)].
5 hydroxytryptamine binds to crude brain membrane preparations with two different affinities (KD = 1 to 2 X 10(-9) M for the highest, 1 to 2 X 10(-8) M for the lowest). LSD also binds with two affinities (KD = 3 to 4 X 10(-9) M and KD = 2 to 3 X 10(-8) M). Subcellular distribution of these sites shows that binding involves the two binding affinities in microsomal membranes but solely the high affinity binding sites are present in purified synaptosomal membranes. High affinity sites for 5 HT and for LSD are different as no direct competitive inhibition is observed in that case. On microsomal membranes, direct relationship occurs between low affinity binding for 5 HT and high affinity binding for LSD.
Animals↗
Measurement of lysergic acid diethylamide (LSD) in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry.
A previously reported procedure for quantification of LSD in urine was modified to permit measurement of the drug in plasma. After addition of deuterium-labelled LSD, the plasma is extracted and the extract is treated with trifluoroacetylimidazole to convert the LSD to its N-trifluoroacetyl derivative. The derivatized LSD is analyzed by capillary column gas chromatography/negative ion chemical ionization. Plasma fortified with known concentrations of LSD gave linear responses from 0.1 to 3.0 ng/mL with this assay. The method was used to determine pharmacokinetic parameters for LSD after oral administration (1 microgram/kg) to a male volunteer. The apparent plasma half-life was determined to be 5.1 h. The peak plasma concentration of 1.9 ng/mL occurred 3 h after administration.
Administration, Oral↗
Cell-free translation of free and membrane-bound polysomes and polyadenylated mRNA from rabbit brain following administration of d-lysergic acid diethylamide in vivo.
Free and membrane-bound polysomes and polyadenylated mRNA isolated from rabbit brain were translated in an mRNA-dependent rabbit reticulocyte lysate system. Electrophoretic analysis of the cell-free translation products demonstrated that although most of the nascent proteins were common to both free and membrane-bound brain polysomes, qualitative and quantitative differences were observed. Compared with the results obtained with purified polyadenylated mRNA, the addition of intact polysomes to the cell-free translation assay was more efficient and produced higher molecular weight products. Analysis of the translation products of free and membrane-bound polysomes revealed the appearance of 74K protein following neither LSD administration or hyperthermia induced by elevated temperature treatment. The presence of this 74K protein was verified by analysis of the translation products by two-dimensional gel electrophoresis.
Animals↗
Drugs that antagonize limb flick behavior induced by D-lysergic acid diethylamide (LSD) in cats.
In cats observed in their home cages limb flicks (LF) are a sensitive measure of the behavioral effects of LSD. LF induced by LSD (50 microgram/kg) were blocked by dextrorphan (0.6 mg/kg), dextromethorphan (0.6 mg/kg), and imipramine (5 mg/kg) at doses that did not produce ataxia or sleep. Levorphanol (0.6 mg/kg), a narcotic that is a congener of dextrorphan, did not block LF induced by LSD possibly because it produced an excitatory effect when given alone. Pentobarbital at low doses (2 and 4 mg/kg) increased the number of LF induced by LSD but at a high dose (8 mg/kg) decreased LF induced by LSD either by producing ataxia, so the cats tended to remain immobile, or by producing sleep. Chlorpromazine (CPZ) at three doses (2, 4, and 8 mg/kg) attenuated the effects of LSD on LF, but did not block LF as completely as the above three blocking drugs, and produced ataxia and sleep.
Animals↗
Electrophysiological studies of d-lysergic acid diethylamide in the visual system.
Experiments involving the use of LSD and observing its effects on neurons involved in the processing of visual information are reviewed. These studies typically involved either intravenous or iontophoretic application of the compound. Both modes of application appeared to block the optic afferent synapse at the level of the dorsal lateral geniculate nucleus and to alter the evoked activity of visual cortical neurons. Increasing the dose of LSD regardless of the manner in which it was applied tended to produce depression of both spontaneous and visually driven activity. The receptive field properties of the neurons at all levels of the visual system appear to remain intact after LSD despite changes in spontaneous activity. The effect of LSD on non-specific afferents to the dorsal lateral geniculate nucleus is depicted in relationship to two of the different kind of relay cells located in this structure. Data on LSD interaction with the effects of midbrain stimulation on "X" and "Y" neurons is presented.
Animals↗
Delta-9-tetrahydrocannabinol and lysergic acid diethylamide: comparative changes in the supraoptic and paraventricular neurosecretory activities in rat hypothalamus.
