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PubMed1984

Acute and chronic effects of LSD and 5-MeODMT on raphe-evoked dorsal root potentials in the cat.

Both acute and chronic effects of lysergic acid diethylamide (LSD) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on the dorsal root potential (DRP), evoked by stimulation of the nucleus raphe magnus of the cat, were examined. Single injections of LSD potentiated while those of 5-MeODMT inhibited the raphe-evoked DRP. The electrophysiologic response produced by each drug correlates well in dosage and time-course with their reported behavioral effects. Following four consecutive daily injections of LSD, complete tolerance developed to the potentiating effect of LSD on this potential. A similar pretreatment schedule with 5-MeODMT failed to alter its acute inhibitory effect on the DRP. These results correlate well with the development of tolerance to the behavioral effects of LSD and 5-MeODMT. This system may thus provide a unique electrophysiological model to examine the effects of these drugs.

Action Potentials↗
PubMedDate not supplied

The effect of LSD on the histology and ultrastructure of the neuroepithelium of young chick embryos: a stereological study.

Five control chick embryos and fifteen exposed to LSD at concentrations of 2.5, 12.5 and 50 mug/ml were examined. The morphometric analysis performed at the light microscope level shows that (1) the section area of the neural tube increases with the two highest doses of lysergic acid diethylamide (LDS) employed, (2) the volume fraction of the intercellular spaces decreases with the two highest doses of LSD, (3) the volume fraction of the nuclei in the neural tube is not modified with any concentrations of LSD employed, (4) the volume fraction of the cytoplasm in the neural tube increases with all three concentrations, and (5) the nucleo-cytoplasmic ratio decreases with all three doses employed. Moreover, at the ultrastructural level, it was found that (1) the volume fraction of mitochondria in the cytoplasm decreases at doses of 12.5 and 50 mug/ml (2) the surface to volume ratio of the mitochondria is unchanged with any of the concentrations of LSD employed and (3) the surface density of the endoplasmic reticulum in the cytoplasm increases only with a dose of 2.5 mug/ml of LSD.

Animals↗
PubMed1981

The stimulus properties of gamma-hydroxybutyrate.

Fourteen rats were trained to discriminate the effects of gamma-hydroxybutyrate (GHB) (sodium salt, 200 mg/kg) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Intermediate responding, i.e., responding not fully appropriate for either training condition was observed in tests following morphine, lysergic acid diethylamide, chlordiazepoxide, and the presumed GABA-mimetics muscimol, gamma-butyrolactone, baclofen, and 3-aminopropane sulfonic acid. Naloxone blocked the intermediate results following morphine, but had no effect on GBH-induced stimulus control. The GABA antagonist bicuculline partially blocked GHB, but pizotyline, phentolamine, and butaclamol were without effect. It is concluded that the compound stimulus produced by GHB is most closely associated with GABAergic systems, but that minor opiate and serotonergic components are present as well.

Animals↗
PubMed1982

Dopaminergic and serotonergic mediation of the discriminable effects of ergot alkaloids.

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.

Animals↗
PubMed1962

Some pharmacological properties of brain ganglioside.

The effects of a preparation of purified brain ganglioside and of neuraminic acid have been studied on various pharmacological test preparations. In concentrations of 10 mug/ml. or more, ganglioside stimulates the isolated guinea-pig ileum; graded responses are usually obtained. Various substances, known to antagonize the actions of other stimulant substances, fail to affect the response to ganglioside. Ganglioside and neuraminic acid neither stimulate the superior cervical ganglion of the cat nor do they affect ganglionic transmission. Ganglioside and neuraminic acid did not change the response of the frog rectus abdominis muscle to acetylcholine, nor did they affect the blood pressure of the cat. Ganglioside (2 mug/ml. or more) stimulates the isolated heart of Venus mercenaria, but the response, which develops slowly, decreases with repeated administration of ganglioside. The response is not blocked by 2-bromo-lysergic acid diethylamide and there is no indication that it is due to the liberation of endogenous 5-hydroxytryptamine or related indole compounds. For both the heart of Venus mercenaria and guinea-pig ileum, the activity demonstrated by brain ganglioside is specifically a property of the whole molecule, since neither neuraminic acid itself nor a preparation of brain ganglioside from which only two-thirds of its neuraminic acid had been removed are active.

Acetylcholine↗
PubMed1976

Serotonin antagonism in isolated canine cerebral arteries.

