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PubMed1987

Effects on in vitro brain protein synthesis of a translational inhibitor isolated from rabbit brain following intravenous administration of LSD.

Inhibition of brain protein synthesis following intravenous administration of d-lysergic acid diethylamide (LSD) is accompanied by generation of a translational inhibitor protein in the postribosomal supernatant of cerebral hemispheres. Addition of an enriched preparation of this factor to a brain cell-free translation system resulted in a selective reduction in the level of phosphorylation of proteins of molecular weight 55K, 41K, and 25K. A similar set of changes was also observed in a brain cell-free system prepared 1 hr subsequent to drug injection. The brain inhibitor reduced the translational capacity of a messenger RNA-dependent reticulocyte lysate programmed with brain polysomes isolated from saline-injected animals however little effect was apparent when polysomes were prepared from LSD-treated animals. The translational inhibitor did not affect the spectrum of translation products from either set of polysomes.

Animals↗
PubMedDate not supplied

LSD and fixed-internal responding in the rat.

A series of 6 doses of lysergic acid diethylamide-25 (LSD) altered the bar-pressing behavior of 6 rats maintained on a fixed-interval, 5 min (FI 5) schedule of reinforcement. High doses of LSD (0.16, 0.32 mg/kg) depressed overall rates of responding. Low response rates, which occurred during the first half of the interval between successive reinforcements, were increased by low (0.01, 0.02 mg/kg), moderate (0.04, 0.08 mg/kg), and high doses of LSD; high rates of responding which occurred during the final half of the interval were decreased only by high doses of LSD. All doses (except the lowest) decreased the Index of Curvature, a statistic describing the temporal distribution of responses. The results were discussed in terms of baseline rate of responding and the presence or absence of timing behavior.

Animals↗
PubMed1974

The nature of the binding between LSD and a 5-HT receptor: a possible explanation for hallucinogenic activity.

1 (+)-Lysergic acid diethylamide (LSD) mimicked 5-hydroxytryptamine (5-HT) in its ability to stimulate fluid secretion, to change transepithelial and intracellular potentials as well as to increase the cyclic 3',5'-adenosine monophosphate (cyclic AMP) concentrations of isolated salivary glands of Calliphora.2 Unlike 5-HT, LSD disengages slowly from the receptor and fluid secretion continues despite repeated washing.3 Both 5-HT and tryptamine prevented LSD from acting on the glands.4 LSD bound to the receptor was slowly displaced when glands were treated with agonists (tryptamine) or antagonists (gramine).5 The property of LSD which permits it to function as an agonist despite remaining tightly bound to the receptor is discussed as a possible basis for its profound effects within the central nervous system.

Alkaloids↗
PubMed1967

The uptake of amines by human erythrocytes in vitro.

1. Human erythrocytes incubated at 37 degrees C in Krebs bicarbonate solution at pH 7.5 took up 5-hydroxytryptamine, histamine and (-)-noradrenaline at slow rates which were proportional to the concentration of the amines in the medium at least up to 16 mug/ml., in accordance with a simple diffusion process.2. The initial velocity of uptake was greatest for 5-hydroxytryptamine, about 4 times less for histamine and about 20 times less for (-)-noradrenaline; (+)-noradrenaline was not taken up.3. Comparison of uptake measurements by bio-assay and by radioactivity indicated that, after 1 hr, about 10% of each amine taken up had been inactivated.4. At 2 degrees C the uptake of all three amines was greatly diminished. The presence of the antagonists cocaine, chlorpromazine, lysergic acid diethylamide, mepyramine and pronethalol (at 10(-6) or 10(-5) g/ml.) did not affect uptake of the amines.5. In the steady state the ratios of concentration of the amines between cells and medium were greater than could be accounted for by a Donnan distribution.6. Cells which had taken up amines lost most but not all of them into amine-free medium, at rates which were slower than the corresponding rates of uptake. It was concluded that the amines are partially bound in the cells, noradrenaline most and histamine least.7. The slow diffusion of amines into, and the small amounts retained by, erythrocytes indicate that they do not contribute significantly to the rapid termination of the pharmacological actions of these amines in vivo.

