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PubMed1984

Influence of long-term zimelidine treatment on LSD-induced behavioural effects.

The effect of lysergic acid diethylamide (LSD) on copulatory and exploratory behaviour in hormone-treated, ovariectomized rats was investigated 4 weeks after chronic treatment with either saline or zimelidine (ZIM). A decrease in sensitivity to the lordosis-inhibiting effect of LSD was observed in the group treated with ZIM. The two groups also differed in their reaction to LSD in the exploratory test. The ZIM-treated animals seemed to be less sensitive to LSD. We therefore suggest that long-term treatment with ZIM reduces the sensitivity of the postsynaptic serotonin receptor.

Animals↗
PubMed1983

Effects of quipazine on pre- and postsynaptic serotonin receptors: single cell studies in the rat CNS.

Many behavioural and biochemical studies have pointed to an agonistic activity of quipazine on serotonin (5-HT) receptors. In the present electrophysiological study, the effect of quipazine on pre- and postsynaptic 5-HT receptors in the rat was studied. Quipazine, administered intravenously, depressed the firing rate of 5-HT-containing dorsal raphe neurones (ED50 = 0.82 mg/kg). Microiontophoretic applications of quipazine on 5-HT-containing neurones in the dorsal raphe and on neurones of two forebrain regions receiving a 5-HT input (the ventral lateral geniculate nucleus and the dorsal hippocampus) consistently depressed neuronal firing rate as did 5-HT and D-lysergic acid diethylamide (LSD). Quipazine was more potent on 5-HT neurones than on the ventral lateral geniculate nucleus and hippocampal neurones: the post/presynaptic efficacy ratio for quipazine was similar to that of LSD. Following a selective denervation of 5-HT neurones with intraventricular injection of 5,7-di-hydroxy-tryptamine in desipramine-pretreated rats, the responsiveness of neurones in the ventral lateral geniculate nucleus to quipazine, applied microiontophoretically, was increased as was that to 5-HT and to LSD. These results provide direct evidence for the agonistic activity of quipazine on both pre- and postsynaptic 5-HT receptors.

Animals↗
PubMed1996

LSD produces place preference and flavor avoidance but does not produce flavor aversion in rats.

The hedonic properties of lysergic acid diethylamide (LSD) were assessed using the place conditioning, taste reactivity, and taste avoidance tests. LSD produced a conditioned place preference, but only at the highest dose tested (0.2 mg/kg). A single preexposure to the conditioning chamber (latent inhibition) prevented the establishment of a place preference. When paired with sucrose, doses of 0.05 to 0.2 mg/kg of LSD produced taste avoidance, but no dose of LSD produced an aversion to the taste as assessed by the taste reactivity test. These results suggest that LSD, like other rewarding drugs, produces taste avoidance by a mechanism other than that produced by emetic drugs.

Animals↗
PubMed1966

An electrophysiological study of 5-hydroxytryptamine receptors of neurones in the molluscan nervous system.

1. 5-Hydroxytryptamine (5-HT) has been iontophoretically applied to the membrane of central neurones of Cryptomphallus aspersa; CILDA neurones (cells with inhibition of long duration) (Gerschenfeld & Tauc, 1964) are the only cells sensitive to 5-HT. The responses to 5-HT is always a depolarization. The CILDA cells studied were also depolarized by ACh.2. From experiments in which pulses of 5-HT and ACh were applied from a double-barrelled micropipette to the CILDA cell soma, it has been calculated that 5-HT and ACh receptors were located at different distances from the injecting micropipette tip. It has also been calculated from the diffusion equation that in the same CILDA cell a 5-HT concentration of 8.2 x 10(-9)M and a ACh concentration of 1.3 x 10(-8)M caused a similar peak depolarization.3. CILDA neurones show ;anomalous' rectification. 5-HT increases the membrane conductance of CILDA.4. 5-HT receptors of CILDA neurone are desensitized by repeated application of 5-HT. The desensitization lasts for ca. 40 sec.5. 5-HT receptors are blocked by lysergic acid diethylamide and its derivatives. Morphine chlorhydrate blocks them non-competitively.6. Some inhibitors of monoamine oxidase (trancylpromine, isocarboxazide, iproniazide and nialamide) have been tested. They do not prolong the action of 5-HT, but block the 5-HT receptors.7. No crossed desensitization between 5-HT and ACh has been observed. Atropine blocks both ACh-receptors and 5-HT receptors, 5-HT receptors appear to be blocked to a greater extent.8. The data presented support the assumption of a excitatory transmitter role of 5-HT to CILDA neurones, but further evidence is necessary to confirm this hypothesis.

