Serotonin Metabolism In Rat Brain Research Articles

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.

Regionally specific effects of diazepam on brain serotonin metabolism in rats: Sustained effects following repeated administration

The effects of single (1mg/kg) and repeated (1mg/kg 2 ∗ daily for 4 days) diazepam administration are investigated on brain regional 5-hydroxytryptamine (5-HT; serotonin) and 5-hydroxy indoleacetic acid (5-HIAA) concentration in rats. Daily treatment decreased food intakes but body weights did not decrease. Administration of diazepam (1mg/kg) to 4 day sahne injected rats on the 5th day decreased 5-HT levels in the hippocampus and increased it in the hypothalamus. 5-HIAA levels were increased in the striatum and decreased in the hypothalamus. 4 day diazepam injected rats injected with sahne on the 5th day also exhibited silmilar changes of 5-HT and 5-HIAA. Cortical levels of 5-HIAA were also smaller in these rats. Administration of diazepam to 4 day diazepam injected rats again decreased 5-HT in the hippocampus and 5-HIAA in the hypothalamus. 5-HT and 5-HIAA were both decreased in the striatum. Regionally specific effects of diazepam on brain serotonin metabolism are discussed in relation to their possible functions.

Immobilization and light-dark cycle-induced modulation of serotonin metabolism in rat brain and of lymphocyte subpopulations: in vivo voltammetric and FACS analyses.

The effect of immobilization and light-dark cycle on the serotoninergic system of the n. raphe dorsalis and on the distribution of blood lymphocyte subpopulations was studied in the rat. As was shown by in vivo voltammetry, 10 min immobilization enhanced serotonin metabolism with a maximum 15 min after immobilization. The distribution of the blood lymphocytes into subpopulations was also affected: pan-T and T helper lymphocytes were reduced during immobilization and reached minimum values after 20 min recovery. The circadian rhythms of serotonin metabolism and the distribution of pan-T and T helper cells exhibited a slight phase shift if compared with each other.

Neurochemical effects of CM 57227 and CM 57373, two anorectic agents, on brain serotonin neurons in rats

The effects of two anorectic drugs, CM 57227 (4-amino-1-[6-chloropyrid-2-yl]piperidine) and CM 57373 (its 6-bromo analog), on brain serotonin metabolism in rats were studied. Both compounds dose-dependently decreased brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) for several hours while causing little or no change in brain concentrations of serotonin. Both compounds antagonized the depletion of brain serotonin by p-chloroamphetamine, an agent whose depletion requires the serotonin uptake carrier, with ED(50) values of about 7 mg/kg. The data suggest these compounds affect brain serotonin neurons primarily by inhibiting the membrane uptake carrier, which may be the mechanism by which they produce anorexia.

Mechanisms of effects of d-Fenfluramine on brain serotonin metabolism in rats: Uptake inhibition versus release

d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. d-Fenfluramine (or the racemate) releases serotonin through a carrier-dependent mechanism, and serotonin release is the mechanism usually thought to produce its serotonergic effects. However, d-fenfluramine also inhibits serotonin uptake in vitro, and serotonin uptake inhibition is sometimes suggested to contribute to its mechanism of anorectic activity. Neurochemical experiments were done to examine serotonin release and serotonin uptake inhibition as mechanisms of action of d-fenfluramine in rats and to compare d-fenfluramine to fluoxetine, a serotonin uptake inhibitor. d-Fenfluramine decreased serotonin concentration in rat brain as early as 1 hr; at 1 hr 5-hydroxyindoleacetic acid (5HIAA) concentration was slightly increased, but at later times 5HIAA was also decreased. Fluoxetine, in contrast, did not change serotonin concentration in whole brain but decreased 5HIAA concentration at all time points. At all time intervals studied, the 5HIAA/serotonin ratio was increased by d-fenfluramine (and by Ro 4-1284, a nonspecific serotonin releaser) but was decreased by fluoxetine, a serotonin uptake inhibitor. No decrease in 5HIAA concentration or in the 5HIAA/serotonin ratio was apparent at any time or after any dose of d-fenfluramine studied. The possibility that doses of d-fenfluramine below those needed for serotonin release might inhibit serotonin uptake was tested by determining whether d-fenfluramine could block the acute depletion of brain serotonin by p-chloroamphetamine, or the long-term neurotoxic effect of p-chloroamphetamine on brain serotonin neurons. No protective effect of d-fenfluramine was found up to doses that themselves did not cause acute or long-term depletion of brain serotonin. Both d-fenfluramine and fluoxetine increased serum corticosterone concentration, but only d-fenfluramine increased serum prolactin concentration. These data in conjunction with earlier published data support the interpretation that d-fenfluramine initially enhances serotonergic function by carrier-dependent release of serotonin and not by uptake inhibition. At longer times and after higher doses of d-fenfluramine, brain serotonin becomes depleted.