Carbon Isotopes↗
PubMed1976

An animal behavior model for studying the actions of LSD and related hallucinogens.

Cats injected with LSD (d-lysergic acid diethylamide) exhibit a group of behaviors that appear to be specific to hallucinogenic drugs. Two of these behaviors, limb flick and abortive grooming, have an extremely low frequency of occurrence in normal cats, but often dominate the behavior of LSD-treated cats. The frequency of occurrence of this group of behaviors is related to the dose of LSD. The behavioral changes are long-lasting following a single injection of LSD, and exhibit tolerance following the repeated administration of LSD. They are not elicited by a variety of control drugs, but are elicited by other indole nucleus hallucinogens. Because the behavioral effects are specific, reliable, easy to score, and quantifiable, they represent an animal model that can be used in studies of the effects of LSD and related hallucinogens.

Animals↗
PubMed1976

Myoclonus after 5-hydroxytryptophan in rats with lesions of indoleamine neurons in the central nervous system.

A myoclonic syndrome consisting of tremor, myoclonus, and seizures was produced following the systemic administration of 5-hydroxytryptophan to adult rats previously given intracisternal injections of 5,7-dihydroxytryptamine and systemic desmethylimipramine, but not in their controls. This behavioral response was blocked by pretreatment with the putative serotonin receptor blocking agents methysergide, lysergic acid diethylamide, and bromolysergic and diethylamide, as well as centrally effective doses of the aromatic amino acid decarboxylase inhibitor Ro4-4602. Blockers of receptors of other neurotransmitters had little effect. This neurologic response in the adult rat may be relevant to some forms of clinical myoclonus and may be useful in testing potential agonists and antagonists of serotonin receptors in the mammalian central nervous system.

5-Hydroxytryptophan↗
PubMed1979

Drugs and the discrimination of duration.

The effects of lysergic acid diethylamide (LSD), d-amphetamine (AMP), chlorpromazine (CPZ), and the most active isomer of marihuana (delta9 - THC) on timing behavior were analyzed with a two-choice, discrete trial procedure in which pigeons were trained to discriminate visual stimuli that differed with respect to duration ('long' vs. 'short'). LSD (0.01, 0.04, 0.16 mg/kg) decreased response speed (increased latency), but otherwise had no significant effects on performance of the discrimination. d-Amphetamine (1.0, 2.0, 4.0 mg/kg) increased perseveration of 'spatial bias' and, at a dose of 4.0 mg/kg, lowered response speed. This compound did not significantly alter accuracy (percentage correct). CPZ (7.5, 15.0, 30.0 mg/kg) significantly decreased accuracy and, at a dose of 30.0 mg/kg, significantly lowered speed; THC also decreased accuracy and lowered speed. Neither CPZ nor THC significantly altered perseveration.

Animals↗
PubMed2002

The effects of psychotomimetics and psychomotor stimulants on two schedules promoting response switching in the rat.

RATIONALE: Psychosis and psychotomimetic drugs result in a disorganisation of the structure of thought and behaviour. Normalising these is one of the objects of antipsychotic therapy, and methods for predicting such a therapeutic effect would be of value. OBJECTIVE: The effects of a number of psychotomimetic agents were examined on the way in which rats distributed responding over two response levers using two different procedures, to assay their effects on behavioural organisation. Previously, amphetamine has been found to increase response switching using these schedules. METHODS: In the first, the random reinforcement procedure, one of the two levers was selected at random as "correct", and responses on this lever were reinforced with food under a random ratio schedule. No signal was given to distinguish the levers. Responding could also result in the food tray being illuminated, but no food pellet was delivered ("no-food" event). Responses on the second lever ("incorrect") had no programmed consequences. After each food delivery or "no-food" event the levers designated as "correct" and "incorrect" were reassigned at random, and the rat had to open the food tray to restart the schedule. In the second procedure, the rats were required to make 21 responses before a switch between the two levers resulted in food delivery [Fixed Ratio (FR) 21-switch]. The responses making up the FR could be distributed freely between the two levers. RESULTS: Phencyclidine (PCP), scopolamine, caffeine and ethanol increased switching under the random reinforcement procedure, but (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and atropine did not. PCP, caffeine, lysergic acid diethylamide (LSD) and atropine increased switching under the FR21-switch procedure, but ethanol did not. The increases in switching produced by PCP, LSD and the anticholinergics were accompanied by marked reductions in response rate, whereas those produced by amphetamine and caffeine were not. The effects of amphetamine, and PCP were strongly dependent on the baseline probability of switching, those of atropine and caffeine moderately so, and those of LSD and ethanol only weakly so. CONCLUSIONS: Of the agents tested, psychomotor stimulants appear to produce the most selective increases in switching. The procedures described here may be useful for assaying the disorganisation of behaviour produced by other psychotomimetics and may have value in the detection of novel antipsychotic drugs.