In helically-cut strips of canine cerebral arteries, the dose-response curve of serotonin was not influenced by 10(-7) M phentolamine but was slightly moved to the right and downward at 10(-6) M. The contractile response to serotonin was unaffected by cocaine (3 X 10(-6)M), atropine (10(-6) M) and propranolol (10(-6) M). The addition of lysergic acid diethylamide (LSD), ergotamine and methysergide caused a dose-dependent contraction. Treatment with LSD (10(-9) and 10(-8) M), ergotamine (10(-10) to 10(-8) M) and methysergide (10(-8) to 10(-6) M) shifted the dose-response curve of serotonin to the right and downward in a dose-dependent manner. The inhibitory effect of methysergide was reversed by washing, while that of ergotamine was not reversed. Apparent pA2 values of LSD, ergotamine and methysergide were 9.17, 9.63 and 7.92, respectively. Contractile responses to 20 mM K+ were not significantly influenced by these blocking agents even in the highest concentrations used. It may be concluded that an alpha-adrenergic mechanism is not involved in the genesis of serotonin-induced contractions and that serotonin acts directly on serotonergic receptors in canine cerebral arteries.

Animals↗
PubMed1983

Decreased number of benzodiazepine receptors in frontal cortex of rat brain following long-term lithium treatment.

Chronic administration of lithium led to a decreased number of benzodiazepine receptors (ca. 20%) in frontal cortex of rat brain, whereas no change was observed in the binding characteristics in the remaining part of the cortex and in the hippocampus and the cerebellum. Long-term lithium treatment did not change the binding of [3H]lysergic acid diethylamide and [3H]quinuclidinyl benzilate to membranes of various brain regions in the rat. We concluded that the effect of lithium on the benzodiazepine receptor is brain region specific and cannot be explained as a consequence of a reduced gamma-aminobutyric acid-ergic stimulation of benzodiazepine receptor, as the change in receptor binding was due to a change in the number of receptors rather than in the affinity constant.

Animals↗
PubMed1986

Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists.

As previously reported, systemic administration of the hallucinogens D-lysergic acid diethylamide (LSD) (5-10 micrograms/kg) and mescaline (2 mg/kg) in the anesthetized rat produced a decrease in spontaneous activity but, paradoxically, facilitated activation of locus coeruleus (LC) neurons by sciatic nerve stimulation. In the present study, the hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) (20-80 micrograms/kg) was found to have similar effects. Systemic administration of the selective 5-HT2 antagonists LY 53857 (0.02-0.8 mg/kg) and ritanserin (0.1-0.3 mg/kg) completely reversed both actions of the hallucinogens on the LC. In contrast, LY 53857 did not reverse the effects of (+)-amphetamine (0.5 mg/kg) on the spontaneous or sensory-evoked activity of the LC. These results suggest that the common actions of indoleamine and phenethylamine hallucinogens displayed in the LC are mediated via 5-HT2 receptors; however, these receptors appear to be located outside the LC itself.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1975

Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors.

Previously, d-lysergic acid diethylamide was found to have a more powerful inhibitory action upon serotonergic (raphe) neurons than upon neurons in areas receiving an identified serotonergic input (e. g., amygdala, ventral lateral geniculate). In the present studies, using microiontophoretic techniques, the relative potencies of 3 indoleamine hallucinogens, psilocin, DMT, and bufotenine were tested upon 5HT neurons in the raphe (presynaptic neurons) and postsynaptic neurons in the ventral lateral geniculate and amygdala of the rat. Psilocin showed the greatest preferential inhibitory effect upon raphe as compared to postsynaptic neurons. DMT was intermdeiate and bufotenine had the least differential activity. This rank ordering correlates with the relative hallucinogenic potencies of these compounds: psilocin greater than DMT greater than bufotenine. The results support the hypothesis that low doses of indoleamine halluciogens act preferentially upon presynaptic serotonin receptors to inhibit raphe neurons, thus releasing postsynaptic neurons from a tonic inhibitory serotonergic influence.

Animals↗
PubMed1984

Adverse reactions to psychedelic drugs. A review of the literature.

The use of naturally occurring and synthetically derived compounds for their "psychedelic" effects has been a part of human culture for thousands of years. The basic pharmacology of the major synthetic psychedelic compounds (primarily lysergic acid diethylamide [LSD]-25) is described and reference is made to their potentially beneficial psychological effects. Adverse reactions, defined as dysphoric and/or maladaptive/dysfunctional responses to the use of these drugs, sometimes require careful clinical judgment in order to diagnose. These reactions can be effectively classified along a temporal continuum. Acute, short-lived reactions are often fairly benign, whereas chronic, unremitting courses carry a poor prognosis. Delayed, intermittent phenomena ("flashbacks") and LSD-precipitated functional disorders that usually respond to treatment appropriate for the non-psychedelic-precipitated illnesses they resemble, round out this temporal means of classification. The question of organic brain damage as well as permanent changes in personality, attitudes, and creativity in patients and normals who have repeatedly ingested psychedelic drugs is controversial, but tends to point to subtle or nonsignificant changes. Future areas for study of the psychedelics' pharmacological, psychological, and therapeutic effects are suggested.

