Serotonergic influences on the social behavior of vervet monkeys (Cercopithecus aethiops sabaeus)

The behavioral effects of altering serotonin neurotransmission by chronic drug treatments in socially living vervet monkeys (Cercopithecus aethiops sabaeus) were examined. Animals received tryptophan (TRP, 20 mg/kg/day), parachlorophenylalanine (PCPA, 80 mg/kg/day), 5-hydroxytryptophan (5-HTP, 40 mg/kg/day), chlorgyline (10 mg/kg/day), or PCPA followed by concurrent PCPA and 5-HTP. Grooming, approaching, resting, and eating were increased by TRP and decreased by PCPA; TRP decreased and PCPA increased locomoting, avoiding, being solitary, and being vigilant. Grooming, being vigilant, and receiving aggression were increased by 5-HTP, and PCPA increased initiating aggression and decreased huddling. Concurrent administration of 5-HTP and PCPA reversed the effects of PCPA on approaching, grooming, and resting; augmented the PCPA effects on avoiding, being solitary, and aggression; and did not alter the PCPA effects on eating, locomoting, and huddling. Chlorgyline increased grooming, approaching, and being vigilant and decreased being solitary. No treatment significantly affected sexual behavior. These data suggest that serotonergic systems contribute relatively substantially to the mediation of grooming and approaching, participate less strongly in resting and locomoting, are implicated still more weakly in being solitary, avoiding, and being vigilant, and have little if any involvement in huddling, aggression, and sexual behavior.     

Renshaw cell discharge at the beginning of muscular contraction and its relation to the silent period

Renshaw cell activity was recorded simultaneously with the motoneuronal discharge during vibration or stretch of the triceps muscles. Both the monosynaptic reflex responses and the phasic discharge of Renshaw cells elicited by the first stroke of the vibrator or by the onset of muscle extension were followed by a period of silence in their electrical recordings. The Renshaw cell burst, recorded at the onset of both stimuli, coincided with the early part of the silent period in motoneuronal discharge. It preceded the onset of muscle contraction and ended within 30 to 40 ms after the silent period began. The silent period could still persist after the pause in the discharge of the primary endings of muscle spindles had completely disappeared. On the basis of these findings, the view that recurrent inhibition could contribute to the early part of the silent period is strongly favored.     

Effects of increasing serotonergic receptor activity in brain on analgesic activity in rats

In the rat, increasing serotonergic receptor activity or functional serotonin in the brain with inhibitors of serotonin reuptake (such as fluoxetine and chlorimipramine), with serotonin, or with the serotonin precursor, 5-hydroxytryptophan, in combination with the peripheral decarboxylase inhibitor benserazide had a significant analgesic effect shown by an increase in the latency to hind-paw lick in the hot plate test. The data indicate that activation of central serotonergic receptors with inhibitors of serotonin reuptake, serotonin, or the serotonin precursor produced pain inhibition.     

Comparison of Stress-induced Changes in Noradrenergic and Serotonergic Neurons in the Rat Hippocampus Using Microdialysis

The effects of stress on the serotonergic and noradrenergic projection to the hippocampus were compared in freely moving rats using microdialysis. Stress-induced changes in 5-hydroxytryptamine (5-HT), noradrenaline and their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the presence of their respective uptake blockers. Local infusion of tetrodotoxin and replacement of Ca²⁺ with Cd²⁺ were used to test dependence on impulse traffic. A 5 min tail pinch or 10 min restraint stress increased 5-HT, 5-HIAA, noradrenaline and DOPAC levels. A subcutaneous saline injection produced an increase in 5-HT and DOPAC but not noradrenaline or 5-HIAA. Although α₂ adrenoceptor agonists and antagonists produced changes in the baseline values of noradrenaline and DOPAC, they had little or no effect on stress-induced changes. Both the abolition of impulse traffic and its enhancement by stress had a greater effect on transmitter than on metabolite levels. Although the responses to stress of the noradrenergic and serotonergic pathway showed many similarities, there was evidence for their activation by separate pathways.     

