Showing papers on "Serotonin published in 1976"

Synaptic facilitation and behavioral sensitization in Aplysia: possible role of serotonin and cyclic AMP.

Abstract: The neural changes accompanying sensitization of the gill-withdrawal reflex in Aplysia are associated with presynaptic facilitation at monosynaptic connections between sensory neurons and motor cells. To analyze the molecular mechanisms underlying the facilitation, the pharmacological actions of serotonin, octopamine, and dopamine were examined. Only serotonin enhanced synaptic transmission between the sensory and the motor neurons. A serotonin antagonist, cinanserin, reversibly blocked the synaptic facilitation. The action of serotonin may be mediated by adenosime 3',5'-monophosphate (cyclic AMP). Exposing the ganglion to dibutyryl cyclic AMP or injecting cyclic AMP into the cell body enhances the synaptic action of a sensory neuron. The mechanism of presynaptic facilitation, therefore, may include activation of one or more serotonergic neurons, which enhance the release of a neurotransmitter by increasing the intracellular concentration of cyclic AMP in the terminals of the sensory neurons.

Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain.

Abstract: Several compounds of relatively rigid molecular structure have been found to exert strong blockade of monoamine uptake by synaptosomal preparations of rat corpus striatum (dopamine and serotonin) and hypothalamus (norepinephrine). These include CP-24,441 (1R, 4S-N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine), EXP-561 (4-phenylbicyclo[2.2.2]octan-1-amine), nomifensine and nefopam. The well-defined molecular geometry of the potent inhibitor EXP-561 is a fundamental structural/conformational requirement for uptake blocking activity for the large family of phenylbutylamine- and phenoxypropylamine-related inhibitors. The tubular configuration of EXP-561 may be the most appropriate for blocking serotonin uptake. The requisite conformation for blocking dopamine uptake appears to be defined by the combination resulting from superimposition of the CP-24,441 and nomifensine structures. The conformation defined by the combination resulting from superimposition of the CP-24-441 and desipramine structures is apparently optimal for blocking norepinephrine uptake. The conformational requirements for diphenylpropylamine-related uptake blockers may be defined by the rigid compound CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2-naphthylamine). The actual potency of any given inhibitor is probably modulated by additional structural and stereochemical factors.

Serotonin and Lysergic Acid Diethylamide Binding in Rat Brain Membranes: Relationship to Postsynaptic Serotonin Receptors

Abstract: [3H]Serotonin (5-HT) binds to membrane preparations of rat brain in a saturable fashion and with substrate specificity and regional variations consistent with its binding to the postsynaptic serotonin receptor. The dissociation constant for [3H]5-HT binding is about 8 nM, and the total number of 5-HT binding sites in the brain is 16 pmoles/g of tissue, wet weight. There is considerable structural specificity in the affinity of various tryptamines for the [3H]5-HT binding sites, with a crucial role played by the 5-hydroxy substituent. d-[3H]Lysergic acid diethylamide (LSD) binding sites have substrate specificity requirements similar to the [3H]5-HT binding sites, but the 5-hydroxy substituent is less critical. 5-HT and related agonists have about 100 times more affinity for 5-HT than LSD binding sites, while classical 5-HT antagonists have 4-100 times greater affinity for LSD binding sites. LSD itself has a similar affinity for 5-HT and LSD binding sites. Raphe lesions which result in degeneration of 5-HT neurons do not lower [3H]5-HT binding, indicating that binding does not take place to presynaptic 5-HT neurons. Regional variations in serotonin and LSD binding are fairly similar. Highest binding occurs in the corpus striatum, hippocampus, and cerebral cortex, with lowest binding in the cerebellum. The ontogeny of 5-HT and LSD binding sites is nearly identical and does not appear to depend on functionally intact presynaptic 5-HT neuronal input.

Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine.

Abstract: Loss of brain serotonin was associated with overeating and increased body weight. Rats injected with p-chlorophenylalanine intraventricularly began overeating after 3 days and continued to display marked hyperphagia, primarily in the daytime, accompanied by increased body weight for 1 to 2 weeks. The effect was related to drug dose and to the degree and duration of serotonin depletion. Norepinephrine and dopamine levels were not significantly affected. It is concluded that p-chlorophenylalanine disinhibits feeding, as it does a number of other behaviors, by depleting serotonin. This suggests that hypothalamic lesions or dietary deficiencies which selectively and sufficiently deplete serotonin would lead to overeating.

Behavioral evidence for supersensitivity following destruction of central serotonergic nerve terminals by 5,7-dihydroxytryptamine.