Acetylcholine↗
PubMed1976

Behavioral evidence for the stimulation of CNS serotonin receptors by high doses of LSD.

Systemic administration of lysergic acid diethylamide (LSD) to rats induces a behavioral syndrome--consisting of tremor, rigidity, Straub tail, hindlimb abduction, lateral head weaving and reciprocal forepaw treading--which is a reflection of increased activation of central serotonin receptors. Utilizing this behavioral measure, a marked supersensitivity to LSD was observed in rats whose serotonin nerve terminals had been selectively destroyed, and a dramatic tolerance to LSD was observed following its repeated administration to normal rats. These data provide direct evidence that LSD can stimulate CNS serotonin receptors to a degree which markedly affects behavior.

Animals↗
PubMed1986

A simple organ bath for electrical stimulation and superfusion of rat brain slices.

A simple organ bath was designed for the rapid screening of drugs using electrically stimulated brain slices. Control parameters for the release of 3H-5-HT from rat caudate slices using a simple pulse sequence were developed. Field-stimulated release of serotonin was shown to be calcium dependent and was not inhibited by tetrodotoxin. Preliminary experiments into the inhibition of 3H-5-HT release by lysergic acid diethylamide showed moderate inhibition of electrically stimulated overflow from rat caudate at low concentrations. The ratio of postdrug tritium overflow (S2) to predrug tritium overflow (S1) was determined and used as the measure of inhibition in these experiments. An investigation into drug-stimulated 3H-5-HT release from rat hippocampal slices by methylenedioxyamphetamine revealed significant stimulation of tritium overflow. Overall the new organ bath has fulfilled our need for a rapid central nervous system screening procedure by demonstrating experimental versatility and reproducible results.

3,4-Methylenedioxyamphetamine↗
PubMed1984

Influence of naloxone on the effects of LSD in monkeys.

Three stump-tailed monkeys were trained in an appetitive behavioral task. Administration of 0.1 mg/kg of lysergic acid diethylamide (LSD) moderately disrupted performance acutely, and produced abnormal motor activity. With repeated administration of LSD, motor activity and task responding returned to normal. When 1.0 mg/kg of naloxone was administered prior to administration of LSD in a crossover design, appetitive responding was abolished acutely in all animals and behavior was substantially more disrupted than with LSD alone. Tolerance did not occur with repeated administration of this combination of drugs. Endorphins and/or opiate receptors may act to attenuate the effects of hallucinogenic agents, and may subserve the development of tolerance to these effects.

Animals↗
PubMed1998

LSD produces conditioned place preference in male but not female fawn hooded rats.

Male and female Fawn Hooded rats were examined for conditioned place preference (CPP) or aversion (CPA) to lysergic acid diethylamide (LSD). Using a biased design, experimental animals were trained with LSD (0.2 mg/kg, I.P.) administered in conjunction with confinement in either the preferred or nonpreferred location. Control animals received confinement in both locations after administration of saline. Results indicated that rats administered LSD while sequestered in the nonpreferred location spent more time in that location during a nondrug test. This effect, indicative of a conditioned place preference, was exhibited only in male animals. Results are discussed in terms of potential sex differences that may mediate serotonergic sensitivity in the Fawn Hooded rat strain.

Analysis of Variance↗
PubMed1969

Effects of immobilization on rat liver tryptophan pyrrolase and brain 5-hydroxytryptamine metabolism.

