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PubMedDate not supplied

Bulbospinal serotonin neurons and hypotensive effects of methyldopa in the spontaneously hypertensive rat.

Systemic methyldopa administration in genetically hypertensive rats evoked a hypotension which was attenuated after prior treatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) given either intracerebroventricularly, to produce a generalised ablation of serotonin nerves in brain and spinal cord, or by injection into the cervical spinal cord, to cause a selective destruction of descending serotonin pathways. Direct microinjection of methyldopa into the ventrolateral medulla in the area of the B1 and B3 serotonin cells was also effective in lowering arterial pressure. The hypotensive response to this medullary administration of methyldopa was again attenuated by 5,7-DHT given either intracerebroventricularly or by intraspinal injection. On the other hand, prior treatment intracerebroventricularly with 6-hydroxydopamine did not affect the hypotensive effect of methyldopa injected into the region of the ventrolateral B1 and B3 cells, supporting the suggestion that this effect of methyldopa is mediated by bulbospinal serotonin neurons and not by descending catecholamine nerves. The fact that methyldopa injection into the ventrolateral medulla in a region coinciding with the B1 and B3 cells lowers blood pressure is consistent with previous studies demonstrating that these neurons serve to maintain or elevate arterial pressure.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa.

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.

5,7-Dihydroxytryptamine↗

PubMed1990

Differences in the central hypotensive actions of alpha-methyldopa and clonidine in the spontaneously hypertensive rat: contribution of neurons arising from the B3 and the C1 areas of the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is the proposed site of origin of bulbospinal excitatory vasomotor neurons, and this brainstem area gives rise to chemically distinct populations of neurons, including serotonin-containing neurons of the B3 group and epinephrine-containing neurons of the C1 group, which independently serve sympathoexcitatory functions. In the present study, we sought to establish (a) whether distinct and chemically specific pathways originating in the C1 or B3 regions are involved in the antihypertensive effects of alpha-methyldopa (methyldopa) and clonidine and (b) if so, whether these effects are related to an activation of alpha-adrenoceptors in these areas. Microinjections of methyldopa (6 nmol) or clonidine (5 nmol) were made in the C1 or B3 area in intact spontaneously hypertensive rats (SHR), pretreated with 5,7-dihydroxytryptamine (5,7-DHT) or with phentolamine. The microinjection of clonidine into both the B3 and the C1 area caused a rapid decrease in arterial pressure, whereas microinjection of methyldopa lowered the arterial pressure only after injection into the B3 area. Pretreatment with intracerebroventricular (i.c.v.) 5,7-DHT attenuated the hypotension produced by microinjection of clonidine into the B3 area, suggesting that this effect is mediated by serotonin-containing neurons. Central pretreatment with phentolamine reduced the hypotensive effects produced by injection of clonidine into either area and of methyldopa into the B3 region, consistent with previous suggestions that these central effects are mediated through alpha-adrenoceptors. These results suggest that both serotonin-containing and epinephrine-containing neurons contribute to the central action of clonidine, whereas the effects of methyldopa injection in RVLM appear to be mediated by serotonin-containing but not by epinephrine-containing neurons.

5,7-Dihydroxytryptamine↗

PubMed1991

Importance of central noradrenergic and serotonergic pathways in the cardiovascular actions of rilmenidine and clonidine.

We examined the role of central monoamine neurotransmitters noradrenaline and serotonin in the cardiovascular actions of the alpha 2-adrenoceptor agonist rilmenidine in the conscious rabbit and compared it to clonidine. Rilmenidine and clonidine were equieffective in producing a maximum 24% reduction in blood pressure and heart rate when given intracisternally (i.c.), but rilmenidine was approximately 20-30 times less potent than clonidine. The effective i.c. doses of both drugs were 25-30 times lower than those required peripherally (i.v.). Comparison of the time course of an equieffective dose of rilmenidine and clonidine showed that the time to reach maximum effect was 10 min for both drugs but time to recovery was greater for rilmenidine (2.5-3 h vs. 1.5 h for clonidine). Destruction of central noradrenergic neuron pathways with i.c. 6-hydroxydopamine attenuated the hypotensive and bradycardic actions of both rilmenidine and clonidine at 2, 4, and 8 weeks after treatment. The maximum observed attenuation of the hypotension was at 8 weeks (40% of control for rilmenidine and 29% for clonidine), while for the bradycardia this was at 2 weeks (9 and 2% of control, respectively) with some recovery by 8 weeks (29 and 50% of control). Destruction of the central serotonergic neurons with i.c. 5,6-dihydroxytryptamine also attenuated the hypotension and bradycardia to rilmenidine and clonidine but was slower in onset, needing the full 8 weeks to reach its maximum effect. At this time the hypotension and bradycardia to rilmenidine and clonidine were reduced to between 35 and 48% of control.(ABSTRACT TRUNCATED AT 250 WORDS)