Perinatal brain serotonin metabolism in rats malnourished in utero.

The fetal brain serotonin metabolism has been studied in two types of gestationally malnourished rats: protein-calorie and after ligation of one branch of the uterine artery. The results showed an elevation of L-tryptophan and serotonin content and an enhancement of tryptophan-5-hydroxylase activity in the malnourished fetal brain, continuing up to day 10 of postnatal life. The possible implications of these early changes of the serotoninergic system in brain differentiation and a lasting change in tryptophan-5-hydroxylase kinetics are proposed for further study.

Effects of elevated calcium on learned helplessness and brain serotonin metabolism in rats

The effects of elevated calcium on learned helplessness in rats was tested by maintaining animals on either distilled water or water containing 2.5% calcium. Animals that were maintained on drinking water containing high calcium showed elevated levels of brain and serum calcium. Rats that were maintained on high calcium drinking water showed significantly longer escape latencies than their non-calcium counterparts after they were pretreated with inescapable electric shocks. Lower levels of 5-hydroxyindoleacetic acid (5HIAA) were found in the forebrain and brainstem of animals maintained on high calcium drinking water. There was no significant correlation between blood or brain calcium or 5HIAA levels and latency of escape. We conclude that elevated levels of calcium enhance learned helplessness and decrease brain serotonin turnover. The relationship between depressive states and calcium homeostasis is worthy of further investigation.

Effect of Middle Cerebral Artery Occlusion on Serotonin Metabolism in Rat Brain

Previously the authors have studied local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) in rats 1 hour after the occlusion of the left middle cerebral artery. It was found that LCGU was decreased in the ipsilateral cerebral cortex and the lateral striatum, where LCBF was also reduced. On the other hand, LCGU was increased in the ipsilateral medial striatum, olfactory tubercle, globus pallidus, subthalamic nucleus, and lateral habenula. They have also investigated changes in catecholamine metabolism in these regions and found very close relationship between LCGU, LCBF, and dopamine metabolism. In the present work, changes in serotonin metabolism were investigated measuring tryptophan (TRP), serotonin (5-hydroxytryptamine, 5-HT), and its metabolite, 5-hydroxy-indoleacetic acid (5-HIAA) in certain regions of the cerebral cortex, basal ganglia, and brain stem using the same ischemic model rats. The results were compared with the changes in LCGU and LCBF. The concentration of TRP was significantly increased in the “ischemic” regions, such as the ipsilateral cerebral cortex and lateral striatum. On the other hand, 5-HT was significantly decreased not only in the “ischemic” regions but also in the “nonischemic” regions such as the globus pallidus. There was a tendency for 5-HT to decrease in the ipsilateral substantia nigra and raphe nuclei. 5-HIAA showed no significant change in the “ischemic” regions but was significantly increased in the globus pallidus and raphe nuclei and had a tendency to increase in the substantia nigra. There was no significant change in any of these parameters in the regions of the contralateral side. The changes in 5-HT metabolism in the “ischemic” regions, such as the ipsilateral cortex and lateral striatum indicate that the synthesis of 5-HT was reduced, but its release was unchanged. Increase in 5-HT metabolism in the “nonischemic” regions, such as the globus pallidus, substantia nigra, and raphe nuclei indicates a presence of neuronally-mediated biochemical diaschisis.

Influence of glucocorticoids on brain serotonin metabolism in rats.

It has been suggested brain serotonin (5HT) plays a role in regulation of the hypothalamic-pituitary-adrenal system, although none of the experimental approaches so far reported has produced unequivocal results, mainly on account of the static tissue 5HT level or the known effects of drugs being employed in interpretation of their data. The present study in rats of the possible feedback influence of glucocorticoids on the brain 5HT was designed to analyze the dynamic turnover of its metabolism. Intracisternal injection of corticosterone (COR) caused no significant changes in 5HT content but increased its turnover dose-dependently in the cortex-cerebellum and the rostral brain stem including the hypothalamus, and lowered the serum COR level at doses less than 5.0 micrograms/kg, reducing its effect with increasing doses. Intracisternal or intraperitoneal administration of miliary doses of dexamethasone (DEX) decreased 5HT turnover in the same brain portions. The effects of glucocorticoids on the brain 5HT metabolism were more potent when injected intracisternally, especially onto the rostral brain stem. Although COR and DEX played controversial roles, the present results suggest that adrenal glucocorticoids may directly act on brain 5HT metabolism and there may be a feed-back relation between adrenal glucocorticoid and brain 5HT.