Inhibition of pontine omnipauser neurons in the cat by 5-hydroxytryptophan

We assessed ocular motor nerve discharges and omnipause neuronal activity in six adult alert cats before and after intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP). In all animals, 5-HTP inhibited omnipause neuron activity synchronously with a disappearance of high-frequency bursts of the ocular motor nerves associated with vestibular-induced fast components. This effect was rapidly reversed by the serotonin blocker, methysergide. Our findings are most consistent with an indirect effect of 5-HTP on omnipause neurons.     

Plasma Serotonergic Activation in Rats during the Course of Experimental Allergic Neuritis

Abstract: The plasma serotonin (5-HT) levels in Lewis rats were measured during the course of experimental allergic neuritis (EAN) induced by use of purified bovine myelin. The plasma 5-HT levels in EAN rats were significantly higher than those in control rats 15 days (day 15) and 20 days (day 20) after the inoculation. On day 15 and day 20, the 5-hydroxytryptophan levels in the EAN rats were higher than those in the control rats. It is suggested that 5-HT plays a role in the clinical course of EAN.     

3H]paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region.

The high-affinity binding of [3H]paroxetine to membranes was measured in different regions of the rat and rabbit brain: cingulate, frontal, parietal, piriform, entorhinal, and visual cortical areas; dorsal and ventral hippocampus; rostral and caudal halves of neostriatum (rat) or caudate nucleus and putamen (rabbit); ventral mesencephalic tegmentum; and midbrain raphe nuclei region. The tissue concentrations of serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxy-l-tryptophan (5-HTP) were also determined by high-performance liquid chromatography (HPLC) in the same brain samples. The regional density of [3H]paroxetine binding varied in both species; the highest values (Bmax) were found in the midbrain raphe region and ventral mesencephalic tegmentum. The cortical values ranged from moderate to low, with a significantly higher density in the cingulate cortex of the rat compared with rabbit. In the rat, there was also a higher density in the ventral than dorsal hippocampus, and the caudal than rostral neostriatum. In the rabbit, the hippocampal and neostriatal values were generally lower and more uniform. In both species, there was an excellent correlation between regional 5-HT levels and specific [3H]paroxetine binding (r = 0.87 in the rat and 0.96 in the rabbit). Considering the available quantitative data on the number of 5-HT nerve cell bodies and axon terminals in different regions of the rat brain, it appears likely that the high amount of [3H]paroxetine binding in the midbrain raphe region and ventral mesencephalic tegmentum reflects the presence of 5-HT uptake sites on 5-HT nerve cell bodies and dendrites as well as axon terminals. In other brain regions, the heterogeneous distribution of [3H]paroxetine binding parallels that of the number of 5-HT axon terminals, emphasizing the potential usefulness of this radioligand as a marker of 5-HT innervation density.     

Histaminergic mechanisms in amygdaloid-kindled seizures in rats

The present study was undertaken to clarify the role of histaminergic neuron system on amygdaloid kindled seizures in rats. A significant decrease in histamine contents in the amygdala was observed after development of amygdaloid kindling. Histidine and metoprine inhibited amygdaloid kindled seizures at doses causing an increase in histamine contents of the brain. H₁-antagonists (diphenhydramine and chlorpheniramine) attenuated histidine-induced inhibition of amygdaloid kindled seizures, however no significant antagonism was observed with H₂-antagonists (zolantidine and ranitidine). The development of amygdaloid kindling was retarded by repeated administration of histidine. These findings suggest that histaminergic mechanisms play a suppressive role in amygdaloid kindled seizures through histamine H₁-receptors.     

