Brain Serotonin Turnover Research Articles

Evidence for involvement of 5-hydroxytryptamine 1B autoreceptors in the enhancement of serotonin turnover in the mouse brain following repeated treatment with fluoxetine

The effect of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine on synthesis and turnover of 5-hydroxytryptamine (5-HT) was studied in the mouse brain in vivo. The concentration of 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was measured in hypothalamus, hippocampus and frontal cortex after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Fluoxetine 6.9 mg/kg s.c. was injected once daily for three weeks. Three days after the final daily injection of fluoxetine 5-HT synthesis (5-HTP accumulation) and turnover (5-HIAA/5-HT ratio) were significantly enhanced compared with saline-treated mice. The 5-HIAA/5-HT ratio was already significantly elevated after 3 days of fluoxetine treatment and continued to increase during treatment for 2–3 weeks. The increase in 5-HIAA/5-HT ratio was considerably larger (150–200% of controls) than the increase in 5-HTP accumulation (110–120%), which reached significance only after 3 weeks of treatment. The increase in 5-HT synthesis may be secondary to that of the turnover. The 5-HIAA/5-HT ratio returned to control values after a 14 days washout period. Simultaneous treatment with the long-acting 5-HT 1B-receptor antagonist, SB 224289 for 14 days counteracted the fluoxetine-induced increase in 5-HIAA/5-HT ratio that indicates involvement of 5-HT 1B autoreceptors in the development of this increase. It is proposed that the fluoxetine-induced enhancement of 5-HT turnover was evoked by the long-lasting stimulation of 5-HT 1B autoreceptors that resulted in an intraneuronal compensatory adaptation of the basal 5-HT release.

Tryptophan metabolism in alcoholism

Acute and chronic alcohol (ethanol) intake and subsequent withdrawal exert major effects on tryptophan (Trp) metabolism and disposition in human subjects and experimental animals. In rats, activity of the rate-limiting enzyme of Trp degradation, liver Trp pyrrolase (TP), is enhanced by acute, but inhibited after chronic, ethanol administration, then enhanced during withdrawal. These changes lead to alterations in brain serotonin synthesis and turnover mediated by corresponding changes in circulating Trp availability to the brain. A low brain-serotonin concentration characterizes the alcohol-preferring C57BL/6J mouse strain and many alcohol-preferring rat lines. In this mouse strain, liver TP enhancement causes the serotonin decrease. In man, acute ethanol intake inhibits brain serotonin synthesis by activating liver TP. This may explain alcohol-induced depression, aggression and loss of control in susceptible individuals. Chronic alcohol intake in dependent subjects may be associated with liver TP inhibition and a consequent enhancement of brain serotonin synthesis, whereas subsequent withdrawal may induce the opposite effects. The excitotoxic Trp metabolite quinolinate may play a role in the behavioural disturbances of the alcohol-withdrawal syndrome. Some abstinent alcoholics may have a central serotonin deficiency, which they correct by liver TP inhibition through drinking. Further studies of the Trp and serotonin metabolic status in long-term abstinence in general and in relation to personality characteristics, alcoholism typology and genetic factors in particular may yield important information which should facilitate the development of more effective screening, and preventative and therapeutic strategies in this area of mental health.

Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain

Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [ 3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood–brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABA B antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.

Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress

Isolation and acute environmental change are risk factors in human depression. In the present study, we investigated the differences in the brain monoamine activity of rats between two rearing conditions, isolated and group. Moreover, we examined the responses to novelty stress. Male F344 rats aged 11 weeks were divided into the above two groups. Four weeks later they were further divided into non-stress and stress groups. The latter received 20 min exposure to novelty stress. Isolation significantly changed brain monoamine levels, with the levels of dopamine (DA) in the nucleus accumbens and midbrain, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the midbrain, and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus increasing. Serotonin (5-HT) levels also increased in all brain areas except the raphe nuclei. HVA levels in the raphe nuclei decreased. Novelty stress significantly altered brain monoamine levels. DA, DOPAC, and HVA levels in the prefrontal cortex decreased, as did those of 5-HT in the prefrontal cortex and hippocampus. DA levels in the nucleus accumbens increased. Isolation attenuated the enhanced brain monoamine turnover elicited by novelty stress. The enhanced DA turnover ratio in the prefrontal cortex of the group-reared group was attenuated in the isolated-reared group, and the unchanged DA turnover ratio in the nucleus accumbens of the group-reared group declined in the isolated-reared group. The enhanced 5-HT turnover ratio in the prefrontal cortex, nucleus accumbens, and hippocampus of the group-reared group was attenuated in the isolated-reared group. Isolation may exacerbate adaptation to stress, and be related to the etiology of human depression.