1. Rat liver tryptophan pyrrolase increased on immobilization. The concentration of 5-hydroxyindoleacetic acid in the brain also rose and that of 5-hydroxytryptamine fell.2. When adrenalectomized rats were immobilized pyrrolase activity did not rise and brain 5-hydroxytryptamine concentration fell to a lesser extent but the 5-hydroxyindoleacetic acid concentration rose as in intact animals.3. When intact rats were injected with the pyrrolase inhibitor Allopurinol both the increase of pyrrolase and the fall of 5-hydroxytryptamine on immobilization were less prominent but the concentration of 5-hydroxyindoleacetic acid rose as before. Allopurinol did not affect the changes in immobilized adrenalectomized rats.4. Immobilization thus appears to cause (a) decreased brain 5-hydroxytryptamine synthesis resulting from pyrrolase induction and (b) increased 5-hydroxytryptamine breakdown by a more direct effect on the brain. Results of experiments on rats injected with lysergic acid diethylamide, and with alpha-methyltryptophan or probenecid are consistent with the above interpretation.5. The 5-hydroxytryptamine and 5-hydroxyindoleacetic acid changes were maximal after 5-6 hours' immobilization and became less on more prolonged immobilization, which suggests regulatory changes.

Adrenalectomy↗
PubMed1999

Relationship between central and peripheral serotonin 5-HT2A receptors: a positron emission tomography study in healthy individuals.

5-HT2A receptors on platelet membranes are often measured as indirect markers of the central 5-HT2A receptors. However, the 5-HT2A receptors on the platelets and those in the brain have never been assessed simultaneously in humans. The purpose of this study was to evaluate the relationship between platelet membrane and neocortical 5-HT2A receptors measured simultaneously in normal healthy volunteers. Twelve healthy volunteers had the 5-HT2A receptors on their platelet membranes assessed in vitro using [3H]lysergic acid diethylamide ([3H]LSD) and their central 5-HT2A receptors measured in vivo using [18F]setoperone and positron emission tomography (PET) imaging. We find no significant correlation between the binding potential (Bmax/Kd) of 5-HT2A receptors on platelets and in brain in the same individual (F1,10 = 0.7, P = 0.42). The study was limited by a small sample and the fact the two different ligands were used (i.e. LSD for platelets and setoperone for brain); nonetheless, the findings suggest that changes in platelet 5-HT2A receptors may not indicate similar changes in central 5-HT2A receptors.

Adult↗
PubMed1984

The stimulus properties of para-methoxyamphetamine: a nonessential serotonergic component.

A group of six rats was trained to discriminate the effects of para-methoxyamphetamine (PMA; 3 mg/kg, 15 min pretreatment time) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. PMA established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 19 (SE = 2, range = 14-24). A second group of ten rats was similarly trained with lysergic acid diethylamide (LSD; 0.1 mg/kg, 15 min pretreatment time) and saline. In rats trained with PMA, LSD yielded intermediate results, i.e., significantly different from both training conditions. Likewise, the response distribution was intermediate in nature when LSD-trained subjects were tested with PMA. Pizotyline did not antagonize PMA-induced stimulus control in rats trained with PMA and saline but did antagonize the intermediate responding produced by PMA in LSD-trained subjects. It is concluded that PMA-induced stimulus control does not depend upon activation of serotonergic receptors but that PMA does possess some LSD-like effects which are mediated serotonergically.

Amphetamines↗
PubMed1990

Serotonin autoreceptor subsensitivity and antidepressant activity.