5,6-Dihydroxytryptamine↗

PubMed1992

A CNS serotonergic mechanism in acute central hypovolemia in conscious rabbits?

We tested whether a brainstem serotonergic mechanism influences the hemodynamic response to acute central hypovolemia. An inferior vena caval cuff was gradually inflated so that mean cardiac index (MCI) fell at a constant rate (approximately 8%/min). Under control conditions, mean systemic vascular conductance index (MSVCI) fell progressively until MCI had fallen by approximately 50% (compensatory phase), at which point MSVCI rose abruptly and arterial pressure fell to approximately 40 mm Hg (decompensatory phase). Intravenous methysergide delayed the decompensatory phase and at a critical dose (300-3,000 nmol) abolished it. Methysergide had similar effects when injected into the fourth ventricle, pontomedullary cistern, or lateral ventricle in doses that were 7-10% of the critical i.v. dose, but had no effect when injected into the spinal subarachnoid space. LY53857 was equipotent to methysergide. None of these treatments attenuated the vasoconstriction of the first, compensatory, phase. Partial depletion of neuronal serotonin (after p-chlorophenylalanine or 5,7-dihydroxytryptamine treatment) had no effect on either phase. We conclude that a serotonergic mechanism, probably located in the brainstem, may be involved in the decompensatory phase of acute central hypovolemia.

5,7-Dihydroxytryptamine↗

PubMed1990

Single cell shape and population densities of indoleamine-accumulating and displaced bipolar cells in Reeves' turtle retina.

Two types of bipolar cell in the Geoclemys reevesii retina were studied quantitatively by means of specific cell labelling with an indoleamine derivative (5,6-dihydroxytryptamine, 5,6-DHT), a nucleic acid stain (4,6-diamidino-2-phenylindole, DAPI) and Lucifer yellow CH. Indoleamine-accumulating (IA) bipolar cells were selectively labelled with 5,6-DHT applied intraocularly. After the cells accumulated 5,6-DHT, the indoleamine fluorescence was photoconverted to diaminobenzidine products to allow observation of morphological details. Close examination of many cells (cell number; n = 120) showed that the IA bipolar cells consist of a single morphological type whose axon collaterals ramify sublaminae 1, 4 and 5 respectively. This terminal branching pattern corresponds to cells that hyperpolarize when their receptive field centres are illuminated (Weiler 1981). The density of IA bipolar cells was highest in the visual streak (4130 cells mm-2) and lowest at the peripheral margin (1970 cells mm-2). By applying a small amount of DAPI to the eye, nuclei located in the most proximal row of the outer nuclear layer were labelled selectively. By using selective intracellular dye injection into DAPI-labelled cells under fluorescence microscope (Tauchi & Masland 1984, 1985), these cells were found to have Landolt's clubs and single descending axons. Dye injections into more than fifty DAPI-labelled somata showed that they belonged exclusively to displaced bipolar cells. These comprised at least two subtypes that differ in the ramification pattern of their axon terminals within the inner plexiform layer: one was monostratified, whereas the other was bistratified. The displaced bipolar cell density was as high as 9400 cells mm-2 in the central retina, falling to 2000 cells mm-2 in the superior margin. In vitro Lucifer labelling revealed that the overall bipolar cell density in the central retina was as high as 39,300 cells mm-2. Both the conventionally located and displaced bipolar cells were included in this population. About 11% of the total bipolar cell population consisted of IA bipolar cells. Assuming that one half of the conventionally located bipolar cells are the centre-hyperpolarizing type, IA bipolar cells represent approximately 28% of the total. As displaced bipolar cells represent almost one quarter of the total bipolar population, the dislocation of their somata stands out morphologically, inviting investigation of possible functional correlates.