Regional heterogeneity of serotonin 1A receptor inactivation and turnover in the aging female rat brain following EEDQ

The turnover of serotonin 1A (5-HT 1A) receptors was investigated in several brain regions of young adult (3 months) and old (22 months) female Fischer 344 rats following irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Equilibrium binding analyses for the 5-HT 1A receptor binding site incorporated [ 3H]8-hydroxy-2-(di- N-propylamino)tetralin ([ 3H]8-OH-DPAT) and were conducted in the frontal cortex, amygdala and hippocampus at 1, 2, 7 and 14 days after treatment with EEDQ (6.0 mg/kg, s.c.) or vehicle. The pattern of 5-HT 1A receptor recovery following EEDQ treatment was found to be age- and region-dependent. For example, in the hippocampus, receptor recovery occurred at a faster rate in the old rats compared to young adult rats. While a significant decrease in affinity for the 5-HT 1A receptor was found in the frontal cortex and amygdala in young adult and old rats following EEDQ, B MAX values for [ 3H]8-OH-DPAT binding in these brain regions were unaltered by EEDQ across age groups. In the frontal cortex and amygdala, significant age-dependent decreases in affinity for the 5-HT 1A receptor were revealed at day 1 following EEDQ administration. The significance of the present findings is discussed in terms of aging and a regionally-defined sensitivity of 5-HT 1A receptors to the irreversible inactivator EEDQ.

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover.

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover

Tryptophan metabolism in alcoholism.

Studies of tryptophan (Trp) metabolism in relation to the serotonin status in alcoholism are of 2 types: (1) those related to the pharmacological effects of ethanol; (2) those concerning the serotonin status in the absence of alcohol intake. In experimental animals, acute and chronic ethanol administration and subsequent withdrawal exert a variety of effects on brain serotonin synthesis and turnover mediated by corresponding changes in Trp availability to the brain secondarily mainly to modulation of liver Trp pyrrolase (TP) activity. Alcohol-preferring mice and rats exhibit a central serotonin deficiency caused by, or in some cases associated with, a higher TP activity. Liver TP also appears to be a target of ethanol in man and evidence has recently emerged that alcoholics with positive family history are serotonin-deficient because of a lower availability of circulating Trp to the brain. Acutely, ethanol depletes brain serotonin in normal subjects, which may explain alcohol-induced aggression in susceptible individuals and also the incidence of depression in alcoholism. Trp availability to the brain is increased before the appearance of the alcohol-withdrawal syndrome in man, raising the possibility that the associated behavioural disturbances may involve the excitotoxic Trp metabolite quinolinate. Further studies of the Trp and serotonin status in relation to these important clinical features of alcohol dependence and alcoholism may therefore yield fruitful results.

Suicide: a four-pathway clinical-biochemical model.