Release of [3H]serotonin elicited by electrical stimulation from rat hypothalamus and its modulation through autoreceptors has been studied after chronic administration of two antidepressants, citalopram, specific inhibitor of serotonin uptake, and milnacipran (previously called midalcipran, F 2207) which blocks the uptake of serotonin and noradrenaline to the same extent. The amount of [3H]serotonin released by electrical stimulation was enhanced and the inhibitory effect of the agonist, LSD (lysergic acid diethylamide), reduced in rats treated with citalopram at 10 and 50 mg/kg per day for 21 days. These effects existed at both doses but were accentuated at the higher dose. Thus a chronic treatment with citalopram provokes a down-regulation of the serotonergic autoreceptor, allowing an increase of serotonin neurotransmission. After 21 days treatment with milnacipran, at 50 mg/kg per day, none of the parameters studied were modified. These data suggest that down-regulation of the serotonin autoreceptor is not a universally applicable hypothesis to explain the action of all antidepressants acting on the uptake of serotonin.

Animals↗
PubMed1972

Effects of 5-hydroxytryptamine on isolated strips of the guinea-pig stomach.

1. The effects of 5-hydroxytryptamine (5-HT) on isolated strips of the longitudinal and circular muscles of the guinea-pig stomach were investigated.2. 5-HT (0.1-1 mug/ml) increased the resting tension of the longitudinal muscle while it decreased that of the circular muscle. These effects were blocked by lysergic acid diethylamide (LSD), but were not affected by tetrodotoxin, hyoscine or morphine.3. Electrical stimulation caused contraction in the longitudinal muscle, and contraction followed by relaxation in the circular muscle. In both the longitudinal and circular muscles, the evoked contractions were potentiated by 5-HT. This effect was blocked by tetrodotoxin, hyoscine and morphine, but was not affected by LSD.4. It is concluded that, in the stomach as well as the intestine of the guinea-pig, there are two kinds of 5-HT receptors: the morphine-sensitive M receptor is situated on the intramural nerves and the D-receptor on the smooth muscle cells.

Animals↗
PubMed2002

[Hawaiian baby woodrose: (Psycho-) Pharmacological effects of the seeds of Argyreia nervosa. A case-orientated demonstration].

The seeds of the Hawaiian baby woodrose ( Argyreia nervosa) are used by adolescents as a supposed hallucinogenic drug. These seeds are legally available and broadly sold. The active components are alkaloids structurally related to lysergic acid diethylamide (LSD). However, the psychic effects are very different from those of LSD and are dominated by rather sedative, uncomfortable autonomic disturbances similar to the effects of scopolamine. The (psycho)pharmacological profile is described on the basis of the active substances lysergacidamide and lysergacidethylamide (and their isomers). It is shown that neither the substances themselves nor the mixture are able to evoke LSD-like perceptual variances. The exposure of Argyreia nervosa is described focusing on potential fetal distress by contained ergometrine and the case history of an intoxication.

Arousal↗
PubMed1999

An X-ray crystallographic study of the binding sites of the azide inhibitor and organic substrates to ceruloplasmin, a multi-copper oxidase in the plasma.

Ceruloplasmin is a multi-copper oxidase, which contains most of the copper present in the plasma. It is an acute-phase reactant that exhibits a two- to three-fold increase over the normal concentration of 300 microg/ml in adult plasma. However, the precise physiological role(s) of ceruloplasmin has been the subject of intensive debate and it is likely that the enzyme has a multi-functional role, including iron oxidase activity and the oxidation of biogenic amines. The three-dimensional X-ray structure of the human enzyme was elucidated in 1996 and showed that the molecule was composed of six cupredoxin-type domains arranged in a triangular array. There are six integral copper atoms per molecule (mononuclear sites in domains 2, 4 and 6 and a trinuclear site between domains 1 and 6) and two labile sites with roughly 50% occupancy. Further structural studies on the binding of metal cations by the enzyme indicated a putative mechanism for ferroxidase activity. In this paper we report medium-resolution X-ray studies (3.0-3.5 A) which locate the binding sites for an inhibitor (azide) and various substrates [aromatic diamines, biogenic amines and (+)-lysergic acid diethylamide, LSD]. The binding site of the azide moiety is topologically equivalent to one of the sites reported for ascorbate oxidase. However, there are two distinct binding sites for amine substrates: aromatic diamines bind on the bottom of domain 4 remote from the mononuclear copper site, whereas the biogenic amine series typified by serotonin, epinephrine and dopa bind in close vicinity to that utilised by cations in domain 6 and close to the mononuclear copper. These binding sites are discussed in terms of possible oxidative mechanisms. The binding site for LSD is also reported.