Acute delta-9-tetrahydrocannabinol (Delta-9-THC) administration (50 mg/kg, i.p.) produced accumulation of stainable neurosecretory materials (NSM) in the neural lobe (NL) region with a concomitant dispersion of stainable NSM in the neuronal perikarya of hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) regions. Chronic treatment with delta-9-THC (10 mg/kg, 15 days) produced marked accumulation of NSM in the NL with more prominent degranulation of the neuronal perikarya of SON and PVN. Acute LSD treatment (50 mug/kg) caused accumulation of stainable NSM in the NL region, with unaltered perikaryal distribution pattern of both SON and PVN; chronic LSD treatment (10 mug/kg, 15 days), on the other hand, caused marked increase of NSM in the neuronal perikarya of SON and PVN with no prominent accumulation in the NL. Results indicated that chronic exposure of delta-9-THC lowered the functional activity of SON and PVN neurons while chronic LSD treatment stimulated the hypothalamo-neurohypophyseal neurosecretory system of rats.
Animals↗
New synthesis and characterization of (+)-lysergic acid diethylamide (LSD) derivatives and the development of a microparticle-based immunoassay for the detection of LSD and its metabolites.
In this paper are reported the synthesis and characterization of three LSD derivatives. On the basis of several analytical characterization studies, the most stable derivative has been selected and a procedure to covalently link the derivative to polystyrene microparticles through a carrier protein has been developed. In addition, two new LSD immunogens have been synthesized and characterized, and from these immunogens antibodies that recognize not only LSD but also several major LSD metabolites have been generated. Using the selected derivative and antibody, a homogeneous microparticle-based immunoassay has been developed for the detection of LSD in human urine with the required sensitivity and specificity for an effective screening assay. The performance of this LSD OnLine assay has been evaluated using the criteria of precision, cross-reactivity, correlation to the Abuscreen LSD RIA and GC/MS/MS, assay specificity, and limit of detection.
Animals↗
Comparison of the effect of intravenous administration of d-lysergic acid diethylamide on free and membrane-bound polysomes in the rabbit brain.
The intravenous administration of LSD to young adult rabbits resulted in the disaggregation of both free and membrane-bound classes of brain polysomes. Based on the analysis of LSD dosage and the time course of the LSD-induced brain polysome shift, it was found that free polysomes were more sensitive to the drug than the membrane-bound polysome fraction. LSD-induced hyperthermia may be involved in the disaggregation of free and membrane-bound polysomes, since a correlation was found between the extent of LSD-induced hyperthermia and the degree of brain polysome shift. Prevention of LSD-induced hyperthermia by maintaining the animal at 4 degrees C blocked the disaggregation of both polysome classes. Induction of hyperthermia by elevation of ambient temperature also resulted in a shift in free and membrane-bound polysomes. In all cases the disaggregation of polysomes to monosomes was not caused by RNase activation. During polysome disaggregation, polyadenylated mRNA associated with both free and membrane-bound polysomes was not degraded but was relocalized from polysomes to monosomes.
Animals↗
Lysergic acid diethylamide: morphological study of its effect on synapses.
A morphometric analysis of the effect of LSD on synapses was performed in the habenulae and the interpeduncular nucleus of the frog. The OsO4-fixed nervous tissue was treated with ethanol phosphotungstic acid (EPTA). Intersection of lattice lines with synapses were counted as a proportion of the total length of lines. LSD-treated frogs had a higher total area of synaptic contact than control frogs. Exocytosis profiles were observed only in LSD-treated frogs Other qualitative changes in the ultrastructural characteristic of synapses were appreciable after LSD administration.
Animals↗
Human platelet 5-hydroxytryptamine receptors: binding of [3H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration.
Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently 125I/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor responsible for 5-HT-induced shape change and aggregation. In a group of patients receiving phenothiazines or thioxanthenes, the Bmax of LSD binding was increased. The mean binding affinity was decreased possibly due to a persistence of neuroleptic in the platelet membrane preparation. Analysis showed that this was not the reason why the mean binding capacity was increased. The results show that chronic phenothiazine and thioxanthene delta treatment 'up-regulates' platelet 5-HT2 binding sites and that this may be accompanied by increased sensitivity to platelet aggregation by 5-HT. In normal subjects desipramine treatment increased the Bmax of platelet LSD binding and this was accompanied by an increased prolactin response to tryptophan which is thought to be mediated by central 5-HT function.
Antidepressive Agents↗
Radioimmunoassay of lysergic acid diethylamide (LSD) in serum and urine by using antisera of different specificities.
We raised high-titre antisera to two LSD-bovine serum albumin conjugates, one linked via the indole nitrogen, the other via the amide side-chain. The antisera were specific for different parts of the LSD molecule, as demonstrated by cross-reactivity studies with LSD, its metabolites, ergot alkoloids, and closely related compounds. The antisera were used to develop a double-antibody radioimmunoassay with a detection limit of about 0.4 mug of LSD per liter of unextracted urine or serum. We saw no nonspecific interference by urine, serum, or from a series of commonly used drugs. There was good correlation between immunoassay values obtained with the two antisera (r = 0.91). However, the antiserum linked via the indole nitrogen gave consistently higher results for samples from persons who had taken LSD, owing to greater cross-reactivity with LSD metabolites. Radioimmunoassay by use of two such antisera is a more specific screening procedure for LSD abuse than has been available previously. In addition, antisera cross-reacting with LSD metabolites allow measurement of these compounds, for which there is no satisfactory method at the concentrations found in biological fluids in man.