5,6-Dihydroxytryptamine↗

PubMed1995

Involvement of brainstem serotonergic interneurons in the development of a vertebrate spinal locomotor circuit.

Brainstem neurons modulate the rhythmic output of spinal locomotor circuitry in adult vertebrates, but how these influences develop is largely unknown. We demonstrate that the ingrowth of serotonergic axons to the spinal cord of Xenopus tadpoles plays a critical role in locomotor burst development by transforming the output of embryonic amphibian swimming circuitry into a more mature and flexible form. Our experiments show that exposure to a monoamine neurotoxin (5,7 dihydroxytryptamine) deletes serotonergic raphespinal projections and prevents the normal maturation of larval swimming. Furthermore, the mature larval rhythm resumes an embryo-like form following either a pharmacological blockade of serotonin receptors or when receptor activation is prevented by acute spinalization.

5,7-Dihydroxytryptamine↗

PubMed2006

Depletion of serotonin selectively impairs short-term memory without affecting long-term memory in odor learning in the terrestrial slug Limax valentianus.

The terrestrial slug Limax is able to acquire short-term and long-term memories during aversive odor-taste associative learning. We investigated the effect of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) on memory. Behavioral studies indicated that 5,7-DHT impaired short-term memory but not long-term memory. HPLC (high-performance liquid chromatography) analysis revealed that 5,7-DHT significantly reduced serotonin content in the central nervous system. The present study suggests that acquisition, retention, and/or retrieval of short-term memory involves serotonin, and neither acquisition nor retrieval of long-term memory requires serotonin at a level as high as that required for short-term memory.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

Importance of central serotonin neurons in the hypotensive action of methyldopa in the rat.

Normotensive (WKY) and stroke prone spontaneously hypertensive (SHR-SP) rats were given methyldopa (200 mg/kg i.p.) daily for five days and their brains were then sectioned and processed with the Faglu method for catecholamine fluorescence. This treatment with methyldopa induced a green fluorescence not seen in control animals, in cells coinciding with the B1-B9 groups of serotonin neurons in the brainstem. Pretreatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, i.c.v.), which is relatively specific for serotonin neurons, prevented the appearance of this green fluorescence in the serotonin cell groups of rats given methyldopa. Pretreatment with 5,7-DHT, i.c.v. approximately halved the magnitude of the hypotensive response to a single dose of methyldopa (80 mg/kg i.p.). We suggest that central serotonin nerves contribute to the hypotensive action of methyldopa. It is our hypothesis that methyldopa is taken up by these serotonin cells and that the green fluorescence reflects the production of alpha-methyldopamine, as a result of decarboxylation by the ubiquitous enzyme, L-aromatic amino acid decarboxylase.

5,7-Dihydroxytryptamine↗

PubMed1994

Host serotonin axons innervate intrastriatal ventral mesencephalic grafts after implantation in newborn rats.

This study investigated the potential of immature and adult serotonin (5-HT) neurons for axonal growth into intrastriatal grafts of ventral mesencephalic tissue. Implantation of dissociated fetal (embryonic days 14-15) ventral mesencephalic tissue was carried out in immature [postnatal days (P) 5-14] and adult rat neostriatum. The brains were processed 2-6 months later for dopamine and 5-HT immunocytochemistry. A few grafts implanted into adult and P7 recipients contained small numbers of cotransplanted 5-HT cell bodies. These also displayed a rich network of 5-HT axons, even in adult rats prelesioned with 5,7-dihydroxytryptamine, indicating the graft origin of these axons. All other grafts were totally devoid of 5-HT cell bodies. After implantation in adults, such grafts contained rare 5-HT axons. In contrast, in P5-P7 recipients, they displayed many 5-HT fibres, which were uniformly distributed. Such was no longer the case after implantation in P14 recipients, which showed minimal 5-HT innervation, as in adult recipients. Processing of naïve rat brain at different ages for 5-HT immunocytochemistry showed that 5-HT axons were still clearly less numerous in the neostriatum at P21 than in adults, whereas in the substantia nigra the 5-HT innervation developed more rapidly and was comparable, at P21, to that of adults. It was concluded that 5-HT axons are able to grow into ventral mesencephalic grafts, but mainly at the fetal stage and with decreasing capacity after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1995

Involvement of serotonin in developmental plasticity of kitten visual cortex.