Abstract: Previous studies have established that a complex behavioral syndrome--consisting of tremor, rigidity, hindlimb abduction. Straub tail, lateral head weaving and reciprocal forepaw treading--is a specific reflection of the activity of central serotonin receptors. This syndrome was utilized in the present study to test for supersensitivity in the central serotonergic system. Specific destruction of central serotonin nerve terminals by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 50 mug) in adult male rats pretreated with a catecholamine uptake blocking agent resulted in marked supersensitivity to serotonin precursors and agonists. The greatest degree of supersensitivity was observed in response to L-5-hydroxytryptophan, for which the ED50 for elicitation of the syndrome was 20% of the value for control rats. A lesser degree of supersensitivity was seen in response to L-tryptophan (following monoamine oxidase inhibition) and the direct-acting serotonin agonist, 5-methoxy-N,N-dimethyltryptamine, for which the ED50 was approximately 50% of the control value in both cases. Supersensitivity begins to develop within 24 hours and is relatively complete by 96 hours after 5,7-DHT. A marked subsensitivity to the serotonin releasing agent, fenfluramine, was found in 5,7-DHT-treated rats. In contrast to the marked supersensitivity to serotonin precursors and agonists which occurs following 5,7-DHT, chronic administration of a serotonin synthesis inhibitor, p-chlorophenylalanine (400 mg/kg every 3 days for a total of 24 days), did not produce supersensitivity to L-5-hydroxytryptophan or 5-methoxy-N,N-dimethyltryptamine. Possible pre- and postsynaptic mechanisms for the development of supersensitivity are discussed.

An inhibitory role for brain serotonin-containing systems in the locomotor effects of d-amphetamine.

Abstract: Locomotor activity induced by d-amphetamine was found to be potentiated by food deprivation, a tryptophan-free diet, p-chlorophenylalanine and drugs proposed to antagonize serotonin receptors in brain. Administration of L-tryptophan 1 hour prior to d-amphetamine injection was found to antagonize the enhanced response to d-amphetamine in starved rats and in rats which had tryptophan removed from their diet. However, tryptophan did not block the potentiated response to d-amphetamine in animals pretreated with p-chlorophenylalanine. These findings suggested that the antagonism of d-amphetamine-induced activity by tryptophan in starved rats and rats fed a tryptophan-free diet was not due to a nonspecific depressant effect of the amino acid. Since accumulation of d-amphetamine and its metabolites was not affected by any of the treatments which enhanced its activity, it seems unlikely that an alteration in the metabolism of d-amphetamine can explain these findings. The present work provides additional support for the view that serotonergic fibers play an important role in the actions of d-amphetamine.

Binding interactions of lysergic acid diethylamide and related agents with dopamine receptors in the brain.

Abstract: In most brain regions saturable binding of d -[3H]lysergic acid diethylamide ([3H]LSD) appears to involve postsynaptic serotonin receptors. In calf caudate, however, a portion of [3H]LSD binding involves postsynaptic dopamine receptors. Thus, in the hippocampus of calf brain, dopamine competes for [3H]LSD binding sites with a single low-affinity component, while in the caudate dopamine competition for [3H]LSD binding displays both high- and low-affinity components. The high-affinity component, accounting for 15-20% of [3H]LSD binding, displays a Ki value for dopamine of about 30 nM, similar to the KD for the binding of [3H]dopamine itself to postsynaptic dopamine receptors in the calf caudate. Addition of serotonin to the incubations increases the proportion of [3H]LSD binding in the caudate competed for by dopamine with high affinity, presumably by occupying serotonin receptors. d -LSD competes stereospecifically for [3H]dopamine binding in the caudate, consistent with the conclusion that LSD binds to dopamine receptors. Of numerous serotonin agonists and antagonists examined, several ergot alkaloids have high affinity for [3H]dopamine receptor binding in calf caudate, with Ki values similar to that of d -LSD. ACKNOWLEDGMENTS We thank Janet Ryan for excellent technical assistance.

The effects of quipazine on 5-HT metabolism in the rat brain.

Abstract: Since quipazine is a potent 5-HT agonist in peripheral organs, its possible stimulatory effects on serotoninergic receptors in the rat brain were investigated. Quipazine administration (10 mg/kg, i.p.) induced a significant decrease in the synthesis and turnover rates of serotonin in the brain stem as well as in the forebrain. It is not likely that these changes were mediated by a negative feed-back mechanism triggered by a direct action of quipazine on central 5-HT postsynaptic receptors. Indeed, in contrast to LSD and 5-methoxy-N,N-dimethyltryptamine, this compound failed to activate the 5-HT sensitive adenylate cyclase in colliculi homogenates of newborn rats. However, quipazine exerted direct effects on serotoninergic terminals. It inhibited competitively the reuptake process in synaptosomes (Ki=1.38 X 10(-7) M) and stimulated the K+ evoked release of newly synthesized 3H-5-HT in slices of the brain stem. Injected in vivo in a dose which affected 5-HT uptake and release, quipazine did not modify MAO activity. However, this activity was non-competitively inhibited by high concentratin of the drug in vitro (Ki=3.0 X 10(-5) M). These actions are very likely indirectly responsible for the stimulation of central 5-HT receptors.

