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At least 757 records · Page 42Linked to original sources
PubMed1970

Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25.

1. 5-Hydroxytryptamine (5-HT), acetylcholine (ACh), noradrenaline (NA), glutamate, D,L-homocysteic acid (DLH), glycine and gamma-aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of D-lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2-bromo-lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied.2. LSD 25 antagonized 5-HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5-HT. Inhibitory effects of 5-HT, the action of glutamate on neurones which could be inhibited by 5-HT and the actions of all the other compounds tested were unaffected by LSD 25.3. Iontophoretically applied UML 491 was also a specific antagonist to 5-HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism.4. It is suggested that antagonism to 5-HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5-HT and glutamate produce excitation where they act on the same neurone.

Acetylcholine↗
PubMed1998

The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells.

The G protein coupling of human 5-hydroxytryptamine5A (h5-ht5A) receptors was investigated in stably transfected human embryonic kidney (HEK) 293 cells, using radioligand and guanosine-5'[gamma-35S]thiotriphosphate binding to membranes and cyclic adenosine monophosphate measurements in cells. 5-Carboxamido[3H]tryptamine bound to high- and low-affinity sites on h5-ht5A-HEK 293 cell membranes. Guanylyl-imidodiphosphate addition and pertussis toxin pre-treatment abolished high-affinity binding, indicating coupling to G proteins of the Gi/Go family. [N-methyl-3H]Lysergic acid diethylamide bound to a single site; guanylyl-imidodiphosphate and pertussis toxin did not alter lysergic acid diethylamide affinity. 5-Hydroxytryptamine stimulated guanosine-5'[gamma-35S]thiotriphosphate binding to 130% over basal and this effect was completely abolished by pertussis toxin. Various 5-hydroxytryptamine receptor ligands were tested for inhibition of 5-carboxamido[3H]tryptamine binding and in guanosine-5'[gamma-35S]thiotriphosphate binding assays. 5-Hydroxytryptamine consistently inhibited forskolin-induced cyclic adenosine monophosphate formation by 25% in h5-ht5A-HEK 293 cells; no effect was detected on basal cyclic adenosine monophosphate levels, on intracellular Ca2+ concentration or arachidonic acid release. Our studies demonstrate functional coupling of the h5-ht5A receptor to pertussis toxin-sensitive G proteins and to inhibition of adenylate cyclase activity.

Adenylate Cyclase Toxin↗
PubMed1976

The effects of hallucinogens on blind monkeys.

Two blind monkeys were studied with an observational profile that was previously shown to distinguish the effects of hallucinogens from those of other classes of drugs. Lysergic acid diethylamide and dimethyltryptamine could be distinguished from saline, chlorpromazine, d-amphetamine sulfate, and bromo-lysergic acid diethylamide by the increased frequency of spasms, stereotypy, bump, and tracking. The hallucinogens also produced dramatic increases in exploration and related behaviors normally seen only in response to real visual or auditory stimuli. These behaviors are discussed in terms of their similarity to behaviors observed with sighted monkeys in light and dark environments.

Animals↗
PubMed1984

Is there a functional linkage between neurotransmitter uptake mechanisms and presynaptic receptors?

The possibility of interaction between neurotransmitter uptake mechanisms and presynaptic receptors regulating transmitter release was investigated using rat brain synaptosomes in superfusion. Various conditions were considered including: absence of substrate for the uptake with uptake potentially operative; absence of substrate and presence of uptake inhibitors; and uptake activated by added substrate, with or without uptake inhibitors. The release of [3H]-5-hydroxytryptamine ([3H]-5-HT) evoked by 15 mM KCl from cerebral cortex synaptosomes was inhibited by lysergic acid diethylamide. The 5-HT uptake inhibitors citalopram and chlorimipramine did not affect the inhibitory action of lysergic acid diethylamide. Clonidine decreased both the K+-evoked release of [3H]norepinephrine and that of [3H]-5-HT in cortical synaptosomes through the activation of presynaptic alpha-2 adrenoceptors. In superfusion conditions, the action of clonidine on [3H]norepinephrine release was not antagonized by the norepinephrine uptake inhibitors desipramine or cocaine; similarly, the inhibition of [3H]-5-HT release was unaffected when 5-HT uptake was blocked. The K+-evoked release of [3H]dopamine from striatal nerve terminals was potentiated by acetylcholine (ACh) through the activation of muscarinic presynaptic receptors. The action of ACh was not modified by the presence of nomifensine, a dopamine uptake inhibitor. Finally, in superfused cortical synaptosomes, the block of the high-affinity uptake of choline by hemicholinium-3 had no effect on the muscarinic autoreceptor-mediated inhibition of [3H]ACh release by ACh. Altogether the present results do not support the previously proposed idea that in nerve terminals a functional coupling may exist between uptake mechanisms and presynaptic receptors.