5-HT2A/C receptors mediate the antipsychotic-like effects of alstonine

The purpose of this study was to determine the effects of alstonine, an indole alkaloid with putative antipsychotic effects, on working memory by using the step-down inhibitory avoidance paradigm and MK801-induced working memory deficits in mice. Additionally, the role of serotonin 5-HT_2A/C receptors in the effects of alstonine on mouse models associated with positive (MK801-induced hyperlocomotion), negative (MK801-induced social interaction deficit), and cognitive (MK801-induced working memory deficit) schizophrenia symptoms was examined. Treatment with alstonine was able to prevent MK801-induced working memory deficit, indicating its potential benefit for cognitive deficits now seen as a core symptom in the disease. Corroborating previously reported data, alstonine was also effective in counteracting MK801-induced hyperlocomotion and social interaction deficit. Ritanserin, a 5-HT_2A/C receptor antagonist, prevented alstonine's effects on these three behavioral parameters. This study presents additional evidence that 5-HT_2A/C receptors are central to the antipsychotic-like effects of alstonine, consistently seen in mouse models relevant to the three dimensions of schizophrenia symptoms.     

Serotonergic stimulation of corticotropin-releasing hormone and pro-opiomelanocortin gene expression

The neurotransmitter serotonin (5-HT) stimulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland via activation of central 5-HT1 and 5-HT2 receptors. The effect of 5-HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin-releasing hormone (CRH). We therefore investigated the possible involvement of CRH in the serotonergic stimulation of ACTH secretion in male rats. Increased neuronal 5-HT content induced by systemic administration of the precursor 5-hydroxytryptophan (5-HTP) in combination with the 5-HT reuptake inhibitor fluoxetine raised CRH mRNA expression in the paraventricular nucleus (PVN) by 64%, increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary lobe by 17% and stimulated ACTH secretion five-fold. Central administration of 5-HT agonists specific to 5-HT1A, 5-HT1B, 5-HT2A or 5-HT2C receptors increased CRH mRNA in the PVN by 15-50%, POMC mRNA in the anterior pituitary by 15-27% and ACTH secretion three- to five-fold, whereas a specific 5-HT3 agonist had no effect. Systemic administration of a specific anti-CRH antiserum inhibited the ACTH response to 5-HTP and fluoxetine and prevented the 5-HTP and fluoxetine-induced POMC mRNA response in the anterior pituitary lobe. Central or systemic infusion of 5-HT increased ACTH secretion seven- and eight-fold, respectively. Systemic pretreatment with the anti-CRH antiserum reduced the ACTH responses to 5-HT by 80% and 64%, respectively. It is concluded that 5-HT via activation of 5-HT1A, 5-HT2A, 5-HT2C and possibly also 5-HT1B receptors increases the synthesis of CRH in the PVN and POMC in the anterior pituitary lobe, which results in increased ACTH secretion. Furthermore, the results indicate that CRH is an important mediator of the ACTH response to 5-HT.     

SEROTONERGIC MECHANISMS IN AMYOTROPHIC LATERAL SCLEROSIS

Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.     

Effects of bright artificial light on monoamines and neuropeptides in eight different brain regions compared in a pigmented and nonpigmented rat strain.

Seasonal affective disorder is a form of depression which recurs at the same time of the year. Exposure to bright artificial light at a dose of 2,500 lux is used to treat seasonal affective disorders. We exposed a pigmented (Brown Norway) and a nonpigmented (Sprague-Dawley) rat strain with bright artificial light for 21 days at two doses (2,500 and 6,100 lux) and analyzed dopamine, dihydroxyphenyl-acetic acid, 5-hydroxytryptamine (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) by high performance liquid chromatography (HPLC) and electrochemical detection in eight different brain regions. Furthermore, we measured tissue levels of substance P (SP), neurokinins (NK), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) with radioimmunoassay. Our data obtained with light microscopy show that bright artificial light at both doses induced a massive destruction of photoreceptors in the retina of albino rats but not of the pigmented rat strain. Retinal lesion of photoreceptors resulted in increased tissue levels of all measured neuropeptides except SP in the hypothalamus and increased VIP in the ventral tegmental area/substantia nigra. Furthermore, increased 5-HT and 5-HIAA tissue levels were found in the ventral tegmental area/substantia nigra. In contrast, in the frontal cortex there was a significant reduction in 5-HIAA tissue levels and a decreased 5-HIAA/5-HT ratio, indicating decreased 5-HT metabolism. Light exposure of the pigmented rat strain revealed no changes in the measured biogenic amines and neuropeptides in any investigated brain region. Our data suggest that retinal lesion but not direct visual neurotransmission induced changes in neurotransmitters in some brain regions. We conclude that Brown Norway rats but not Sprague-Dawley rats are useful to study neurochemical effects of bright artificial light. However, Sprague-Dawley rats may be a useful tool to study biochemical mechanisms of photoreceptor damage by bright light.     