Serotonin, noradrenaline, dopamine metabolites in transcendental meditation-technique

Abstract: The highly significant increase of 5-HIAA (5-hydroxyindole-3-acetic acid) in Transcendental Meditation technique suggests systemic serotonin as "rest and fulfillment hormone" of deactivation-relaxation. Furthermore 5-HT (5-hydroxytryptamine, serotonin) is considered to be the EC-cell (enterochromaffine-cell) hormone requested by Fujita and Kobayashi and its role for EEG synchronisation via area postrema chemoreceptor as anti arousal agent is being discussed. The significant decrease of the catecholamine metabolite VMA (vanillic-mandelic acid) in meditators, that is associated with a reciprocal increase of 5-HIAA supports as a feedback necessity the "rest and fulfillment response" versus "fight and flight". As the adreno medullary tissue serves for hormonal reinforcement of orthosympathetic activity, the Enterochromaffine Cell System (having taken the form of distinct organs in some species as octopus and discoglossus) is suggested to serve via serotonin for humoral reinforcement of parasympathetic activity in deep relaxation.

Neurotoxic indoleamines and monoamine neurons.

Abstract: In 1968 Thoenen & Tranzer (1) discovered that the long-lasting depletion of NA in sympathetically innervated organs by 6-OH-DA is due to degeneration of NA terminals. This provided the basis for the development of a new concept in neurobiological research: the method of selective chemical neurodegeneration. The successful application of this method to produce degeneration of DA and NA neurons in brain (2,3) stimulated a search for compounds with comparable effects on central 5-HT neurons. In studies with a restricted number of 5-HT analogs, we were able to show that certain dihydroxylated tryptamines caused toxic damage to serotonin terminals. The recent findings by Bjorklund, Baumgarten & Rensch (4) and Gerson & Baldessarini (5) that DMI treatment prior to intraventricular 5,7-DHT injection prevents the damaging effect of the latter drug on NA but not on 5-HT neurons indicate that powerful and probably rather selective destruction of central indoleamine-containing axons and terminals can be achieved.

Neurochemical correlates of behavior

Abstract: Publisher Summary This chapter describes the measurement of changes in the levels of transmitter or modulator suspects, such as acetylcholine (Ach), 5-hydroxytryptamine (serotonin or 5-HT), and norepinephrine (NE) as well as their associated enzyme systems in specific brain areas and their temporal relationship to changes in the quantitatively measured behavior of animals. A number of nitrogen-containing compounds called neurotransmitters or modulators have major effects on the behavior of living organisms by their individual or grouped action on the central nervous system. The results show that the injections of the serotonin precursor, 5-hydroxytryptophan, produces a behavioral disruption in pigeons or rats working on approach schedules of reinforcement and caused an elevation of serotonin levels in the forebrain structures during the same time period that the behavior was depressed. Changes in a telencephalic cholinergic system and a midbrain noradrenergic system probably operate in the maintenance of the behavioral excitation.

Cholinergic stimulation of the rat hypothalamus: effects of liver glycogen synthesis

Abstract: Cholinergic stimulation of the lateral hypothalamic neurons with intrahypothalamic microinjections of acetylcholine or carbachol caused a marked increase in the content of the active form of glycogen (starch) synthase in the liver. Total activity of the enzyme (active plus inactive forms) was not increased significantly. The lowest effective dose of acetylcholine was 5 X 10(-10) mole, and the optimum dose was 5 X 10(-9) mole. Similar applications of other neurotransmitters, such as norepinephrine, dopamine, serotonin, and gamma-aminobutyric acid, did not affect the enzyme's activity.

The role of free serum tryptophan in the biphasic effect of acute ethanol administration on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid.