Acetylcholine↗
PubMed1987

Interaction between neuronal uptake inhibitors and presynaptic serotonin autoreceptors in rat hypothalamic slices: comparison of K+ and electrical depolarization.

In rat hypothalamic slices prelabeled with [3H]-5-hydroxytryptamine ([3H]-5-HT), exposure to the 5-HT receptor agonist lysergic acid diethylamide (0.1-1 microM) or 5-methoxytryptamine (0.1-10 microM) decreased in a concentration-dependent manner the release of 3H-transmitter elicited by high K+ or electrical stimulation. Exposure to the 5-HT autoreceptor antagonist methiothepin (0.1-1 microM) increased in a concentration-dependent manner the K+ stimulation-evoked overflow of [3H]-5-HT and a similar increase was observed under conditions of electrical stimulation. In contrast, exposure to the nontricyclic 5-HT uptake inhibitor citalopram (0.1-1 microM) did not modify by itself the electrically evoked overflow of [3H]-5-HT, but increased in a concentration-dependent manner the release of 3H-transmitter elicited by K+ stimulation. This effect of citalopram on transmitter release was potentiated when the endogenous stores of 5-HT were depleted by pretreatment with para-chlorophenylalanine methyl ester (300 mg/kg i.p.). Citalopram was shown previously to antagonize the inhibition by lysergic acid diethylamide of the electrically evoked release of [3H]-5-HT in rat hypothalamic slices. Yet, this inhibitor of neuronal uptake of 5-HT did not antagonize the effects of lysergic acid diethylamide when the release of [3H]-5-HT was evoked by K+ depolarization. Electrical stimulation represents a more physiological experimental model for transmitter release than exposure to high K+, and therefore the interaction between 5-HT uptake blockade and presynaptic inhibitory 5-HT autoreceptors, observed in the hypothalamus with electrical stimulation but not with K+ depolarization, remains of biological relevance.

5-Methoxytryptamine↗
PubMed1990

(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity.

The stimulus properties of 3,4-methylenedioxymethamphetamine (MDMA)-like compounds were studied in rats trained to discriminate saline from (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] hydrochloride (7.18 mumol/kg; 1.75 mg/kg), the alpha-ethyl homolog of MDMA. In previous experiments with (+)-MBDB as a test drug, complete substitution was observed for MDMA but not for (+)-lysergic acid diethylamide or (+)-amphetamine. In the study reported here, the (+)-MBDB cue generalized to MDMA and the parent drug, 3,4-methylenedioxyamphetamine. All three drugs exhibited a similar stereoselectivity, the (+)-isomer having potency greater than the (-)-isomer. By contrast, the hallucinogens, (+)-lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine and mescaline and the psychostimulants (+)-amphetamine and (+)-methamphetamine did not substitute for (+)-MBDB. Cocaine produced partial substitution. The results support the hypothesis that the primary behavioral activity of MDMA-like compounds is unlike that of hallucinogens and stimulants and may represent the effects of a novel drug class, given the name entactogens. Although the mechanism of action for the discriminative stimulus properties of MDMA-like compounds is not known, there is evidence that presynaptic serotonergic, but not dopaminergic, mechanisms are critical. Finally, 5,6-methylenedioxy-2-aminoindan a non-neurotoxic 3,4-methylenedioxyamphetamine rigid analog that was previously found to substitute for MDMA but not for (+)-lysergic acid diethylamide was found in the study described here to substitute completely for (+)-MBDB. The N-methyl derivative 5,6-methylenedioxy-2-methylminoindan produced similar results. The demonstration of entactogen-like discriminative stimulus properties, for drugs devoid of neuronal degenerative toxicity potential, serves as evidence of the independent mechanisms for these effects in rats.

3,4-Methylenedioxyamphetamine↗
PubMed1982

Serotonin-stimulated cyclic AMP synthesis in the rabbit corneal epithelium.