During a critical period of postnatal development, neuronal connections in the kitten visual cortex are susceptible to experience-dependent modifications. These modifications are facilitated by the neuromodulators noradrenaline and acetylcholine. To address the question of whether serotonin (5-hydroxytryptamine; 5-HT), the other major neuromodulator in the cerebral cortex, also plays a role in developmental plasticity, we investigated whether interference with serotoninergic transmission in the kitten visual cortex affects ocular dominance (OD) plasticity. The serotonin neurotoxin 5,7-dihydroxytryptamine or the serotonin receptor blockers ketanserin and methysergide were infused into the visual cortex of kittens undergoing monocular deprivation. We found that both methods of disrupting serotoninergic transmission reduced OD plasticity. However, to be effective, the receptor blockers ketanserin and methysergide had to be applied in combination, suggesting that coactivation of serotonin receptor subtypes of both the 5-HT1 and 5-HT2 families have a permissive function in OD plasticity. Since activation of 5-HT2 receptors stimulates phosphoinositide hydrolysis, our data suggest that second messengers from the phospholipid pathway may play an important role in developmental plasticity of visual cortex.

5,7-Dihydroxytryptamine↗

PubMed1996

Acquisition of conditioned inhibition in rats is impaired by ablation of serotoninergic pathways.

The effects of chronically ablating the serotoninergic inputs to various regions of the rat brain on the ability to solve a feature-negative discrimination was measured. After intracerebroventricular administration of the specific neurotoxin 5,7-dihydroxytryptamine, the rats exhibited an impaired capacity to solve such a discrimination, irrespective of whether auditory or visual stimuli were used. Further behavioural analysis revealed that this effect was not due to a reduced capacity to form excitatory associations, since both groups responded equally to reinforced stimuli. By contrast, the lesion more likely resulted in a failure to endow the non-reinforced stimuli with inhibitory properties. This suggestion was supported by the observation that, in a retardation test, the conditioned inhibitor aroused less inhibition in the lesioned group than in vehicle-injected controls. Furthermore, the conditioned inhibitor failed to pass a summation test in lesioned animals, again indicating that their hampered ability to master the discrimination was the result of an impairment in the formation of inhibitory associations. It is concluded that destruction of central 5-hydroxytryptamine-containing pathways impairs the functioning of brain areas underlying inhibitory associative learning.

5,7-Dihydroxytryptamine↗

PubMed1996

Lesion study of the distribution of serotonin 5-HT4 receptors in rat basal ganglia and hippocampus.

The regional distribution of 5-hydroxytryptamine (5-HT4) receptors labelled with [3H]GR113808 was examined in rat basal ganglia and hippocampus after specific lesions. Lesion of serotonin neurons induced by injections of 5,7-dihydroxytryptamine into the dorsal and medial raphe nuclei resulted in increased 5-HT4 receptor binding in most regions examined, compared with controls. More precisely, there was a 78% increase in the rostral but no change in the caudal part of caudate-putamen, and 83% and 54% increases in the shell and core of the nucleus accumbens respectively. In the substantia nigra, the increase in 5-HT4 binding was larger (72%) than that in the globus pallidus (32%). In the hippocampus, 63%, 30% and 28% increases were measured in CA2, CA1 and CA3 respectively. Following lesion of dopamine neurons by intranigral injection of 6-hydroxydopamine, increased 5-HT4 receptor binding was observed in the caudal (59%), but not the rostral part of caudate-putamen, as well as in the globus pallidus (93%). Since no decreases in 5-HT4 receptor density were detected after the dopamine lesion, it was concluded that these receptors are not expressed in dopamine neurons. Kainic acid lesions of the caudate-putamen were associated with dramatic local decreases in 5-HT4 receptor binding on the injected side (-89%), which suggested that striatal neurons express 5-HT4 receptors. Corresponding decreases of 72 and 20% in receptor density were detected in globus pallidus and substantia nigra, consistent with a presumed localization of 5-HT4 receptors on striatal GABA neurons projecting to these regions. In the substantia nigra, the decrease in [3H]GR113808 binding was localized to the pars lateralis, indicating that striatal neurons belonging to the cortico-striato-nigro-tectal pathway, and containing GABA and dynorphin, express 5-HT4 receptors.