Serotonergic mechanisms in brains of suicide victims

Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT₁, 5-HT₁ and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [³H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression.     

Changes in serotonin in rat brain during slow-wave sleep and paradoxical sleep: application of the microwave fixation method to sleep research

Neural responses to several chemicals of the pit organs and terminal buds on the facial skin of the carp were compared electrophysiologically. Nerve inpulses from the pit organs were larger than those from the terminal buds. The pit organs were more sensitive to salts and especially acids than the terminal buds. The former did not respond to sucrose, silk worm pupa extract, betaine and amino acids except acidic ones. The latter, however, responded well to them.     

Phencyclidine inhibition of the rate of development of amygdaloid kindled seizures

Administration of (5, 10, 20 or 35 mg/kg, i.p.) phencyclidine (PCP) 15 min prior to each stimulation significantly reduced the rate of kindling induced by daily electrical stimulation of the amygdala in the rat. All four doses significantly reduced the rate of kindling measured by the behavioral ranking (BR) and the afterdischarge duration (AD). The drug at 2.5 mg/kg had no significant effect on the rate of kindling. The 20- and 35-mg/kg PCP doses significantly reduced the afterdischarge duration evoked by the first stimulation to 40.2 ± 16.1% and 13.5 ± 9.2% (mean ± se) of the control value. The 5- and 10-mg/kg doses reduced the initial AD to approximately 65% of control. After switching from PCP to normal saline all rats kindled. The 5-mg/kg group which was injected 12 days with PCP required 15.0 ± 0.9 stimulations to develop a maximal BR whereas the control group required only 10.2 ± 0.5 stimulations. The saline controls were injected with 5 mg/kg PCP after their BR was maximal. This dose minimally reduced the AD to 88.8 ± 6.8% of the previous two stimulations and had no effect on the BR. It is apparent that 5 mg/kg PCP will inhibit the initial afterdischarge and the rate of kindling while minimally affecting fully kindled seizure activity. Naloxone at 6 mg/kg failed to reverse the inhibition of the rate of kindling produced by 5 mg/kg PCP daily. Neither 5 mg/kg morphine, an opiate agonist, nor 5 mg/kg quipazine, a serotonergic agonist, significantly affected the rate of kindling in similar experiments. Pretreatment of rats with 10 or 20 mg/kg PCP once daily for 4 days prior to the beginning of daily kindling stimulations did not affect the rate of kindling.     

Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis

Summary Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT_1a agonists, (±)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT_1a/b agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinylpyrolo[1,2-a]-quinoxaline (CGS 12066B), the 5-HT_1a/b ligands and -adrenoceptor antagonists, (±)pindolol and (±)alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT_1a /5-HT₂ antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT_1a antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT₂ agonist, (±)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT₂ antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT_1a or 5-HT₂ receptors and that other receptors may be involved.     

Tryptophan metabolism and the occurrence of amino acids and serotonin in the leech (Hirudo medicinalis) nervous system.