Amphetamine↗
PubMed1986

Pizotifen (BC-105) attenuates orienting and Pavlovian heart rate conditioning in rabbits.

The cardiac component of the orienting reflex (OR) was elicited in rabbits by 75 dB, 4-sec duration tones of either 304 or 1216 Hz. The conditioned cardiac response was also studied using the same tones and paraorbital electric shock as conditioned and unconditioned stimuli, respectively, using a differential Pavlovian conditioning paradigm. Subcutaneous injections of the central 5-HT antagonist pizotifen (BC-105), the peripheral 5-HT antagonist xylamidine, the central 5-HT agonist d-lysergic acid diethylamide (LSD), and LSD in conjunction with BC-105 were administered 15 min prior to behavioral assessment. Both the heart rate (HR) conditioned response (CR) and the OR consisted of bradycardia. BC-105 attenuated, but xylamidine had no effect on, OR habituation. LSD reduced the magnitude of the OR, an effect which was blocked by BC-105. BC-105 also produced a dose-related attenuation of the bradycardiac HR CR; however, xylamidine had no effect on HR conditioning, suggesting that the attenuation of the HR CR by BC-105 was central rather than peripheral in origin. LSD potentiated the bradycardiac HR CR, but BC-105 in conjunction with LSD attenuated this response. These results suggest that central 5-HT neurons may modulate the magnitude of bradycardiac responses during orienting and aversive Pavlovian conditioning.

Animals↗
PubMed1985

Antagonism of the LSD cue by putative serotonin antagonists: relationship to inhibition of in vivo [3H]spiroperidol binding.

In two groups of rats trained to discriminate 0.08 or 0.16 mg/kg of lysergic acid diethylamide (LSD) from saline, pirenperone and ketanserin completely blocked the stimulus effect of LSD. Pizotifen (BC-105) blocked the LSD cue when the training dose was 0.08 mg/kg, but had variable effects in the 0.16 mg/kg of LSD-trained group. The antagonism of the 0.08 mg/kg cue occurred at doses of the antagonists which blocked [3H]spiroperidol labeled 5-HT2 receptors in the frontal cortex in vivo; binding in the striatum was unaffected by the LSD antagonists. However, in doses which produce the LSD cue, neither LSD nor the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, which substitutes for LSD, inhibited the binding in either the cortex or the striatum. The results are discussed in relation to the possible neuropharmacological basis for the LSD cue.

Animals↗
PubMedDate not supplied

Identification and quantitative determination of LSD by fluorescence: new data.

Tests for the detection of lysergic acid diethylamide (LSD) are not always specific; to cope with this problem the authors have developed a fluorimetric apparatus and technique for the detection and identification of LSD in samples seized from illicit traffic in drugs. The fluorimeter is not electronic and is simple to make and use, inexpensive, easy to handle and suitable for field analyses. With the new, highly sensitive and selective method of synchronous excitation spectrofluorimetry, a toxicological analytical laboratory can confirm measurements made in the field and make an immediate determination of the quantity of LSD in the samples seized. The agreement between results obtained using differential fluorimetry or synchronous spectrofluorimetry and chromatographic techniques was found to be excellent. Quantitative analysis is very useful because the amount of LSD per "dose" can vary, from one batch to another, from a few tenths of a microgram to several hundred micrograms.

