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The cardiovascular effects of intraventricular 5,6-dihydroxytryptamine in conscious hypertensive rats.

1. Conscious experimental hypertensive rats injected intraventricularly with 5,6-dihydroxytryptamine (50 microgram) responded with a rapid and long-lasting (4 days) fall in blood pressure and this was accompanied by a bradycardia of similar duration. 2. The acute actions of 5,6-dihydroxytryptamine on the cardiovascular system were not modified by pretreatment with bromolysergide (0.5 mg/kg, i.p.), methysergide (2.5 mg/kg, i.p.) or intraventricular phentolamine (200 microgram). 3. The results suggest that central serotonergic neurones play an important role in the regulation of blood pressure. However, the site of action remains to be investigated.

5,6-Dihydroxytryptamine

Correlation between the increase in tyrosine hydroxylase activity and the decrease in serotonin content in the rat locus coeruleus after 5,6-dihydroxytryptamine.

A correlation is demonstrated between the increase in tyrosine hydroxylase activity and the decrease in serotonin concentration in the rat locus coeruleus after various doses of 5,6-dihydroxytryptamine and gradual protection of serotonin neurons by pretreatment with two serotonin uptake inhibitors: fluoxetine or citalopram.

5,6-Dihydroxytryptamine

Hippocampal innervation by serotonin neurons of the midbrain raphe in the rat.

The organization of the brainstem serotonin neuron projection to the hippocampal formation was analyzed in the rat. This projection arises in the raphe nuclei of the midbrain. Following destruction of the midbrain raphe nuclei, chiefly nucleus centralis superior, there is a 72% decrease in hippocampal serotonin content. Injection of tritiated amino acid into the midbrain raphe nuclei results in transport of tritiated protein to the hippocampal formation and this transport is blocked in animals pretreated by intraventricular administration of 5,6-dihydroxytryptamine (5,6-DHT). Autoradiographic analysis indicates that the transport reaches the hippocampal formation primarily via two major pathways, the cingulum and the fornix. Cingulum fibers terminate predominantly in the dorsal hippocampus whereas the fornix distributes throughout the entire hippocampal formation. Some fibers reach the ventral hippocampus from the entorhinal area. Within the hippocampus there is dense labeling in a restricted lamina of the CA1 stratum lacunosum-moleculare with moderate labeling in stratum radiatum. Stratum oriens is sparsely labeled in CA1 and moderately so in CA2 and CA3. Stratum radiatum and stratum lacunosum-moleculare are moderately densely labeled in CA2 and Ca3. The area dentata is sparsely to moderately labeled in the molecular layer and heavily labeled in a thin lamina of the hilar zone immediately beneath the granule cell layer. The remaining hilar zone is moderately labeled. All of the discrete labeling of the hippocampus and area dentata described above is absent in animals pretreated with 5,6-DHT. These observations indicate that serotonin neurons of the midbrain raphe provide a highly organized innervation of the hippocampal formation in the rat.

5,6-Dihydroxytryptamine

Evaluation of the cytotoxicity of dihydroxytryptamines and 5-hydroxytryptamine antagonists as cytotoxic agents in dimethylhydrazine-induced adenocarcinomata.

The cytotoxicity of 5,6-dihydroxytryptamine (5,6-DHT), 5,7-dihydroxytryptamine (5,7-DHT), bromolysergic acid diethylamide (BOL), methysergide, and cyproheptadine, and also of 5,6-DHT together with either BOL, methysergide, or cyproheptadine in dimethylhydrazine-induced (DMH) carcinomata of rat colon was evaluated by estimating the percentage of necrotic cells in histological sections of tissues taken 15 h after injection of each of the drugs. In addition, the influence of methysergide and cyproheptadine on the tumour cell mitotic rate was estimated by means of a stathmokinetic technique. Both 5,6-DHT and 5,7-DHT were cytotoxic at each dose tested and for each of these agents the percentage of necrotic cells was directly correlated with the dose of drug used. BOL was not found to be cytotoxic to the colonic carcinomata, whereas both methysergide and cyproheptadine did cause detectable tumour cell necrosis. Methysergide was also found to accelerate tumour cell proliferation, whereas cyproheptadine did not. BOL competitively inhibited the cytotoxicity of 5,6-DHT and neither methysergide nor cyproheptadine potentiated the effect of 5,6 DHT.

5,6-Dihydroxytryptamine

Methodological problems in the measurement of drug-induced rotational behaviour: continuous recording reveals time-course differences undetected by previous techniques.