Azides↗
PubMed1991

The novel 5-HT2 receptor antagonist, RP 62203, selectively blocks serotoninergic but not dopaminergic-induced inhibition in the rat prefrontal cortex.

The influence of the novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, RP 62203, on serotoninergic neurotransmission was investigated using an in vivo electrophysiological technique. For this purpose, the ability of RP 62203 (1-3 mg/kg i.p.) to block the inhibitory responses of prefrontal cortical neurons induced by electrical stimulation of the median raphe nucleus was examined in anesthetized rats. In addition, the effects of RP 62203 on the dopaminergic inhibitory responses induced in the prefrontal cortex by stimulation of the ventral tegmental area and on the enhancement of these responses by lysergic acid diethylamide (LSD, a 5-HT2 receptor agonist, 30 or 60 micrograms/kg i.p.), were analyzed. RP 62203 blocked the inhibition induced by median raphe nucleus stimulation in a dose-dependent and reversible fashion. In contrast, RP 62203 failed to affect the inhibitory responses induced in prefrontal cortical cells by stimulation of the ventral tegmental area. However, the enhancement by LSD of the inhibition induced by stimulation of the ventral tegmental area in the prefrontal cortex was blocked by RP 62203. These results demonstrate that RP 62203 selectively blocks serotoninergic, but not dopaminergic, neurotransmission in the prefrontal cortex.

Animals↗
PubMed1995

Hallucinogenic drugs in psychiatric research and treatment. Perspectives and prospects.

Clinical research with hallucinogens has resumed after a generation's hiatus. To place these new studies in context, this article reviews the history of hallucinogens' use and abuse, discusses their pharmacological properties, and highlights previous human studies. Research with lysergic acid diethylamide and related hallucinogens with thousands of patients and control subjects was associated with acceptable safety when subjects were carefully screened, supervised, and followed up. Data were generated regarding hallucinogens' psychopharmacology, overlap with endogenous psychoses, and psychotherapeutic efficacy. Current American and European studies emphasize systematic psychopharmacology, in addition to psychotherapy protocols. Human hallucinogen research will help define unique mind-brain interfaces, and provide mechanistic hypotheses and treatment options for psychiatric disorders. It is critical that human hallucinogen research in the 1990s make use of state of the art methodologies, or consensually define when modifications are required. Training and supervisory issues also must be explicitly addressed.

Combined Modality Therapy↗
PubMed1980

The effects of LSD and some analogues on the responses of single cortical neurons of the cat to optical stimulation.

The effects of lysergic acid diethylamide (LSD) and its analogues, 2-bromo-LSD (BOL) and methysergide, have been investigated on the responses to photic stimulation of single neurons in the striate cortex of the paralyzed, anesthetized cat. Systemic LSD (0.1--50 micrograms/kg, i.v.) produced: (a) enhancement or depression of evoked activity, the former being common with low, the latter with high doses; (b) changes in directional selectivity; and (c) changes in unstimulated background discharges. The effectiveness of the drug was reduced by repeated administration. Both BOL (10--75 micrograms/kg) and methysergide (100-700 micrograms/kg) produced effects qualitatively similar to LSD, but were considerably less potent. Microelectrophoretic administrations of LSD to single cortical neurons had actions similar to those caused by intravenous administration. BOL and methysergide required much larger currents to produce any effect and sometimes no effect could be induced by iontophoresis. It was concluded that these drugs influence visually evoked neuronal responses mainly by acting directly on cortical cells or synapses; and that the interference with visual cortical function could account for the distortion of visual perception caused by lysergic acid analogues; but that the hallucinogenic and psychotomimetic actions of LSD probably require additional subcortical effects.

Animals↗