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PubMed1980

The effects of d-lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and d-amphetamine on operant responding in control and 6-hydroxydopamine-treated rats.

The purpose of the present study was to determine the role of central catecholaminergic neuronal systems in the effects of LSD, DOM and d-amphetamine on fixed ratio (FR) operant responding in rats. Food-deprived male rats were trained to press a bar for food reinforcement on a FR-40 schedule. Control responding on this schedule is characterized by a rapid, constant rate of responding (approximately 100 responses/min) throughout a 40 min test session. LSD and DOM, as with other hallucinogens, produced dose-dependent periods of nonresponding or "pausing," followed by reinstatement of responding at or near the control rate. Administration of the non-hallucinogen, d-amphetamine, did not produce "pausing," but caused the response rate to slow and become erratic. In animals pretreated intraventricularly with 6-hydroxydopamine (6-OHDA; 200 micrograms/10 microliter X 2), the response to LSD and DOM was unchanged, while the response to d-amphetamine was significantly diminished. The neurotoxin significantly decreased brain catecholamines to less than 25 percent of control in al regions examined, without altering 5-HT concentrations in these same regions. These data demonstrate that the effects of LSD and DOM on FR-40 responding are quite different from those of d-amphetamine, and that this difference may be due to the extent of catecholamine involvement in the effects of these agents.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1982

Chronic intraventricular administration of lysergic acid diethylamide (LSD) affects the sensitivity of cortical cells to monocular deprivation.

In kittens, but not in adult cats, depriving one eye of pattern vision by suturing the lids shut (monocular deprivation or MD) for one week reduces the proportion of binocular units in the visual cortex. A sensitivity of cortical units in adult cats to MD can be produced by infusing exogenous monoamines into the visual cortex. Since LSD interacts with monoamines, we have examined the effects of chronic administration of LSD on the sensitivity to MD for cortical cells in adult cats. Cats were assigned randomly to one of four conditions: MD/LSD, MD/No-LSD, No-MD/LSD, No-MD/No-LSD. An osmotic minipump delivered either LSD or the vehicle solution alone during a one-week period of MD. The animals showed no obvious anomalies during the administration of the drug. After one week the response properties of single units in area 17 of the visual cortex were studied without knowledge of the contents of the individual minipumps. With the exception of ocular dominance, the response properties of units recorded in all animals did not differ from normal. In the control animals (MD/No-LSD, No-MD/LSD, No-MD/No-LSD) the average proportion of binocular cells was 78%; similar to that observed for normal adult cats. However, in the experimental animals, which received LSD during the period of MD, only 52% of the cells were binocular. Our results suggest that chronic intraventricular administration of LSD affects either directly or indirectly the sensitivity of cortical neurons to MD.

Animals↗
PubMedDate not supplied

[Characteristics of the development of model psychosis in rats in intracerebral administration of lysergic acid diethylamide].

Chronic experiments on rats with a microcannula implanted into the brain were made to study the effect of diethylamide of lisergic acid (DLA) on spontaneous behavior, locomotion and emotional behavioral reactions. Administration of DLA into the lateral brain ventricles and mesencephalic reticular formation demonstrated that the action of DLA becomes manifest in extremely low doses and within the narrow dose range. The action of DLA is biphasic in nature: the first phase is noted for increased locomotion, while the second one for inhibition. The development of the first phase is linked with a direct effect of DLA on the mesencephalic reticular formation which appeared sensitive to the drug action. It is suggested that the effect of DLA on the central nervous system is realized with the aid of the triggering mechanism.

Animals↗
PubMed1980

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat. Hydrolysis of glucuronic acid conjugates in the gut lumen.

1. Biliary elimination in female Wistar albino rats 3 h after i.p. injection of [3H]phenolphthalein, [3H]morphine, 14C-LSD and [14C]diphenylacetic acid was 90%, 45%, 75% and 57% respectively, predominantly as glucuronides. 2. Infusion of 3 h bile from the previous experiments into the duodena of bile-duct-cannulated animals demonstrated enterohepatic circulation, amounting in 24 h to 85%, 41%, 28% and 66% of the infused doses of the conjugates of phenolphthalein, morphine, LSD and diphenylacetic acid respectively. 3. Pretreatment with antibiotics to suppress intestinal microflora decreased this enterohepatic recirculation to 22%, 8.6% and 21% in 24 h for phenolphthalein, morphine and diphenylacetic acid glucuronides respectively. Antibiotic pretreatment did not influence the absorption and re-excretion of infused doses of the free aglycones, thus demonstrating the importance of bacterial beta-glucuronidase hydrolysis of the biliary conjugates. 4. The extent of intestinal absorption of the aglycones after bacterial beta-glucuronidase hydrolysis of the conjugates is related to their lipid-solubility as estimated by octan-1-ol:0.1 M phosphate buffer partition ratios (P-values). 5. The persistence of compounds in the enterohepatic circulation is determined by the faecal and urinary elimination of the circulating compounds. Faecal elimination is governed by the extent of intestinal absorption of the circulating compounds, which is influenced by the efficacy of intestinal hydrolysis of the conjugates and the relative lipophilicity of the aglycones released.