Rats were lesioned unilaterally in the medial forebrain bundle with either the catecholamine neurotoxin 6-hydroxydopamine or the indoleamine neurotoxin 5,6-dihydroxytryptamine. Their rotational responses in automated rotameters to a challenge with the dopamine-receptor agonist apomorphine were compared using four different techniques in current use, and by assessment of complete rotation curves using both conventional statistical procedures and elementary computer-derived elements of curvature. The rotational responses of the two groups, characterized neurochemically by identical depletions of striatal dopamine but with a greater depletion of striatal 5-hydroxytryptamine in 5,6-dihydroxytryptamine-lesioned animals, were indistinguishable using each of the four current techniques. Assessment of rotation curves by both methods revealed significant differences between the two groups, characterised by faster onset and offset of the rotational response in 5,6-dihydroxytryptamine-lesioned animals. Some current techniques may implicitly exclude the detection of such time-course differences in rotational behaviour. Assessment of complete rotation curves may best allow valid comparisons between experimental groups.

5,6-Dihydroxytryptamine

Studies on membrane receptor sites for serotonin in the brain.

The competitive effect of 5,6-dihydroxytryptamine, morphine and chlorpromazine on the binding of serotonin (5-HT) to rat brain slices was investigated. Ths busynaptosomal localization of the binding of morphine in bovine midbrain preparations was compared to that of 5-HT and found to be considerably higher. The condensation of 5-HT and tryptamine receptor carbonyl groups in brain with phenylisopropylhydrazine was shown in vitro and vivo. Membrane particles labeled with [14C] tryptamine or 5-HT in presence or absence of sodium borohydride (NaBH4) were extracted with chloroform-methanol (C-M) 2:1. The labeled proteolipid precipitated by ether from these extracts showed on electropherograms one single radioautographic spot which was more intense with samples treated with sodium borohydride. In column chromatography, the bound radioactivity peak eluted with the gel void volume, was associated with a protein peak. The eluted, lyophilized material of this fraction was extracted by chloroform methanol (2:1) thus suggesting its proteo-lipid nature.

5,6-Dihydroxytryptamine

Specificity of serotoninergic inhibition in Limulus lateral eye.

The receptor specificity for synaptically mediated lateral inhibition in Limulus lateral eye retina was studied by structure-activity correlations of the action of the putative indoleaminergic neurotransmitter, serotonin (5-HT), and its isomers and structural analogs, tryptamine (TRYP), 6-hydroxytryptamine (6HT), 5,6-dihydroxytryptamine (5,6-DHT), 5-hydroxydimethyltryptamine (5-HDMT), and 5-hydroxytryptophan (5-HTP). The 5-HT blockers, lysergic acid diethylamide (LSD), bromo-LSD (BOL), and cinanserin, were also tested. The inhibitory action of the indoleaminergic agonists is highly structure-specific. An hydroxyl group in the 5 position of the indole nucleus, sterically unencumbered by hydroxyls in neighboing positions, is essential. In order of decreasing potency, 5-HT, 5-HDMT, and 5-HTP are active agonists; TRYP, 6-HT, and 5,6-DHT are inactive. Configuration and mobility of the side chains of the active agonists also affect the interaction, and these side-chain characteristics correlate with agonist potency. The receptors for inhibitory action and for transmembranal transport in reuptake are different. Both active agonists and inactive analogs appear to be taken up (Adolph and Ehinger, 1975. Cell Tissue Res. 163:1-14). LSD and BOL have bimodal actions: direct inhibition and agonist blockade. These actions may be mediated via low-specificity presynaptic uptake receptor sites rather than highly specific, postsynaptic, agonist receptor sites.

5-Hydroxytryptophan

Serotonin neurons of the midbrain raphe: ascending projections.

The ascending projections of serotonin neurons of the midbrain raphe were analyzed in the rat using the autoradiographic tracing method. Axons of raphe serotonin neurons ascend in the ventral tegmental area and enter the medial forebrain bundle. A number of fibers leave the major group to ascend along the fasciculus retroflexus. Some fibers enter the habenula but the majority turn rostrally in the internal medullary lamina of the thalamus to innervate dorsal thalamus. Two additional large projections leave the medial forebrain bundle in the hypothalamus; the ansa peduncularis-ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate medial hypothalamus and median eminence and form a contrelateral projection via the supraoptic commissures. Rostrally the major group in the medial forebrain bundle divides into several components: fibers entering the stria medullaris to terminate in thalamus; fibers entering the stria terminalis to terminate in the amygdala; fibers traversing the fornix to the hippocampus; fibers running through septum to enter the cingulum and terminate in dorsal and medial cortex and in hippocampus; fibers entering the external capsule to innervate rostral and lateral cortex; and fibers continuing forward in the medial olfactory stria to terminate in the anterior olfactory nucleus and olfactory bulb.

5,6-Dihydroxytryptamine