5HT Metabolism Research Articles

Unilateral Destruction of Dopamine Pathways Increases Ipsilateral Striatal Serotonin Turnover in Rats

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (5HT), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain 5HT metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways (>90% DA loss) were made by infusing the neurotoxin 6-hydroxydopamine into either the left medial forebrain bundle (MFB) or the left substantia nigra (SN). At 6 weeks after the lesions, levels of 5HT and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined bilaterally in the striatum, frontal cortex, and hypothalamus. In the striatum of the lesioned hemisphere, the 5HT level decreased by more than 50%, while the ratio of 5HIAA:5HT (an index of 5HT turnover) increased by more than 90%. In the same rats, cortical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in 5HT turnover and a net depletion of 5HT in the striatum. To verify that the loss of DA was responsible for the observed striatal 5HT changes, we examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats, The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the 5HT levels and 5HIAA:5HT ratios. It appears that DA normally acts to inhibit 5HT release in the striatum. Accordingly, the loss of DA innervation results in overactive 5HT transmission, which leads to a net depletion of 5HT stores. As striatal 5HT levels and turnover can be restored to normal by sustained infusion of DA in the lesioned rats, the presence of DA in the striatum appears crucial for the maintenance of normal 5HT function.

Exercise training: Significance of regional alterations in serotonin metabolism of rat brain in relation to antidepressant effect of exercise

Alterations of 5HT and its chief metabolite 5HIAA were studied in four regions of the rat brain following acute 1-h swim exercise and 4 week chronic swim exercise (30 min/day, 6 days per week). Acute exercise significantly increased the synthesis and metabolism of 5HT in brain stem. Hypothalamus also showed increased levels of 5HT. However, no changes were observed in the cerebral cortex and hippocampus. Chronic exercise activated not only the synthesis but also the metabolism of 5HT in the cerebral cortex; this neuronal adaptation was sustained even 1 week after the termination of training. In brain stem, increased 5HT turnover was observed immediately after training. In hypothalamus, decrease in 5HT and 5HIAA levels occurred immediately after training, followed by a rebound increase in their levels after 1 week posttraining rest. In hippocampus, a delayed effect was observed, because 5HT level was unaltered immediately after the training, but its turnover decreased after 1 week rest. These findings have been discussed in an attempt to explain the antidepressant effect of exercise based on the 5HT deficiency theory of endogenous depression.

Effects of nutritional status on contents of tryptophan, serotonin and 5-hydroxyindoleacetic acid in rat brain

Effects of nutritional status on the levels of tryptophan (Trp), serotonin (5HT), and its metabolite, 5-hydroxyindoleacetic acid (5HIAA) in six brain regions of rats were investigated. 1) A low-protein high-carbohydrate diet decreased Trp, 5HT and 5HIAA levels in the cortex and hippocampus, and those of 5HT and 5HIAA in the hypothalamus. This diet did not affect the contents of Trp and 5HT in the midbrain, but decreased 5HIAA. No significant changes of Trp, 5HT and 5HIAA were observed in the pons and medulla and striatum. 2) A low-carbohydrate high-protein diet increased the levels of Trp, 5HT and 5HIAA in the striatum, and 5HT and 5HIAA in the cortex, but showed no effect on the contents of Trp, 5HT and 5HIAA in the hippocampus, midbrain, pons and medulla and hypothalamus. 3) An energy-restriction low-carbohydrate diet increased Trp, 5HT and 5HIAA contents in the striatum, and 5HT and 5HIAA in the cortex and pons and medulla. In the hypothalamus, only 5HIAA was increased by this diet. The diet did not influence Trp, 5HT and 5HIAA contents of the midbrain and hippocampus. These results suggest that i) lowered fat and carbohydrate intakes enhance 5HT synthesis and metabolism in the cortex and that lowered carbohydrate intake enhances them in the striatum, ii) energy restriction enhances the 5HT metabolism in the cortex, pons and medulla and hypothalamus, and 5HT synthesis in the cortex and pons and medulla, iii) lowered protein intake inhibits 5HT metabolism in the cortex, midbrain, hippocampus and hypothalamus, and 5HT synthesis in the cortex, hippocampus and hypothalamus.

Serotonergic Response to Spinal Distraction Trauma in Experimental Scoliosis

The effects of distraction injury to the spinal cord on serotonin (5HT) content and metabolism in a rat model of scoliosis were studied. Previous studies in this laboratory (Salzman et al., 1987a) have identified the 5HT response as a major component of the posttraumatic progression of spinal injury after impact trauma in the rabbit. The present study was designed to determine the universality of this response by examining a different model of injury in a different species. The results demonstrate that distraction trauma in the rat, like impact injury in the rabbit, is associated with a rapid and robust increase in the local spinal cord content and metabolism of 5HT and a long-term depletion of 5HT below the site of injury. The roles of the blood platelet and the raphe-spinal tract in the acute response and the disruption of axoplasmic transport during the chronic phase of injury are discussed.