The occurrence and distribution of serotonin (5-HT) and amino acids along the central nerve chain of the leech, Hirudo medicinalis, was analyzed using dansyl-chloride in order to obtain information on the functional roles of amines and amino acids. There was no statistical variation in the occurrence of most of the amino acids or serotonin in the different parts of the dorsal nerve chain of the leech. A variation in the serotonin content was found during the year with the highest level occurring in winter. Leech ganglia also accumulated 3H-tryptophan and metabolized part of it to form 5-HTP, 5-HT, and 5-HIAA. The results are discussed from the point of view of 5-HT being a transmitter substance.     

Time-dependent effects of actinomycin S3 on sleep and brain concentrations of 5-hydroxytryptamine in the rat

Changes in the sleep pattern were investigated in rats given actinomycin S3 (AcS3, 0.25 mg/kg, intraventricularly), an inhibitor of RNA synthesis, at 0000, 0600, 1200, and 1800. The amounts of slow-wave (SS) and paradoxical sleep (PS) were increased during the dark period (1800 to 0600) in the groups treated at 0000, 0600, and 1200. In the 1800 injected group, PS was decreased. 5-Hydroxytryptamine (5-HT) was determined in the 0600 injected group. The 5-HT concentration in the AcS3-treated group was twofold higher than in the control group at 1800 (12 h after administration) in the cerebral cortex and lower brain stem but returned to control values at 0000 (18 h after) while sleep time continued to increase. Thus, AcS3 affected the circadian rhythm of the sleep-wake cycle. The increase of sleep time in the dark period was independent of changes in brain 5-HT content.     

Pineal vasotocin and sleep: Involvement of serotonin containing neurons

Extremely small amounts (10^?4 pg) of arginine vasotocin (AVT) injected into the third ventricle of unanesthetized cats induce non-rapid eye movement (NREM) sleep and suppress rapid eye movement (REM) sleep. The same amount (10^?4 pg) of intraventricularly injected AVT increased at 15 and 30 min 5-hydroxytryptamine (5-HT) and decreased at 30 and 60 min 5-hydroxyindole acetic acid (5-HIAA) levels of the brain. Fluoxetine, a specific 5-HT uptake inhibitor, greatly enhanced the NREM sleep induced by AVT. Neither arginine vasopressin, nor oxytocin at the doses used (10^?4 pg), was able to affect indole levels of the brain or to enhance NREM sleep and to suppress REM sleep after fluoxetine, demonstrating the high specificity of AVT effects. Methergoline, a selective central 5-HT receptor blocker, completely prevented AVT induction of NREM sleep. Extremely small amounts of AVT (10^?6 pg), which in some cats were unable to induce NREM sleep and to suppress REM sleep, become effective after pretreatment with small amounts of 5-hydroxytryptophan (5-HTP). It is suggested that AVT induces NREM sleep and suppresses REM sleep by interfering with 5-HT release at postsynaptic receptor sites. The present results strongly support the monoaminergic theory of sleep providing the first evidence that a peptide synthesized by the brain induces sleep by a serotoninergic mechanism.     

Serotonergic receptors in the brain of in utero undernourished rats

In this study, we report that 5-HT(1A) receptors are already present in fractions of axonal growth cones, from the normal rat fetal brain (E-17). Also, in utero undernourished (UN) rat pups at birth show a noteworthy enhancement in the B(max) of [3H]5-hydroxytryptamine (5-HT) and [3H]8-hydroxy-(2-N,N-dipropilamin)-tetralin (([3H])8-OH-DPAT), in the brainstem and cerebral cortex up to the second week after birth. Afterwards, there is a significant decrease in the binding of these ligands. [125I]Cyanopindolo binding in the cerebral cortex only showed a decrease in the same period. An elevation of brain serotonin in both regions was also present. These findings together, suggest that the mechanisms of regulation of serotonergic receptors' expression during the period studied, may not depend on the amount of neurotransmitter in the synaptic cleft, because in the early UN brain it would be expected only a lower receptor's density due to the chronic serotonin increase. On this basis, we propose that developmental activation of brain serotonin biosynthesis observed in early UN animals may disrupt the mechanism regulating the expression of 5-HT receptors during development.