5,7-Dihydroxytryptamine↗

PubMed2006

Selective prefrontal serotonin depletion impairs acquisition of a detour-reaching task.

We have recently shown that serotonin in the primate orbitofrontal cortex (OFC) contributes to the flexible control of behaviour. 5,7-dihydroxytryptamine-induced 5-HT depletions of OFC impair performance on a serial reversal discrimination task [Clarke et al. (2004)Science, 304, 878-880]. The deficit is characterized by perseverative responding to the previously rewarded stimulus, a deficit similar to that seen following lesions of the intrinsic neurones of the OFC [Dias et al. (1996)Nature, 380, 69-72]. The effect is neurochemically selective as dopaminergic lesions of the OFC, induced by 6-hydroxydopamine, have no effect [Clarke et al. (2006)Cerebral Cortex]. In order to test for the generality of the effect of serotonin on orbitofrontal processing and, in particular, its effects on flexible behaviour, the present study investigated the effects of serotonin depletions of OFC on performance of another task dependent upon an intact OFC, the detour-reaching task [Wallis et al. (2001)European Journal of Neuroscience, 13, 1797-1808]. Successful performance of this task requires inhibition of the animal's prepotent response tendency to reach directly along its line of sight to the reward. Compared with sham-operated controls, we found that lesioned monkeys made significantly more barrier reaches directly along their line of sight to the visible reward during task acquisition. This finding provides further support for the role of prefrontal serotonin in inhibitory control processes specifically in tasks sensitive to OFC dysfunction.

5,7-Dihydroxytryptamine↗

PubMed1985

Assessment of noradrenaline and 5-hydroxytryptamine uptake in intact rat brain.

A method for the measurement of 3H-monoamine [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake into intact brain following intracerebroventricular injection is described. Most of the accumulated monoamine was associated with nerve terminals (synaptosomes). Radioactivity in the synaptosomal fraction was retained by 0.45-micron filters and was osmotically sensitive, features indicative of accumulation within particles rather than binding to membranes. [3H]5-HT associated with synaptosomes was reduced in animals pretreated with the neurotoxin 5,7-dihydroxytryptamine, in parallel with a reduction in endogenous 5-HT levels. Oral administration of tricyclic antidepressants including clomipramine, desipramine, and imipramine inhibited the synaptosomal accumulation of 3H-monoamines. Overall, the features of the accumulation of 3H-monoamines, after intracerebroventricular administration, displayed many of the characteristics expected of a physiological monoamine reuptake system.

5,7-Dihydroxytryptamine↗

PubMed1985

[3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to pre- and postsynaptic 5-hydroxytryptamine sites in various regions of the rat brain.

The specific binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([ 3H]8-OH-DPAT) to 5-hydroxytryptamine (5-HT)-related sites was investigated in several regions of the rat brain. Marked differences were observed in the characteristics of binding to membranes from hippocampus, striatum, and cerebral cortex. Hippocampal sites exhibited the highest affinity (KD approximately 2 nM) followed by the cerebral cortex (KD approximately 6 nM) and the striatum (KD approximately 10 nM). Ascorbic acid inhibited specific [3H]8-OH-DPAT binding in all three regions but millimolar concentrations of Ca2+, Mg2+, and Mn2+ enhanced specific binding to hippocampal membranes, whereas only Mn2+ increased it in the cerebral cortex and all three cations inhibited specific binding to striatal membranes. Guanine nucleotides (0.1 mM GDP, GTP) inhibited binding to hippocampal and cortical membranes only. As intracerebral 5,7-dihydroxytryptamine markedly decreased [3H]8-OH-DPAT binding sites in the striatum, but not in the hippocampus, the striatal sites appear to be on serotoninergic afferent fibers. In contrast, in the hippocampus the sites appear to be on postsynaptic 5-HT target cells, as local injection of kainic acid decreased their density. Both types of sites appear to be present in the cerebral cortex. The postsynaptic hippocampal [3H]8-OH-DPAT binding sites are probably identical to the 5-HT1A subsites, but the relationship between the presynaptic binding sites and the presynaptic autoreceptors controlling 5-HT release deserves further investigation.