This chapter, based on a review of recent research as well as data presented in this report, proposes four hypothetical pathways leading to suicide in clinical depression: (1) an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor (CRF or CRH) levels, (2) trait baseline and reactivity hopelessness, (3) severe anhedonia, and (4) trait impulsiveness associated with low brain serotonin turnover and low total cholesterol as a possible peripheral correlate. Clinical research showing evidence for acute versus chronic high-risk suicide factors and other studies linking severe anxiety/agitation to high CRF levels will be presented as associated with acute suicidal risk, which is potentially reversible with recognition and treatment. Evidence for anhedonia severity as a risk factor and trait, as well as evidence that baseline hopelessness and sensitivity are traits related to chronic suicide risk, will be presented. Finally, evidence relating low serum cholesterol to suicide in depressed inpatients will be presented in the context of literature suggesting a relationship between low serum cholesterol and violent death and suicide in population studies. Data suggesting a relationship between low serum cholesterol and decreased CSF 5-HIAA, suggesting reduced serotonin turnover, will be presented, in light of prior studies relating low CSF 5-HIAA and violent suicide. These data taken together suggest four pathways to suicide that are worth investigating in order to better understand the mechanisms leading to this behavior. Future possibilities and applications of these findings are discussed.

Sleep deprivation increases brain serotonin turnover in the rat.

IN order to study possible time-dependent changes in serotonin metabolism in rat brain, male Wistar rats were subjected to 3, 6 or 12 h total sleep deprivation (SD) by gentle handling. In addition two groups of rats subjected first to 6 h SD were allowed 2 or 4 h rebound sleep. Tissue concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured from several brain areas using HPLC/ECD. SD significantly increased the 5-HIAA/5-HT ratio in frontal cortex, hippocampus, hypothalamus and brain stem, indicating increased 5-HT turnover in those areas. After 2 and 4 h rebound sleep, the 5-HIAA/5-HT ratio was similar to that in controls. We conclude that a short SD increases 5-HT turnover in the rat brain for the duration of SD only.

Acute and chronic effects of fluoxetine and haloperidol on mouse brain serotonin and norepinephrine turnover

Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In limited previous neurochemical research, acute treatment with selective serotonin reuptake inhibitors (SSRIs) has been reported to increase rat brain norepinephrine (NE) turnover or release We have examined the neurochemical effects of 2 hr, 4 day, and 20 day treatment with the SSRI fluoxetine, and the neuroleptic haloperidol, on regional brain monoamine metabolism. Short and long-term fluoxetine treatment produced substantial decreases (to 65–79% of control) in serotonin (5HT) turnover However no effects of fluoxetine on mouse brain NE turnover - as assessed by forebrain, hypothalamus, and hindbrain 3-methoxy-4-hydroxvphenylglycol (MHPG) levels or MHPG/NE ratios - were observed. Acute (2 hr) fluoxetine also did not alter regional NE turnover in rat brain. In contrast, haloperidol tended to increase MHPG levels and MHPG/NE ratios in the mouse brain regions studied The persistence of decreased 5HT turnover during fluoxetine treatment, the lack of an effect of fluoxetine on NE turnover, and the increased NE turnover seen after haloperidol may have important implications regarding drug responsivity and the mechanism of akathisia induction

P2-286 - Effect of fluvoxamine on serotonin turnover in rat brain

P2-286 - Effect of fluvoxamine on serotonin turnover in rat brain

Changes of aggressive behavior and brain serotonin turnover after very low-dose X-irradiation of mice

Social isolation has been widely described to induce compulsive aggressive behavior and produce a large decrease of brain serotonin turnover in male mice. The aggressiveness by isolation in mice has been often used as a means for a better understanding of disturbed behavior in human beings. We found that male ICR white Swiss mice exhibiting isolation-induced aggression became gradually calm and showed remarkably quiet behavior 7 to 10 days after whole body irradiation of very low-dose X-rays (5–15 cGy). Higher doses (25–35 cGy), however, could not induce such effects. We also obtained the data on brain biochemistry giving a further support for the above low-dose effects on the mouse behavior. Brain serotonin turnover which has been known to be related to aggressive behavior in 5 or 15 cGy irradiated mice was faster than in aggressive control animals.