Serotonin receptor sensitivity in major depression

Research on the role of serotonin (5-hydroxytryptamine, 5HT) in depression spans well over two decades. The most consistc~t finding is that the cerebrospinal fluid (CSF) concentration of the 5HT metabolite, 5-hydroxyindoleacetic acid (SHIAA) is lowered in about ,..10% of patients with major depression (MD) (review: Kalus et al. 1989). The fall of CSF 5HIAA levels suggests a decrease of 5HT metabolism in the CNS, which may be the result of, or lead to, increased 5HT receptor sensitivity. Studies examining 5HT receptor sensitivity, however, have provided conflirting results. One study reported increased 5HT receptor sensitivity in MD, using the 5HT precursor, 5-hy&'oxytryptophan (5HTP) as a 5HT challenger (Meltzer etal. 1984). However, Westenberg et al. (1982), using the same oral dose of 5HTP in combination with a decarboxylase inhibitor, found normal responses in depressed subjects..qty.!dies using tryptophan and fenfluramine as 5HT challenge agents found decreased (Heninger et al. 1984; Siever et al, 1984; Coctaro et al. 1989) or normal (Asnis et al. 1988) 5HT receptor sensitivity in depressed patients. The conflicting findings may be the result of the nonselectivity of these agents and their indirect stimuiation of 5HT receptors (van Praag et al. 1987). in contrast to the studies reviewed above, the

Endocrine Effects of Blinding in Male Syrian Hamsters Are Associated With Increased Hypothalamic 5‐Hydroxyindoleacetic Acid/Serotonin Ratios

The antigonadal, antithyroid, and antiadrenal effects of blinding were studied in male Syrian hamsters receiving propylthiouracil (PTU) or PTU plus thyroxine (T4) replacement. Ten weeks after blinding, the expected gonadal involution and reduction of circulating levels of T4, as well as a reduction of circulating levels of corticosterone, were observed. T4 treatment significantly increased testicular weights, but it did not prevent gonadal involution. Neither PTU nor T4 administration significantly influenced the inhibition of serum corticosterone levels observed in blinded hamsters. The increase in serum thyroid-stimulating hormone (TSH) observed in hypothyroid (PTU-treated) hamsters was significantly greater in intact hamsters than in blind hamsters. Blinding was associated with a small but highly significant increase in ratios of 5-hydroxyindoleacetic acid (5HIAA) to serotonin (5HT) in extracts of the medial basal hypothalamus. Based on the assumption that 5HIAA represents primarily intraneuronal metabolism of excess 5HT, the present results are consistent with reduced 5HT release in blinded hamsters. Daily evening melatonin administration also increased the 5HIAA/5HT ratios of the mediobasal hypothalamus concurrently with gonadal involution, reduction of circulating levels of T4, and reduction of circulating levels of corticosterone. These results are consistent with the view that serotonergic neurons entering the hypothalamus are components of the photoneuroendocrine system of the hamster.

Regional studies of 5HT metabolism in human cerebral cortex

Regional studies of 5HT metabolism in human cerebral cortex

Relation of blood serotonin and benzylamine oxidase to clinical symptoms and prognosis in Parkinson's disease.

In 21 parkinsonian patients, we investigated the contents of blood serotonin (5HT) and benzylamine oxidase (BzAO) before and during L-dopa therapy. Then, we studied the patients prospectively, and evaluated the relationship between 5HT and BzAO and the clinical characteristics. The levels of blood 5HT and BzAO varied not only with the treatment, but also with the duration and clinical type of the disease. We postulated that in certain types of Parkinson's disease, the generalized defect of 5HT and enzyme metabolism might primarily exist, and might influence the efficacy of L-dopa therapy and the prognosis of the disease.

In vivo electrochemistry - principles and applications

Differential pulse voltammetry (DPV) with electrically pretreated carbon fibre microelectrodes has been used to monitor dopamine (DA) and serotonin (5HT) metabolism in specific regions of the rat brain in vivo . Using this technique we have located the 5HT receptor subtype responsible for controlling 5HT release and metabolism in the suprachiasmatic nucleus. The autoreceptor involved in the control of DA metabolism has also been studied and the effects of chronic neuroleptic administration on their sensitivity determined.

Dietary fat source influences neuronal mitochondrial monoamine oxidase activity and macronutrient selection in rats