Effects of swimming exercise on circadian sleep-waking rhythms and brain serotonin metabolism in rats.

Polygraphic recordings of circadian sleep-waking rhythms of rats were made before and after swimming exercise which was loaded to the animals in the dark period. By visual inspection of the recordings, an exercise-induced increase in the amount of slow-wave sleep (SWS) was observed in the next dark period. In the dark period, 15 hours after the swimming, tryptophan (TRP), serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in several regions of rat brain were measured to clarify the mechanisms of the exercise-induced increase in SWS. The concentrations of TRP and 5-HIAA in the midbrain of the exercised rats were significantly higher than in the control ones. The cortical level of 5-HIAA was also high in the exercise group. The serotonin levels in both the brain regions of the exercised rats were nearly the same with the control. From these results, it is inferred that the increased amount of SWS after the swimming exercise might be attributable to enhanced activity of serotonergic neurons in the midbrain and the cerebral cortex.

Effect of γ-hexachlorocyclohexane on serotonin metabolism in rat brain

1. 1. The administration of acute doses of γ-hexachlorocyclo-hexane (180 and 240 mg/kg) induces a general increase in the concentration of serotonin, (except 10 min after the administration of lower dose of pesticide) and 5-HIAA. 2. 2. The results suggest that γ-hexachlorocyclohexane increases the synthesis of serotonin and that the administration of pesticide does not interfere with the transport of 5-HIAA except in the case of the higher dose.

The effects of des-enkephalin-γ-endorphin and des-Tyr 1-α-endorphin on regional serotonin metabolism in rat brain

Des-enkephalin-γ-endorphin (β-endorphin 6–17; DEγE) causes a significant reduction of the serotonin concentration of the raphe area of the mesencephalon and of the dorsal hippocampus of the rat. DEγE does not, however, alter the pargyline-induced accumulation of serotonin in either of these two brain regions or in the mediobasal hypothalamus. Des-Tyr 1-α-endorphin (β-endorphin 2–16; DTαE), on the other hand, inhibits the accumulation of serotonin following MAO-inhibition by pargyline in all 3 brain regions, while, in addition to causing a transient reduction in the serotonin concentration of the raphe area, it decreases the serotonin concentration of the mediobasal hypothalamus. These results indicate that DEγE and DTαE, which have been shown to exert opposite effects on behavior in various behavioral tests, both affect regional serotonin metabolism in rat brain and that they do so differently.

Effects of chronic methamphetamine administration on tryptophan hydroxylase activity, [ 3H]serotonin synaptosomal uptake, and serotonin metabolism in rat brain following systemic tryptophan loading

Chronic administration of methamphetamine (20 mg/kg, i.p., every 12 hr for 6 days) produced significant decreases in the V max of brainstem (−32.8%) and forebrain (−31.5%) tryptophan hydroxylase when measured 12 hr after the final injection. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and [ 3H]5-HT synaptosomal uptake were decreased by a similar magnitude following chronic drug treatment. Administration of fluoxetine prior to each methamphetamine injection prevented these neurochemical changes. Neither acute nor chronic methamphetamine treatment produced any significant changes in the K m of tryptophan hydroxylase for either substrate or cofactor. Systemic tryptophan loading (50 mg/kg, i.p.) one hour prior to sacrifice in chronic methamphetamine treated rats restored brain 5-HT and 5-HIAA levels to normal. These data suggest that chronic methamphetamine treatment decreases central serotonergic neurotransmission by reducing the activity of the rate-limiting enzyme in 5-HT biosynthesis, possibly by disrupting serotonergic nerve terminals.

O-16) - Effects of d-amphetamine on serotonin metabolism in rat brain

O-16) - Effects of d-amphetamine on serotonin metabolism in rat brain

Influence of histamine on serotonin metabolism in rat brain.