Adolescent↗
PubMed1981

Activity of a non-hallucinogenic ergoline derivative, lisuride, in an animal behavior model for hallucinogens.

The behavioral effects of IP administration of lisuride, a non-hallucinogenic iso-lysergic acid amide analog structurally related to d-lysergic acid diethylamide (LSD), were examined in 15 cats. Ten animals were given saline or 6.25, 12.5, 25, 50, or 100 micrograms/kg of lisuride and observed for 1 h by a rater blind to dose. There was a statistically significant effect of lisuride dose on the frequency of occurrence of the behaviors limb flicking, grooming, and abortive grooming. A time-course study with five cats at the most effective lisuride dose, 50 micrograms/kg, revealed that the frequencies of occurrence of these behaviors reached a maximum during the first 2 h post dose, and were comparable to frequencies after saline by 6 h post dose. An acute tolerance study with four cats scored for 90 min post dose revealed no significant tolerance to a 50 micrograms/kg lisuride test dose administered 6, 24, or 72 h after an initial 50 micrograms/kg dose. Acute cross tolerance studies with four cats scored for 90 min after an initial dose of 50 micrograms/kg of LSD or of lisuride, followed 24 h later by 50 micrograms/kg of lisuride or LSD, revealed no significant cross tolerance. The potency of lisuride relative to LSD was evaluated in six cats that were scored for 60 min following 25 and 50 micrograms/kg of LSD and of lisuride. On a molar basis, scores after lisuride were 51% and 67% those after LSD for limb flicking and grooming. These results indicate that lisuride, a non-hallucinogenic iso-lysergic acid derivative, is a false positive in the animal behavior model for hallucinogens.

Animals↗
PubMed1980

Characterization and radioautography of [3H]LSD binding by rat brain slices in vitro: the effect of 5-hydroxytryptamine.

Binding of D-[3H]lysergic acid diethylamide (LSD) to rat coronal brain slices and its blockade by 5-hydroxytryptamine (5-HT) had characteristics similar to those of brain homogenates in respect of KD, kinetics and reversibility of binding. Radioautography was done on slices that had been incubated in 6 nM [3H] LSD and on adjacent slices incubated in the same concentration of tritiated LSD plus 10(-5) M of 5-HT. Choroid plexus showed densest labeling of [3H] LSD. In neuropil, dense labeling occurred within parts of the hippocampal formation except for fields CA2 and CA3 which were sparsely labeled. All layers of the cortex except the posterior cingulate gyrus were labeled by LSD. 5-HT blocked labeling of choroid plexus, hippocampal formation, septum, pons, medulla and parts of cortex but only reduced labeling of most other structures. LSD binding sites may relate to some of its pharmacological effects.

Animals↗
PubMed1986

Local cerebral glucose utilisation following indoleamine- and piperazine-containing 5-hydroxytryptamine agonists.

Substances with varying structural components have been shown to have 5-hydroxytryptamine (5-HT)-like properties in the CNS. In this study, putative 5-HT agonists with indoleamine moeities--lysergic acid diethylamide (LSD) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)--and with piperazine moieties--quipazine (Quip) and 6-chloro-2-(1-piperazinyl)pyrazine (6-CPP) were administered to rats. Local cerebral glucose utilisation was measured using the [14C]2-deoxyglucose autoradiographic technique. It was found that in most cerebral structures, these substances produced dose-dependent reductions in glucose utilisation. However, Quip and 6-CPP increased glucose utilisation in specific areas of the diencephalon (e.g., nucleus reuniens) and produced a biphasic effect in some but not all extrapyramidal structures (e.g., ventromedial caudate nucleus). No such increases in local cerebral glucose utilisation were measured following LSD or 5-MeODMT administration. These results indicate that although similarities exist between the effects of indoleamine- and piperazine-containing 5-HT agonists on local cerebral glucose utilisation there are also significant differences in the overall patterns of response produced.

Animals↗
PubMed1993

Platelet serotonin-2 receptors in obsessive-compulsive disorder.

To examine the role of serotonin-2 (5-HT2) receptors in obsessive-compulsive disorder (OCD), we studied 5-HT2 receptors in platelets obtained from patients with OCD (n = 20) during a drug free baseline period, as well as in normal control subjects (n = 25). The maximum number of binding sites (Bmax) and the apparent dissociation constant (Kd) of 5-HT2 receptors were determined by receptor binding techniques using 125I-lysergic acid diethylamide (LSD) as radioligand. We observed that the mean Bmax of 125I-LSD binding in platelets of patients with OCD was not significantly different when compared with normal control subjects. There was also no significant difference in Kd values between patients with OCD and normal control subjects. To examine whether the baseline 5-HT2 receptors are related to the severity of illness, we determined the relationships of the baseline Bmax and Kd with baseline scores of the Hamilton Depression Rating Scale (HDRS), the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the National Institute of Mental Health (NIMH) Obsessive-Compulsive scale (GOCS). We found no significant correlation between baseline Bmax and Kd with the baseline HDRS, Y-BOCS, or NIMH-GOCS scores. Our results do not indicate abnormal 5-HT2 receptors in platelets of patients with OCD.

