High-affinity 3H-serotonin binding to caudate: Inhibition by hallucinogens and serotoninergic drugs

Whitaker, Patricia M.; Seeman, Philip

doi:10.1007/bf00428022

Cited by 56 publications

(13 citation statements)

References 11 publications

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“…3) [3H]LSD (with APS) was similar to that found in our work on 5-[3H1hydroxytryptamine binding (39). The two sets of data are correlated in Fig.…”

Section: Discussionsupporting

confidence: 82%

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

Whitaker¹,

Seeman²

1978

Proc. Natl. Acad. Sci. U.S.A.

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Since it was known that d-lysergic acid diethylamide (LSD) affected catecholaminergic as well as serotoninergic neurons, the objective in this study was d-Lysergic acid diethylamide (LSD) has been extensively studied since its discovery (1). The structural resemblance of serotonin (2) to LSD was subsequently noted, and evidence accumulated suggesting that LSD exerts its effects through the serotoninergic neurotransmitter system (3-11). Convincing evidence also indicates dopaminergic involvement in LSD activity (12)(13)(14)(15)(16)(17)(18)(19) clearance); this piston, rotating at 500 rpm, was passed up and down 10 times. The crude homogenate was incubated at 370C for 60 min and then stored in 5-ml aliquots at -20°C for future use. Before use, the samples were thawed, resuspended with an additional 5 ml of buffer, and centrifuged at 39,000 X g for 15 min at 4°C. The supernatant was discarded and the pellet was resuspended in 15 ml of buffer by using five up-and-down strokes of a ground-glass homogenizer. This suspension was then homogenized by a Polytron homogenizer (Brinkmann, Westbury, NY) at a setting of 7 (full range = 10) for 10 sec, using a PT-10 homogenizer probe and a 50-ml polycarbonate tube to contain the suspension. This resulted in a final protein concentration of 0.2 mg per tube. Because the membrane homogenate was made up immediately prior to use, it was not necessary to store it on ice.Serotonin-Specific [3HJLSD Binding Assays. The assays were done by using 12 X 75 mm glass test tubes in which the following aliquots were placed (Eppendorf Brinkmann pipettes with polypropylene tips) for control binding: 0.1 ml of nonradioactive LSD (final concentration, 200 nM) or 0.1 ml of buffer; 0.1 ml of buffer containing apomorphine, phentolamine, and spiperone (final concentration, 50 nM for each, referred to as the APS system); 0.2 ml of [3H]LSD (11.5 Ci/mmol; New England Nuclear; final concentration, 2.0 nM); and 0.2 ml of brain homogenate. For tubes with varying concentrations of drugs competing against [3H]LSD, the final contents of the tubes were the same as for control except that the 0.1 ml of buffer or nonradioactive LSD was replaced with 0.1 ml of drug solution.Abbreviations: LSD, d-lysergic acid diethylamide; IC50, concentration that inhibits [3HJLSD binding by 50%; APS system, mixture containing 50 nM each of apomorphine, phentolamine, and spiperone.

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“…3) [3H]LSD (with APS) was similar to that found in our work on 5-[3H1hydroxytryptamine binding (39). The two sets of data are correlated in Fig.…”

Section: Discussionsupporting

confidence: 82%

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

Whitaker¹,

Seeman²

1978

Proc. Natl. Acad. Sci. U.S.A.

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“…In the present study, although RU 24969 was of moderate potency, it was considerably less potent than serotonin, suggesting that the site is not identical to the 5 HT-1 B site (Hoyer et al, 1986b;Peroutka, 1986). It may thus be possible that the site we describe in human putamen is similar to the 3H-serotonin binding site described in bovine caudate nucleus (Fillion et al, 1978;Whitaker and Seeman, 1978;Heuring and Peroutka, 1987). Although limited, the pharmacological data obtained in the present study are similar to that described for 3H-serotonin binding in bovine caudate nucleus (Heuring and Peroutka, 1987).…”

Section: Discussionsupporting

confidence: 87%

High affinity serotonin binding sites in human brain: a comparison of cerebral cortex and basal ganglia

Cross¹,

Slater

1989

J. Neural Transmission

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The high-affinity binding of 3H-serotonin and 3H-DPAT was studied in membrane preparations and tissue sections of cerebral cortex and basal ganglia of human brain. In tissue sections, 3H-serotonin bound to sites present at high density in the cerebral cortex, hippocampus and basal ganglia. 3H-DPAT bound predominantly to the outer layers of the cerebral cortex and the hippocampus, no significant binding was observed in the basal ganglia. In cortical membranes 3H-serotonin bound to a heterogeneous population of sites, one of which was similar to a binding site labelled by 3H-DPAT (the putative 5HT-1A receptor). 3H-serotonin binding to membranes prepared from the putamen displayed low affinity for DPAT, mesulergine and spiperone, RU24969 was considerably less potent than serotonin itself. This 3H-serotonin binding site does not have the properties of those sites described in rodent brain (5HT-1A, 5HT-1B, and 5HT-1C), and may represent a novel serotoninergic binding site.

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“…In ongoing studies using this agonist, pregnant rats are injected from gestational day 12 until birth and then the pups injected individually up until postnatal day 20 at a dose of 1 mg/kg. 5‐MT has relatively high potency at all tested serotonin receptors, approximately 1/10th the potency of serotonin itself (Whitaker and Seeman, 1978a, 1978b). Using this potency and known pharmacokinetic principles for calculating blood concentration based on the presumed volume of distribution, this dose would approximate the effects of the 50% increase in blood serotonin seen in autism.…”

Section: Animal Studies Relevant To Hyperserotonemia and Autismmentioning

confidence: 99%

Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

Whitaker‐Azmitia

2004

Intl J of Devlp Neuroscience

252

192

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The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so-called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood-brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5-methoxytryptamine (5-MT). In work using 5-MT to mimic hyperserotonemia, Sprague-Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and "autistic-like" behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear-responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.

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High-affinity 3H-serotonin binding to caudate: Inhibition by hallucinogens and serotoninergic drugs

Cited by 56 publications

References 11 publications

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

High affinity serotonin binding sites in human brain: a comparison of cerebral cortex and basal ganglia

Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

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