Biogenic amines have long been known to be highly reactive substances which control many important biological functions. During the past few years progress has been made in the study of possible interaction between different amines, among them a relationship between histamine (HI) and serotonin (5HT) systems in mammals. Bevan et al. (1975) showed that noncontractile doses of HI can augment contractile responses of 5 HT in the isolated rabbit basilar artery; the results suggested direct or indirect interactions between H1 and 5HT receptors. Eyre et al. (1973) noted that the increase of plasma HI level in systemic calf anaphylaxis was antagonized by antiserotonin drugs, e.g. methysergide, but not by pyrilamine, a blocker of H1 histamine receptors. In our laboratory it was shown that HI-induced hypothermia in the rat was significantly reduced by both histamine H2-receptor and 5HT receptor antagonists, CIM and metergoline, respectively; by cyproheptadine, possessing anti-histamine H1-receptor and anti-5HT receptor activities, by PCPA, which impairs 5HT synthesis (Pilc and Nowak, 1979).

Influence of corticosterone on serotonin metabolism in rat brain.

The influence of corticosteroids on higher nervous activity is now well documented and properly substantiated [1-4]. However, the mechanism of the influence of steroids on the central nervous system is not clearly understood. Many authors believe that serotoninergic neurons of the central nervous system can play a role in regulating the functioning of the axis of the hypophysis -the adrenal glands [6, 7], and it is quite possible that the serotoninergic system of the brain is of considerable importance in the influence of corticosteroids on the central nervous system and the behavior of animals [8].

Effect of doxepin on serotonin metabolism in rat brain and serotonin uptake by human blood platelets

1. 1. Application of doxepin, an antidepressant with tertiary amine group, in a dose of 60 mg/kg i.p. produced a marked increase in the concentration of rat brain tryptophan and slight, but statistically significant elevation in serotonin (5-HT) concentration. 2. 2. Two hours after the doxepin injection no change in the steady state level of brain 5-hydroxyindoleacetic acid (5-HIAA) was observed. However, in rats treated with pargyline, an inhibitor of monoamine oxidase (MAO), doxepin retarded 5-HIAA decline. Moreover, in rats receiving probenecid, a drug that blocks elimination of acidic metabolites from central nervous system (CNS), doxepin decelerated the rate of 5-HIAA accumulation. 3. 3. In vitro doxepin inhibited the uptake of 5-HT into human blood platelets. 4. 4. Our data indicate, that doxepin exerts its effect on brain serotoninergic neurons by same or similar mechanisms as the other tricyclic antidepressants with tertiary amine in side chain, i.e. by inhibition of 5-HT reuptake mechanism.

Effect of food restriction on serotonin metabolism in rat brain.

The brain concentration of 5-hydroxytryptamine (5-ht) and 5-hydroxyindoleacetic acid (5-HIAA) increased in rats maintained on restricted volume of low-protein or normal-protein diet, whereas these two agents decreased in rats fed low-protein diet ad libitum. In these two food-restricted groups brain 5-HT and 5-HIAA concentrations were not correlated with brain tryptophan hydroxylase activity, but the concentrations correlated closely with cerebral tryptophan concentrations. The cerebral tryptophan concentration in the two food-restricted groups was not consistent with the total or free tryptophan concentration in plasma. In these restricted rats cerebral tryptophan concentration was elevated, and, unlike the plasma tryptophan, it showed no diurnal variation. These results suggested that tryptophan uptake into the brain from plasma was enhanced by limiting food volume intake. Tryptophan uptake was increased by glucagon injection without changing the plasma tryptophan level, but injection of hydrocortisone or insulin had little or no effect on tryptophan concentration in either the plasma or brain. D-Glucose injection elevated plasma tryptophan concentration but decreased brain tryptophan concentration.

Effect of the administration of (d-Ala) 2methionine-enkephalin on the serotonin metabolism in rat brain.

The effect of cerebroventricular injection of [D-Alanine] methionine-enkephalin (DALA), a synthetic analog of met-enkephalin, on the serotonergic system of rat brain has been studied. This opioid peptide caused an increase in 5HT turnover which was particularly evident in the limbic forebrain. This effect was completely antagonized by naloxone pretreatment.

Effect of S-adenosyl-L-methionine on serotonin metabolism in rat brain

1. 1. The administration of S-adenosyl-L-methionine (SAMe) to rats caused an increase in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in some regions of the rat brain. 2. 2. The 5-HT turnover rate, determined by the steady state kinetic method, was higher in rats receiving repeated administrations of SAMe. 3. 3. SAMe enhanced the increase in 5-HIAA which follows reserpine treatment. 4. 4. The hypothesis that the effect of SAMe on the serotonergic system may be secondary to an increase in brain melatonin is discussed.