Characterization of 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced brain serotonin metabolism in the rat

It has previously been shown that a lethal dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) increases the brain concentrations of serotonin precursor, tryptophan, and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in TCDD-suceptible Long-Evans but not in TCDD-resistant Han/Wistar rats. In the present study, TCDD (50 μg/kg; LD 100 for Long-Evans and nonlethal for Han/Wistar rats) enhanced de novo biosynthesis of serotonin in the brain of Long-Evans but not Han/Wistar or food-restricted Long-Evans rats 10 days after exposure. Furthermore, TCDD increased the plasma level of free trytophan in Long-Evans rats alone, which may be causally related to the observed effects of TCDD on brain tryptophan levels. Administration of hemin modified the time course of TCDD-induced anorexia although 10 day cumulative food consumption was not altered. Hemin tended to attenuate TCDD-elicited increases in brain serotonin turnover, whereas a β-adrenergic blocker, propranolol, did not. In the majority of Long-Evans rats, TCDD inhibited the main tryptophan degrading enzyme in the liver, tryptophan pyrrolase, but the rest exhibited augmented activities; these effects were not altered by hemin. TCDD increased the plasma levels of nonesterified fatty acids in Long-Evans (five-fold) but not in Han/Wistar rats. A slight elevation (two-fold) was also seen in food-restricted Long-Evans rats. It is concluded that TCDD selectively promotes brain serotonin turnover in Long-Evans rats and this acceleration is related to increased plasma levels of free tryptophan. The inhibition of tryptophan catabolism in the liver and elevation of plasma nonesterified fatty acids may contribute to these changes.

Effects of long-lasting voluntary running on the cerebral levels of dopamine, serotonin and their metabolites in the spontaneously hypertensive rat

The brain regional dopamine (DA) and serotonin (5-HT) levels and turnover were studied in the spontaneously hypertensive rat (SHR), following voluntary, long-lasting (7 weeks) wheel-running exercise. Groups of rats were sacrificed 1–2 h, 23–24 h or 47–48 h after termination on the last running session, and the cerebral tissue levels of 5-HT, 5-HIAA, DA and DOPAC were determined and compared to corresponding levels obtained in sedentary controls. In the exercised animals, there was a selective decrease in the limbic forebrain levels of DOPAC in the immediate post-exercise period (1–2 h), while the DA turnover (DOPAC/DA ratio) was not altered. In addition, the 5-HT and 5-HIAA levels in the serotoninergic nerve terminal limbic forebrain and the 5-HT turnover (5-HIAA/5-HT ratio) in the cell body-containing brain stem areas were decreased in the immediate post-exercise period. No significant changes in the DA, DOPAC, 5-HT or 5-HIAA levels, nor in the DA and 5-HT turnover, were obtained in the remainder of the brain regions analyzed, regardless of time after termination of running. Taken together, the present study indicates that voluntary exercise in the SHR gives rise to differentiated regional effects on brain DA and 5-HT levels and turnover, thus supporting the view that changes in central monoaminergic activity are involved in the functional effects of long-term exercise. Interestingly, the psychomotor-associated limbic forebrain areas appeared particularly susceptible.

The effect of low-level deoxynivalenol on neurotransmitter levels measured in pig cerebral spinal fluid

Deoxynivalenol (DON) is one of the major mycotoxins produced by Fusarium fungi, and is known to affect feeding behaviour in economically important animals. In this study the effect of low-level DON on cerebral spinal fluid (CSF) neurotransmitter concentrations, as a reflection of altered brain activity, was investigated in swine. Animals were given repetitive doses (6) at 30 min intervals, either intravenously (iv) (10 micrograms/kg) or intragastrically (ig) (30 micrograms/kg). Serial CSF samples were collected via a novel permanent indwelling catheter placed intracerebrally, and changes in catecholamine levels monitored. Results showed a rapid and sustained increase in 5-hydroxyindoleacetic acid (5HIAA) occurred following ig administration, remaining elevated for up to 20 hr post-dosing, and to a lesser extent after iv dosing, lasting up to 6 hr post-dosing. This was indicative of increased CNS serotoninergic activity and indicative to the theory that links elevated brain serotonin turnover to a decrease in feed intake. Also observed were alterations in dopamine (DA) metabolism. Following ig dosing, a delayed increase in homovanillyl alcohol (HVOL) suggested an enhancement of the dopaminergic response occurred as serotoninergic activity diminished. Following iv dosing, a rapid drop in homovanillic acid (HVA) levels alluded to a more direct toxic effect, possibly acting as an inhibitor of DA-metabolizing enzymes.