Antibody Specificity↗
Developmental changes in [3H]lysergic acid diethylamide ([3H]LSD) binding to serotonin receptors in the human brainstem.
The ontogeny of serotonin receptors in the human brainstem is largely unknown, despite the putative roles of serotonin in neural development, synaptic transmission, brainstem modulation of vegetative functions, and clinical disorders of serotonergic function. This study provides baseline information about the quantitative distribution of [3H]LSD binding to serotonergic receptors (5-HT1A-1D, 5-HT2) in the human brainstem, from midgestation through maturity, with a focus upon early infancy. Brainstems were analyzed from 5 fetuses (19-25.5 weeks postconception), 5 infants (42-55.5 weeks postconception), and 3 mature individuals (4, 20, and 52 years). Tissue autoradiography was used with [3H]LSD for total serotonergic receptor binding and [3H]LSD and serotonin for nonspecific binding; computer-based quantitation was applied. The highest levels of [3H]LSD binding occurred prenatally throughout the brainstem. At all ages, the highest relative binding localized to the rostral raphe. A marked decline in [3H]LSD binding occurred between the midgestation and infancy in brainstem regions involved in control of cardiovascular function, respiration, and pain. The fetal peak in [3H]LSD binding to 5-HT receptors is consistent with a trophic role of serotonin in immature human brainstem, and a decrease, between midgestation and infancy, in serotonergic modulation of vegetative functions controlled by the brainstem.
Adolescent↗
Stereospecific binding of D-lysergic acid diethylamide (LSD) to brain membranes: relationship to serotonin receptors.
D-[3H]LSD binds saturably, reversibly, and with a high affinity (KD = 10 nM) to rat brain membranes. The association and dissociation rates of binding are temperature dependent and fastest at 37 degrees C. Binding is enriched in crude microsomal (P3) membranes. D-[3H]LSD binding is stereospecific as L-LSD, the psychotropically inactive enatiomer, is 1000 times weaker than D-LSD as a displacing agent. The potencies of other LSD analogues parallel their psychotropic activity with the exception of 2-bromo-LSD (psychotropically inactive) which is as potent as D-LSD in displacing bound D-[3H]LSD. Serotonin is the only putative neurotransmitter with affinity (ED50 = 3 muM) for the LSD binding site, and psychotropically active alkylindoleamines are also potent displacing agents. Destruction of presynaptic serotonin neuronal elements by lesioning the midbrain raphe nuclei does not chang the affinity or maximum number of detectable in vitro D-[3H]LSD bindind sites. The regional distribution in monkey brain of D-[3H]LSD binding and high affinity [3h]serotonin uptake, a marker for pre-synaptic serotonin nerve terminal density, shows some correlation. The most notable exceptions are cerebral cortical areas which are highest in D-[3H]LSD binding and only intermediate in [3h]serotonin uptake. Our evidence suggests that D-[3H]LSD binds to post-synaptic serotonin receptors.
Animals↗
Effects of lysergic acid diethylamide on autonomic post-ganglionic transmission.
1. Six sites of autonomic post-ganglionic transmission were examined for susceptibility to LSD. Inhibition of transmission by LSD was confined to the three sympathetic junctions. 2. Inhibition of sympathetic transmission was maximal with short trains of pulses and declined considerably as train length was increased. 3. Evidence for a presynaptic mode of action was obtained. This was the predominant effect of LSD in the rat anococcygeus and dog retractor penis because alpha-adrenoceptor-blocking properties were feeble or absent; but in dog splenic strips LSD produced marked post-synaptic alpha-blockade. 4. The presynaptic inhibitory effect of LSD was unrelated to its 5-hydroxytryptamine-blocking property because it was not shared by methysergide. Neither was it mediated by prostaglandin release because it was unaltered by indomethacin, which suppresses prostaglandin synthesis. 5. In the rat anococcygeus and dog retractor penis larger doses of LSD induced slow contractions and, as a result of the concurrent block of motor transmission, revealed relaxation responses on transmural stimulation, caused by the excitation of sacral inhibitory fibres present in these muscles. 6. The LSD contractions were due to stimulation of post-synaptic alpha-adrenoceptors because they were abolished by phentolamine or yohimbine but were present as usual in preparations taken from reserpinized animals. 7. LSD blocked presynaptic alpha-adrenoceptors in the cholinergic motor fibres to the longitudinal muscle of the guinea-pig ileum.
Adrenergic alpha-Antagonists↗