Hallucinogens↗
PubMed1984

Discriminative stimulus properties of lergotrile.

Although withdrawn from clinical trials because of liver toxicity, the ergot derivative lergotrile has been useful in the treatment of disorders involving dopaminergic systems (e.g., parkinsonism). In various biochemical and behavioral assays, this compound acts most potently as a dopamine (DA) agonist but also has DA antagonist as well as serotonin (5-HT) agonist properties. To elucidate further its effects in vivo, rats were trained to discriminate 0.5 mg/kg of lergotrile from saline in a two-lever water-reinforced task. In tests for similarities to other ergolines, dose-related substitutions were observed with lisuride (0.003-0.04 mg/kg) and d-lysergic acid diethylamide (0.01-0.08 mg/kg); partial substitution occurred with ergonovine (0.063-0.5 mg/kg). The DA agonist apomorphine (0.016-0.5 mg/kg) also substituted for lergotrile whereas the 5-HT agonist quipazine (0.25-2.0 mg/kg) elicited primarily saline-appropriate responding. Tests involving drug combinations indicated that the DA antagonist haloperidol (0.016-0.5 mg/kg) attenuated responding on the drug-appropriate lever; however, neither the DA (D2) antagonist sulpiride (2.0-16.0 mg/kg) nor the 5-HT antagonist BC-105 (1.0-4.0 mg/kg) had an effect upon the lergotrile cue. These results indicate that DA neuronal systems are probably more important than 5-HT neuronal systems in mediating the discriminative stimulus properties of lergotrile; however, the contribution of other neurotransmitter systems (e.g., norepinephrine) to these effects still must be evaluated.

Animals↗
PubMed2006

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine.

RATIONALE: Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training. OBJECTIVE: The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA. MATERIALS AND METHODS: Thirty-two male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups. RESULTS: The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%). CONCLUSIONS: The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.

Animals↗
PubMed2000

Analysis of LSD in human body fluids and hair samples applying ImmunElute columns.

Immunoaffinity extraction units (LSD ImmunElute) are commercially available for the analysis of lysergic acid diethylamide (LSD) in urine. The ImmunElute resin contains immobilized monoclonal antibodies to LSD. We applied the ImmunElute procedure to serum and also to human hair samples. For hair analysis the samples were first extracted with methanol under sonication. The extracts were then purified using the ImmunElute resin. LSD analysis was carried out with HPLC and fluorescence detection. The immunoaffinity extraction provides highly purified extracts for chromatographic analysis. The limit of detection (signal-to-noise ratio = 3) has been determined to be < 50 pg regardless of which sample material was used. The procedure was applied to authentic hair samples from drug abusers (n = 11). One of these samples tested positive with an amount of 110 pg LSD in 112 mg extracted hair corresponding to a concentration of 1 pg/mg.

Adolescent↗
PubMed1979

A characteristic effect of hallucinogens on investigatory responding in rats.

The disruption of the temporal distribution of investigatory responses by rats in a novel hole-board following lysergic acid diethylamide-25 (LSD), as described in a companion paper (Geyer and Light, 1979), was found to be a characteristic effect of a variety of hallucinogens. Similar effects were produced by indoleamine hallucinogens, such as LSD, N,N-dimethyltryptamine, and psilocin, and by phenylethylamine hallucinogens, such as mescaline or 2,5-dimethoxy-4-methylamphetamine (DOM). Congeners of DOM that are inactive in humans had no significant effects. Furthermore, of a variety of other psychoactive drugs tested, only apomorphine produced an effect similar to that of the hallucinogens. These results suggest that a simple behavioral measure of exploration in a hole-board may provide a useful animal model with which to examine the common effects of hallucinogens.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1986

Canine basilar artery contractions mediated by 5-hydroxytryptamine1A receptors.