Brain serotonin, type II alcoholism and impulsive violence.

There is ample evidence that low CSF 5-HIAA concentration is associated with a tendency to exhibit impulsive violent behavior under the influence of alcohol. This is especially true for subjects who fulfill criteria for psychiatric diagnoses often associated with early onset alcoholism such as antisocial personality disorder and intermittent explosive disorder. Brain serotonin turnover as indicated by CSF 5-HIAA concentration does not correlate with CSF free testosterone concentration. The latter is more strongly associated with outward-directed aggressiveness and lack of socialization than impulsiveness. CSF ACTH concentration on the other hand correlates positively with socialization.

Changes induced by sodium cromoglycate on brain serotonin turnover in morphine dependent and abstinent mice.

This study was designed to explain the action of sodium cromoglycate (CRO) on the brain serotonergic system in control, morphine tolerant (by SC implantation of a 75 mg morphine pellet), and also in morphine dependent mice just before naloxone-precipitated withdrawal. After SC injections of CRO in control mice, morphine tolerant mice (day 4 of addiction), and 1 h before abstinence (withdrawal was induced by SC injection of 1 mg/kg naloxone on day 4 of addiction), animals were decapitated and various brain areas were rapidly removed. 5HT (Serotonin) and 5HIAA (5-hydroxyindole-3-acetic acid) were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). The ratio 5HIAA/5HT provided one index by which the turnover of the indoleamine was measured. CRO increased the turnover of 5HT in most of the brain areas studied in both control and morphine dependent mice. Furthermore, previous administration of CRO prior to naloxone challenge induced a significant increase in the 5HIAA/5HT ratio in the hypothalamus and striatum. These results are discussed as the reason for the preventive effect of CRO on jumping behaviour in morphine abstinent mice.

Uptake and utilization of [beta- 11C] 5-hydroxytryptophan in human brain studied by positron emission tomography

The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the β position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of [β- 11C]5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments. The kinetic model defines regional utilization as the relative regional radioactivity accumulation rate. Repeat studies showed good reproducibility. Pretreatments with benserazide, p-chlorophenylalanine (PCPA) and unlabeled 5-HTP all significantly increased uptake of [β- 11C]5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using [β- 11C]5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP. We tentatively interpret uptake and utilization as a measure of brain serotonin turnover, the selectivity of which was shown by pharmacological interventions in vivo.

Effect of PCPA or tryptophan on brain serotonin and on consumption of a high protein or high carbohydrate diet by rainbow trout, Oncorhynchus mykiss

The effect of increased or decreased brain serotonin on consumption of a high protein or a high carbohydrate diet by rainbow trout, Oncorhynchus mykiss, was evaluated. Groups of rainbow trout were acclimated to either a high protein or a high carbohydrate diet for 6 weeks. Fish then received a dietary pretreatment meal containing 5% p-chlorophenylalanine, which decreased brain 5-HT and 5-HIAA, or 7% crystalline tryptophan, which increased brain 5-HIAA and 5-HIAA/5-HT. Intake of a challenge meal (high protein or high carbohydrate, consistent with the diet to which they had been acclimated) was then determined. Food consumption by fish fed the high protein diet was unaffected by either dietary pretreatment meal. Conversely, both p-chlorophenylalanine and tryptophan pretreatment decreased food consumption by fish fed the high carbohydrate diet. These results suggest that changes in brain serotonin turnover in rainbow trout are not important in controlling intake of a high protein diet. Furthermore, because consumption of the high carbohydrate diet was decreased both by p-chlorophenylalanine, which decreased serotonin turnover, and by tryptophan, which increased serotonin turnover, this also suggests that serotonin turnover may not be an important signal controlling consumption of high carbohydrate diets by rainbow trout.