Animals↗
PubMed1997

Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

Barbiturates↗
PubMed1977

Vesicular and juxtavesicular serotonin: effects of lysergic acid diethylamide and reserpine.

An extensive analysis of subcellular serotonin (5-HT) compartmentation with and without reserpine was undertaken in order to localize further the effect of LSD on rat brain 5-HT. Modification of the subfractionation procedure resulted in an increase in purity of fractions and a decrease in variability of 5-HT content. With the modified procedure, the administration of LSD produced a significant increase in 5-HT in the nerve-ending fraction prepared from rat whole brain. LSD caused a 50% increase in 5-HT in the vesicular fraction which was recovered after osmotic disruption of nerve-endings. The increase of 5-HT in the vesicular fraction after LSD was not demonstrable in rats treated with reserpine for as long as 2 weeks postreserpine. Instead, with reserpine pretreatment the LSD-induced increase in 5-HT was localized to the intrasynaptosomally derived "end supernatant" as early as 48 hours postreserpine. Thus, an unanticipated "juxtavesicular" site capable of 5-HT retention or binding was detected. In crude subcellular fractions, by contrast, significant increase in 5-HT were not observed with LSD administration until 4 days after reserpine, at which time at least a 50% 5-HT repletion had occurred. This study of drug interactions suggests a juxtavesicular compartment that may be of functional importance in presynaptic binding or transport of 5-HT.

Animals↗
PubMed2001

Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.

The trace amine para-tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently thought that the biological activities elicited by trace amines such as p-tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines p-tyramine, beta-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

Amino Acid Sequence↗
PubMed1958

Observations concerning the action of 5-hydroxytryptamine on the peristaltic reflex.

In isolated guinea-pig intestine 5-hydroxytryptamine increased the longitudinal muscle contractions in response to acetylcholine while the ganglionic action of nicotine was first facilitated and then blocked. Phenyldiguanide, veratrine, veratridine and protoveratrine, like 5-hydroxytryptamine, depressed the response to nicotine, leaving that to acetylcholine unaffected.The sensory stimulants, like 5-hydroxytryptamine, facilitated the peristaltic reflex when applied to the mucosa, and abolished it when applied to the serosa. Preceding the block, the initial effect of low concentrations of 5-hydroxytryptamine applied to the serosa was a short stimulation of peristalsis.Concentrations of 5-hydroxytryptamine which had an approximately equal stimulant action (mucosal 1 to 4 x 10(-6), serosal 2 to 8 x 10(-8)) were tested when various parts of the reflex arc were blocked. During block by procaine introduced into the lumen, mucosal application of 5-hydroxytryptamine re-established peristalsis, but serosal application of 5-hydroxytryptamine had no effect. During block by hexamethonium or atropine present in the bath, 5-hydroxytryptamine restored peristalsis more effectively by serosal application than by mucosal application. During block by serosal application of 5-hydroxytryptamine, morphine, phenoxybenzamine or dihydroergotamine, mucosal application of 5-hydroxytryptamine restored the peristaltic reflex while serosal application had no effect. During block by 2-bromo-lysergic acid diethylamide or lysergic acid diethylamide acting from the serosal surface, 5-hydroxytryptamine had no effect whether acting on the mucosal or on the serosal surface.It is concluded that 5-hydroxytryptamine facilitates the peristaltic reflex at two sites: when introduced into the lumen it stimulates mucosal sensory receptors; when acting from the serosal surface it sensitizes the muscle to the transmitter acetylcholine. There is also a transient stimulant action on the ganglia which is soon followed by inhibition; this indicates that 5-hydroxytryptamine applied to the serosa abolishes peristalsis by ganglion block.

Acetylcholine↗
PubMed2002

Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations.

Animals↗
PubMed2003

Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features.

An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Adolescent↗
PubMed1979

The intracranial injection of drug in goldfish. I: Hallucinogens and their antagonism to smooth muscle activity.

A simplified method of studying the surfacing reaction of goldfish to hallucinogens is described. Goldfish weighing up to three grams are injected intracranially. Employing this method, d-lysergic acid diethylamide (LSD-25), d-2-acetyl lysergic acid diethylamide (ALD-52), 1-methyl d-lysergic acid butano-lamide (UML-491), and 5-methoxy dimethyl tryptamine (5-MEO-DMT) were found to be as pharmacologically active as previously noted in fish and in man. The relationship of these drugs to their anti-serotonin activity is of particular interest to the allergist because of the way in which the congeners and derivatives of LSD block the action of serotonin on smooth muscle.

Animals↗
PubMed1997

Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

Animals↗