Serotonin increases the level of cyclic AMP in incubated rabbit corneas; the concentration of agonist producing half-maximal stimulation is approximately 1.5 microM. Nialamide, an inhibitor of monoamine oxidase, potentiates the response to serotonin but not to epinephrine. Amitriptyline, an inhibitor of neuronal uptake of serotonin, does not potentiate the stimulation of cyclic AMP synthesis. Lysergic acid diethylamide, but not timolol, antagonizes the response to serotonin; the half-maximal inhibitory concentration is approximately 6 nM lysergic acid diethylamide. A comparison of the time course of the increase in cyclic AMP synthesis after addition of serotonin or epinephrine to the incubation media indicates that serotonin, but not epinephrine, must penetrate a barrier to its free diffusion. We conclude that the corneal epithelium contains specific serotonergic receptors that, upon activation, cause the synthesis of cyclic AMP, which mediates the stimulation of chloride transport (c.f. companion article, Klyce et al.). The serotonergic receptors must be at a location posterior to the beta-adrenergic receptors, which are on the anterior-surface of the apical cells.

1-Methyl-3-isobutylxanthine↗
PubMed1999

The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens.

In a previous study it was observed that fluoxetine potentiates the stimulus effects of lysergic acid diethylamide (LSD). In the present investigation, stimulus control was established in groups of rats using as training drugs the hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 3 mg/kg). A two-lever, fixed-ratio 10, positively reinforced task with saline controls was employed. The hypotheses tested were that (a) monoamine uptake inhibitors other than fluoxetine potentiate the discriminative effects of LSD, and (b) hallucinogens other than LSD are potentiated by acute pretreatment with monoamine uptake inhibitors. The effects of a range of doses of each of the training drugs were determined both alone and following pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine. In LSD-trained subjects, all three reuptake inhibitors caused a significant increase in LSD-appropriate responding. Similar results were observed in rats trained with (-)-DOM and with ibogaine. In 5-MeO-DMT-trained subjects, only fluoxetine resulted in an enhancement of drug-appropriate responding. The reuptake inhibitors given alone elicited varying degrees of responses appropriate for the respective training drugs. For fluoxetine in rats trained with LSD and ibogaine, for venlafaxine in LSD trained, and for fluvoxamine in (-)-DOM trained, the degree of responding met our criterion for intermediate responding, i.e., significantly different from both training conditions. Subsequent experiments in (-)-DOM-trained subjects examined a range of doses of each of the reuptake inhibitors in combination with a fixed dose of (-)-DOM (0.1 mg/kg), which alone yielded about 50% (-)-DOM-appropriate responding. With the exception of the point obtained with the highest dose of venlafaxine, all data were compatible with additivity of effects rather than true potentiation. In summary, the present data extend our previous observation of the augmentation of the stimulus effects of LSD by fluoxetine to include other hallucinogens. The mechanisms by which these interactions arise and possible differential effects of acute and chronic treatment remain to be established.

Adrenergic Uptake Inhibitors↗
PubMed1961

A quantifiable behavioral correlate of psychotogen and tranquilizer actions.

A representative psychotogen, lysergic acid diethylamide (LSD-25), in doses small enough to be devoid of gross effects, increases response latency in rats to a tone indicating the availability of water reward; this effect is greatly reduced by prophylactic administration of a representative phenothiazine tranquilizer, chlorpromazine (CPZ), in doses that per se do not affect performance. The nature of the chlorpromazine action and its competition with lysergic acid diethylamide is revealed by the effects of chlorpromazine in larger doses.

Animals↗
PubMed1975

LSD as an agonist at mesolimbic dopamine receptors.

The dopamine agonist apomorphine (1.0 mg/kg i.p.) produced an enhanced stimulation of locomotor activity compared to control animals in rats injected bilaterally 14 days previously with 6-hydroxydopamine (6OHDA) into the nucleus accumbens. (+)-Lysergic acid diethylamide (LSD) also produced a marked stimulation of locomotor activity in the 6OHDA treated animals at a dose (1.0 mg/kg i.p.) which was ineffective in control rats. (+)-Bromo-lysergic acid diethylamide (2.0 mg/kg i.p.) did not stimulate locomotor activity in 6OHDA treated rats. The locomotor stimulation produced by LSD was blocked by pretreatment with the dopamine antagonist pimozide (0.5 mg/kg i.p.). It is suggested that LSD acts as an agonist at mesolimbic dopamine receptors.

Animals↗
PubMed1961

Effect of 5-hydroxytryptamine on the respiration of excised lamellibranch gill.

5-Hydroxytryptamine, but not acetylcholine or catecholamines, stimulated the endogenous respiration of the excised gills of Modiolus demissus and mytilus edulis. Respiratory stimulation by 5-hydroxytryptophan is presumed to have occurred only after it had been decarboxylated to 5-hydroxytryptamine. 2-Bromolysergic acid diethylamide inhibited the effect of 5-hydroxytryptamine, while lysergic acid diethylamide mimicked it. The glycogen that was degraded during incubation of the gill cannot account for all of the oxygen that was consumed, indicating that some other substrate within the gill was also oxidized. That the metabolic actions of 5-hydroxytryptamine may be related to its cilio-acceleratory activity is discussed.