A series of 11 agents was analyzed at both 5-hydroxytryptamine1A (5-HT1A) sites labeled by [3H]-8-hydroxy-2-(N,N-dipropylamino)tetralin and total 5-HT1 binding sites labeled by [3H]-5-HT in rat brain membranes. Three distinct patterns of relative inhibition were noted. First, drugs such as 8-hydroxy-2-(N,N-dipropylamino)tetralin n-(3-acetylaminophenyl)piperazine hydrochloride, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-1,2-benziso-thiazol-3 -(2H)one-1,1-dioxidehydrochloride] and buspirone display 1.0 to 15 nM potency for the 5-HT1A subpopulation of 5-HT1 binding sites but are more than two orders of magnitude less potent at total 5-HT1 sites. Secondly, 5-methoxy-N,N-dimethyltryptamine and methysergide are approximately one order of magnitude more potent at 5-HT1A than total 5-HT1 sites. In the third group, 5-HT, d-lysergic acid diethylamide, 1-(m-trifluoromethylphenyl)piperazine, 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyrimidinyl) 1H indole, quipazine and pirenperone are essentially equipotent at both 5-HT1A and 5-HT1 sites. Thus, the 5-HT1A binding site has a pharmacological profile which, depending on the agents studied, could be significantly different from the pharmacological profile derived from total 5-HT1 binding. Drug interactions were also analyzed with canine basilar artery segments using 5-HT, 10 putative serotonergic agonists and a selective 5-HT2 antagonist, pirenperone. The maximal contraction was obtained using 5-HT (Cmax = 6.6 +/- 0.6 g). However, each of the 10 other putative 5-HT agonists elicited a less forceful contraction of the canine basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Effect of cocaine and 5-HT3 receptor antagonists on 5-HT-induced [3H]dopamine release from rat striatal synaptosomes.

The effect of serotonin (5-HT) on the release of tritium from striatal synaptosomes previously loaded with [3H]dopamine ([3H]DA) was studied. 5-HT stimulated both the spontaneous and Ca(2+)-evoked efflux of tritium in a concentration-dependent manner. This effect was not mimicked by the non-selective 5-HT agonist, d-lysergic acid diethylamide. Further, the stimulatory effects of 5 muM 5-HT were unaffected by the selective 5-HT3 receptor antagonists, MDL-72222 and GR-38032F. On the other hand, cocaine and the selective DA uptake inhibitor, nomifensine completely antagonized the effect of 5 muM 5-HT on spontaneous tritium efflux with IC50 values of 0.2 and 0.09 muM, respectively. The effect of 5-HT on Ca(2+)-evoked tritium efflux was also blocked by these DA uptake inhibitors, albeit at somewhat higher concentrations. These data support the hypothesis that 5-HT induces the release of DA from striatal nerve terminals via a mechanism involving the transport of 5-HT into the dopaminergic terminal, rather than by activating 5-HT3 receptors as has been proposed to account for the effect of 5-HT observed in striatal slices.

Animals↗
PubMed1985

Distribution of histaminergic, muscarinic and serotonergic binding sites in cat spinal cord with emphasis on the region surrounding the central canal.

[3H]Quinuclidinyl benzilate (QNB), [3H]lysergic acid diethylamide (LSD) and [3H]pyrilamine were used with radiohistochemistry to determine the distribution of muscarinic, serotonergic and histaminergic binding sites, respectively, in cat spinal cord. Each ligand displayed a unique pattern of binding sites in the superficial laminae of the dorsal horn [3H]Pyrilamine binding sites were localized most superficially, while [3H]LSD binding sites were densest in the region of the laminae II/III border. The distribution of [3H]QNB binding sites partially overlapped those of LSD and pyrilamine. In the region surrounding the central canal, pyrilamine binding sites were concentrated within a zone 100 microns lateral to the canal while [3H]QNB and [3H]LSD binding sites were localized outside of this zone. The distribution of binding sites in the region surrounding the central canal may provide an important neurochemical correlate for lamina X in the cat as defined by Rexed.

Animals↗