Adult↗
PubMed1988

Evidence for antiserotonergic properties of yohimbine.

Yohimbine (YOH) is a widely used pharmacological tool employed to produce a selective blockade of alpha 2-adrenergic receptors. In the present study operant behavior was used as a biobehavioral assay to determine the activity of YOH at serotonergic receptors, as indicated by its ability to antagonize the behavioral effects of a serotonergic agonist, lysergic acid diethylamide (LSD). Rats were trained to respond on a Fixed Ratio 15 schedule for food reinforcement. YOH (0.5-5.0 mg/kg) or vehicle and LSD (50 micrograms/kg) were administered (IP) 30 min and immediately prior, respectively, to the 30-min operant session. In a separate study, the ability of YOH (0.5-2.5 mg/kg) to antagonize a higher dose of LSD (100 micrograms/kg) was examined. Relatively low doses of YOH (0.5-1.0 mg/kg) were able to partially, but significantly antagonize the LSD-induced suppression and typical hallucinogen-induced disruption of schedule-controlled responding. These results suggest that YOH, even at moderate doses, may act nonselectively as an antagonist at 5-HT receptors, in addition to its antagonist action at alpha 2-adrenergic receptors. This study demonstrates the utility of operant behavior as a biobehavioral assay to study the receptor mediated action of drugs.

Animals↗
PubMed1997

5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat.

The possible effect of 5-HT2A/2C receptor agonists on an amphetamine-induced behavioral response was examined using the two-lever drug discrimination paradigm. The experiments were designed to investigate an interaction of the hallucinogenic 5-HT2A/2C agonists lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with the discriminative stimulus elicited by a relatively low dose of (+)-amphetamine (1.35 micromol/kg, 0.25 mg/kg, which produced approximately 50% selection of the drug lever). DOI and LSD did not produce amphetamine-like responding at any dose tested or time of administration. However, LSD alone was able to induce a drug-appropriate response in two of nine amphetamine-trained rats. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Pre-administration of DOI (3 hr) or of LSD (2 hr) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggest that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine.

Amphetamine↗
PubMed1999

Screening postmortem blood and tissues for nine classes [correction of cases] of drugs of abuse using automated microplate immunoassay.

A commercially available enzyme-linked immunosorbant assay (ELISA) was evaluated as a screening procedure for the detection of nine classes of abused drugs in postmortem blood and tissue specimens. Specifically, postmortem blood, fluid and/or tissue homogenates were screened for amphetamine (AMP), methamphetamine (MET), barbiturates (BARB), benzodiazepines (BZD), cannabinoids (CNB), cocaine (benzoylecgonine; BE), morphine-specific (MOR), opiates (class; OPI), phencyclidine (PCP) and lysergic acid diethylamide (LSD) by ELISA and by coated tube radioimmunoassay (CTR) (BARB, BE, OPI, PCP, LSD) or double-antibody radioimmunoassay (DAR) (AMP/METH, BZD, CNB). Specimens that screened 'positive' by any method were confirmed and quantitated by gas chromatography/mass spectrometry (GC/MS). The only assay that appeared to perform less optimally than RIA was the MOR assay (five false negatives). However, this assay is very specific for free morphine while the GC/MS confirmation method provided a total morphine value. The OPI assay was more sensitive, producing fewer false negatives, and is recommended for broad class opiate screening. EIA is an adequate alternative to RIA for screening postmortem specimens, including blood and tissue, for nine major classes of drugs.

Amphetamine↗
PubMed1967

LSD: injection early in pregnancy produces abnormalities in offspring of rats.

One of five rats given a single subcutaneous injection of lysergic acid diethylamide (LSD) early in pregnancy appeared to abort early; two delivered stunted stillborn offspring at term, one delivered a littler of seven healthy and one underdeveloped young, and the last one delivered an apparently normal litter. All five matched controls, given saline injections, went to term and delivered healthy litters of 11 to 16 offspring; there were no abortions and no stillbirths. In a replicate experiment, one of five rats given LSD on the 4th day of gestation aborted, two delivered some stillborn offspring, one gave an abnormally small litter of four, and the last one produced an apparently normal litter of ten. All matched controls delivered healthy litters, totaling 66. Some surviving offspring treated with LSD failed to develop as well as control animals. Treatment of five additional rats with LSD late in pregnancy had no obvious effect on the offspring.

Abnormalities, Drug-Induced↗