5-Hydroxytryptophan↗
PubMed1967

2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug.

We have assessed the effects in normal control volunteers of 2,5-dimethoxy-4-methyl-amphetamine, the chemical present in the hallucinogenic drug STP, in two independent trials. In low doses, this compound produces a mild euphoria. Doses greater than 3 milligrams may cause pronounced hallucinogenic effects lasting about 8 hours and similar to those produced by hallucinogenic doses of lysergic acid diethylamide, mescaline, and psilocybin. 2,5-Dimethoxy-4-methyl-amphetamine, which is chemically related to mescaline and amphetamine, is about 100 times more potent as a hallucinogen than mescaline and only one-thirtieth as potent as lysergic acid diethylamide. Its psychological effects are not accentuated by chlorpromazine.

Adult↗
PubMed1998

Homologous desensitization of the D1A dopamine receptor: efficacy in causing desensitization dissociates from both receptor occupancy and functional potency.

The role of drug efficacy in agonist-induced desensitization was studied in C-6 glioma cells transfected with the monkey dopamine D1A (mD1A) receptor. Dopamine pretreatment for 2 hr produced greater than 80% loss of responsiveness in the stimulation of cAMP accumulation that was blocked by the D1 antagonist SCH23390. A series of full and partial D1 agonists from structurally dissimilar classes were then examined. Three full agonists (dihydrexidine, SKF82958, A77636) desensitized the receptor to the same extent as dopamine, whereas two other full agonists (dinapsoline and A68930) and all the partial agonists tested (SKF38393, pergolide and d-lysergic acid diethylamide tartrate) produced only partial desensitization (i.e., 50% that of dopamine). Whereas partial agonists (i.e., SKF38393, pergolide and d-lysergic acid diethylamide tartrate) caused no alteration in ligand-accessible mD1A receptors, four of the full agonists (dopamine, dihydrexidine, dinapsoline, A68930) caused a 30 to 40% reduction in receptor number. One full agonist, A77636, caused nearly an 80% decrease in receptor number, despite the fact that the degree of functional desensitization was similar to the other full agonists. The desensitization of the D1 receptor was homologous, not affecting beta-2 adrenergic receptors endogenous to C-6 cells. Neither incubation with cAMP analogs, nor inhibition of protein kinase A, affected dopamine-induced desensitization, suggesting a cAMP-independent mechanism in this cell line. Together, these data suggest that functional desensitization of the mD1A receptor expressed in C-6 glioma cells is a cAMP-independent mechanism, cannot be predicted reliably from agonist efficacy for stimulating adenylate cyclase and can occur in the absence of changes in receptor number.

Animals↗
PubMed1969

LSD: autoradiographic study on the placental transfer and tissue distribution in mice.

(14)C-lysergic acid diethylamide administered intravenously passed in a few minutes from the blood into the tissues. In addition to the brain, the adrenals, hypophysis, kidneys, liver, and lungs showed the highest uptake, much higher than the blood concentration. Excretion into the bile started immediately; this was the most inmportant elimination route. In the early stage of pregnancy, 2.5 percent (and in the late stage, 0.5 percent) of the radioactive dose passed the placental barrier into the fetus in 5 minutes. Over 70 percent of this fetal radioactivity was unchanged (15)C-lysergic acid diethylamide.

Animals↗
PubMed1986

Lack of effect of antagonists on serotonin-induced inhibition in rat hippocampus.

Four putative central nervous system 5-hydroxytryptamine antagonists, methysergide, cyproheptadine, metergoline, and ketanserin and also lysergic acid diethylamide were applied by iontophoresis to firing CA1 hippocampal pyramidal cells to test their action on the inhibition produced by 5-hydroxytryptamine. In contrast to a previous report, none of these peripherally active 5-hydroxytryptamine antagonists altered the inhibitory response to submaximal doses of 5-hydroxytryptamine, but they did block after-excitations that followed the inhibitions. All the antagonists and lysergic acid diethylamide produced a depression of firing. When picrotoxin was used to drive the cells, 5-hydroxytryptamine was still able to produce a normal inhibition. The results of this study suggest that CA1 hippocampus is another structure, innervated by serotonergic neurones, where all (peripherally active) serotonin antagonists tested to date are ineffective against 5-hydroxytryptamine induced inhibition.

Action Potentials↗