5,7-Dihydroxytryptamine↗

PubMed1985

Further studies on the nature of postsynaptic dopamine uptake and metabolism in rat striatum: sodium dependency and investigation of a possible role for carrier-mediated uptake into serotonin neurons.

The nature of postsynaptic sites involved in the uptake and metabolism of striatal 3,4-dihydroxyphenylethylamine (dopamine, DA) was investigated. The accumulation of [3H]DA (10(-7) M) into slices of rat striatum was found to be greatly dependent (greater than 99%) on the presence of sodium ion in the incubation medium. However, the formation of the [3H]dihydroxyphenylacetic acid (DOPAC) and [3H]homovanillic acid (HVA) was only partially reduced in the absence of sodium (DOPAC, 27% of control; HVA, 47% of control). Inhibition of carrier-mediated DA neuronal uptake with nomifensine (10(-5) M) significantly decreased DA accumulation (18% of control) and [3H]DOPAC formation (62% of control), but enhanced [3H]HVA production (143% of control). Inhibition of the 5-hydroxytryptamine (5-HT, serotonin) neuronal uptake system with fluoxetine (10(-6) M) or selective 5-HT neuronal lesions with 5,7-dihydroxytryptamine (5,7-DHT) had no effect on [3H]DOPAC or [3H]HVA formed from [3H]DA in the presence or absence of nomifensine. These results demonstrate that the uptake and subsequent metabolism of striatal DA to DOPAC and HVA is only partially dependent on carrier-mediated uptake mechanism(s) requiring sodium ion. These data support our previous findings suggesting a significant role for synaptic glial cell deamination and O-methylation of striatal DA. Further, experiments with fluoxetine or 5,7-DHT suggest that 5-HT neurons do not significantly contribute in the synaptic uptake and metabolism of striatal DA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Identification of multiple binding sites for [3H]5-hydroxytryptamine in the rat CNS.

Recent studies indicate that there may be multiple subtypes of [3H]5-hydroxytryptamine ([3H]5-HT) binding sites. Mianserin and spiperone inhibited the specific binding of [3H]5-HT (2-3 nM) to rat brain cortical membranes with shallow displacement curves. The displacement data for spiperone were best described by the presence of three independent binding sites, for which spiperone had high, medium, and low affinities. The displacement data for mianserin were best fitted by two independent, high- and low-affinity sites. The inclusion of mianserin (250 nM) to inhibit [3H]5-HT binding to the mianserin-sensitive site selectively blocked one of the sites discriminated by spiperone. These results suggest the presence of three binding sites for [3H]5-HT, one blocked by low concentrations of spiperone (5-HT1A), one blocked by low concentrations of mianserin (5-HT1C), and one blocked only by high concentrations of both mianserin and spiperone (5-HT1B). Regional differences in the relative densities of the three sites were observed. The hippocampus was rich in 5-HT1A sites, whereas the striatum contained mainly 5-HT1B and 5-HT1C sites. Selective degeneration of 5-HT-containing nerve terminals induced by the neurotoxin 5,7-dihydroxytryptamine increased binding to all three sites in the cerebral cortex. Binding of [3H]5-HT to the three sites was differentially modulated by CaCl2 and guanylimidodiphosphate. The present data suggest the presence of three independent 5-HT1 binding sites having different affinities for mianserin and spiperone and having different regional distributions.

5,7-Dihydroxytryptamine↗