Abstract: 1. Acute administration of ethanol exerts a biphasic effect on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. Both effects are associated with corresponding changes in the availability of circulating free tryptophan. 2. The initial increases in the above concentrations are prevented by ergotamine, are unaltered by allopurinol and are potentiated by theophylline, whereas the later decreases are prevented by both ergotamine and allopurinol. 3. It is suggested that the initial enhancement by ethanol of brain tryptophan metabolism is caused by catecholamine-mediated lipolysis followed by displacement of protein-bound serum tryptophan, whereas the activation of liver tryptophaan pyrrolase, which is produced by the same mechanism, leads to the later decreases in the brain concentrations of tryptophan and its metabolites. 4. The initial effects of ethanol can be reproduced by an equicaloric dose of sucrose, and a comparison of the two treatments alone could therefore be misleading. 5. The effects of ethanol on liver and brain tryptophan metabolism have also been examined in mice, and a comparison of the results with those previously reported suggests that the ethanol effects are strain-dependent.

Serotonin deficiency and prolonged bleeding in beige mice.

Abstract: Beige mice have been observed to bleed excessively from small wounds. Platelets obtained from these mice were deficient in adenine nucleotides and serotonin and in vivo uptake of labeled serotonin was impaired. Heterozygotes of beige and C57BL/6 mice have adenine nucleotide and serotonin levels comparable to control and do not manifest a bleeding tendency, consistent with the recessive mode of inheritance of the beige mouse syndrome. Morphologic confirmation of the observed biochemical defects was obtained by the demonstration that serotonin storage organelles were not observed in electron photomicrographs of beige mouse platelets. The demonstration that small doses of serotonin were effective in reversing the bleeding tendency in beige mice suggested a causal role for defective storage and release of endogenous serotonin as the basis for the bleeding tendency, acting either independently or synergistically with impaired release of adenine nucleotides.

Serotonin accumulation in the guinea-pig myenteric plexus: ion dependence, structure-activity relationship and the effect of drugs.

Abstract: The specific accumulation of serotonin in neurons of the guinea-pig myenteric plexus was examined. Nonadrenergic neurons have been shown to be responsible for this accumulation. Serotonin accumulation, known to be sodium-dependent, was found to be inhibited by elevating the external potassium concentration. Accumulation was inversely related to the concentration of potassium and was also decreased in the presence of 0 mM Ca++ or 12 mM Ca++. The affinity of analogous molecules for the myenteric plexus was greatly reduced in compounds which had no alkyl amino side chain, in which the amino group was methylated or which had no 5-hydroxyl group. Most analogs competitively inhibited serotonin accumulation and 6-hydroxytryptamine was demonstrated by histofluorescence to be taken up into the myenteric plexus after chemical sympathectomy with 6-hydroxydopamine. Serotonin accumulation was also inhibited by tricyclic antidepressants and amphetamines. The inhibition of serotonin accumulation by these compounds differed from their inhibition of accumulation of norepinephrine. As in the central nervous system, chlorimipramine was the most potent tricyclic antidepressant against accumulation of serotonin while desmethylimipramine was the most potent inhibitor of the accumulation of norepinephrine. Amphetamines were more effective inhibitors of serotonin accumulation than were tricyclic antidepressants, but all of these drugs were more effective against the accumulation of norepinephrine than serotonin. This study confirms the existence of a unique population of axons int he mammalian myenteric plexus which are distinguishable by their characteristic accumulation of serotonin and have not been found elsewhere in the peripheral nervous system.

The role of serotonergic pathways in isolation-induced aggression in mice.

Abstract: Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed beteen potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced aggression is discussed.

Dopaminergic Agents: Influence on Serotonin in the Molluscan Nervous System

Abstract: Treatment of the mussel Mytilus edulis with 6-hydroxydopamine or with alpha-methyl-p-tyrosine decreased dopamine and increased serotonin in the nervous system. Treatment with dopamine decreased serotonin concentrations and prevented the effect of 6-hydroxydopamine. The serotonin concentration appears to be determined in part by the concentration of dopamine.

Cerebral arterial spasm. Part 4: in vitro effects of temperature, serotonin analogues, large nonphysiological concentrations of serotonin, and extracellular calcium and magnesium on serotonin-induced contractions of the canine basilar artery.

Abstract: In vitro experiments were performed using a small volume chamber to study serotonin-induced contractions of the canine basilar artery. Temperature was found to have a profound effect on the artery's response to serotonin. Raising the temperature to 40 degrees C (104 degrees F) increased the maximum response by 20% and lowering the temperature by 10 degrees C caused a 40% reduction in the maximum contraction. Cumulative log-dose response curves for analogues of serotonin demonstrated a high degree of specificity for the serotonin receptor and large nonphysiological concentrations of serotonin caused relaxation of the contracted artery. Extracellular calcium was shown to be an absolute requirement for serotonin-induced contractions. Extracellular magnesium, in contrast, was shown to inhibit serotonin-induced contractions.