We previously reported that qualitative changes in dietary fat influence certain monoaminergic mediated behaviours such as pain sensitivity and thermoregulation in a cold environment after an amphetamine challenge. The purpose of this study was to further explore the behavioural consequences of alterations in dietary fat intake by examining another behaviour known to be mediated by the monoamines—food intake regulation—and to begin investigating a biochemical link between dietary fat composition and behaviour. Rats were stabilized to 20% (w/w) soybean oil (SBO) or lard diets for 10 days and then allowed to select for protein (PRO) and carbohydrate (CHO) intake. While total food intake was unchanged, rats fed the SBO diet selected lower PRO (3.1±0.6 vs. 4.9±0.6 g/day, SBO vs. lard, respectively) and higher CHO (9.6±0.7 vs. 7.8±1.2) intakes than those consuming the lard based diet. Comparable differences were seen in a second trial. Current evidence suggests that the regulation of PRO and CHO intake is under serotonergic control. Therefore to determine whether dietary fat is mediating its effect on macronutrient selection via alterations in serotonin (5HT) metabolism, brain stem concentrations of 5HT and its metabolite 5-hydroxyindole acetic acid (5HIAA) and whole brain (minus brain stem) mitochondrial monoamine oxidase (MAO) activity were measured in a separate set of animals fed the SBO or lard diets for 28 days. Vmax of MAO was decreased in rats fed the SBO diets (20.2±7.4 vs. 27.9±8.9 nmol/mg prot/20′) compared to those fed the lard diets. Km was unaltered by dietary fat fed. The change in activity of MAO was insufficient to alter steady-state levels of 5HT or 5HIAA. We propose that changes in neuronal functioning, induced by altered dietary fat, contributed to the differences seen in PRO and CHO selection.

Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

Acute exposure of rats to air ions: Effects on the regional concentration and utilization of serotonin in brain

Exposure to electrically charged gas molecules (air ions) has been reported to influence physiological and behavioral functions in animals and humans although there is controversy as to whether these findings are valid. A popular hypothesis concerning the reported effects of air ions is that alterations in serotonin (5HT) metabolism, particularly in the brain, are involved. We measured the concentration and turnover of 5HT in rats exposed to 5.0 X 10(5) ions/cm3 for up to 66 hours. Contrary to previous reports of other investigators, we were unable to demonstrate any effect of exposure to air ions or associated DC electric fields on the concentration or turnover of 5HT in rats under carefully controlled and characterized exposure conditions.

Age-related changes in metabolic responses to chronic monoamine depletion in central dopaminergic and serotonergic systems of rats treated with reserpine

Groups of 5, 15, and 27-month-old rats were treated with reserpine (5 mg/kg IP) and killed after 1, 7, 14, and 21 days. Reserpine's effects on dopamine (DA) and serotonin (5HT) metabolism were studied in the striata and limbic areas, on the basis of changes in metabolite concentrations and a calculated index [Δ (C/M)] expressing changes in the molar ratio between metabolite and parent monoamine. Twenty-four hours after drug treatment, when the two monoamines reached a new steady-state, about 10% of the normal concentration, there was evident enhancement in the metabolism of striatal DA, indicated by HVA levels and Δ (C/M) changes. This increase was significantly lower in the senescent rats. In contrast with HVA, the levels of DOPAC were lowered in reserpinized rats. This effect, present in all three age groups, lasted up to 21 days in young and 14 days in adult and old rats. However, for this metabolite too, the Δ (C/M) indicated an increase in its formation which was lower in 27-month-old rats. Similar effects were observed in limbic areas, but here the age-related differences were less evident. Serotonin metabolism was also increased by reserpine as indicated by the Δ (C/M). This parameter was lower in young than in adult and old rats, at least in limbic area. Similarly, 5HIAA increased only in the senescent rats. These age-related differences were not evident in striata. In this rat population, aging apparently modified the compensatory metabolic responses of some dopaminergic and serotonergic systems. The direction of these changes, however, depends on the system and the brain region considered.

Monitoring 5HT Metabolism in the Brain of the Freely Moving Rat

The techniques of repeated CSF withdrawal and intracerebral dialysis are described. They were used to monitor 5HT metabolism in the brains of freely moving rats. Evidence indicates that results obtained proportionately reflect changes of 5HT metabolism in whole brain (CSF method) and in the striatum (intracerebral dialysis). The potential value of the methods is illustrated by two behavioral studies. The first suggested that 5HT turnover values (determined two weeks prior to behavioral testing by the CSF method) were predictive for neck + body biting in a social interaction test. The second study showed a consistent pattern of change of hypothalamic dialysate 5HIAA concentration associated with feeding in rats on a restricted food intake schedule.

In vivo voltammetry in the suprachiasmatic nucleus of the rat: Effects of RU24969, methiothepin and ketanserin

Differential pulse voltammetry was performed in the suprachiasmatic nucleus (SCN) of anaesthetised rats. Peripheral administration of RU24969 (10 mg/kg) a 5HT 1 receptor agonist, decreased the size of the 5HIAA oxidation peak whereas it was increased by the non-selective 5HT receptor antagonist methiothepin (10 mg/kg). The effects of RU24969 were attenuated by methiothepin while the 5HT 2 receptor antagonist ketanserin (5 mg/kg i.p.) did not affect the response to RU24969. The results suggest that in vivo 5HT release and metabolism in the SCN is probably under the influence of the 5HT 1 receptor.

Endocrinological function in schizophrenic patients under haloperidol treatment: plasma PRL, HGH and 5HT levels after L-5HTP loading.

In order to examine 5HT metabolism in the hypothalamo-pituitary (HP) system of chronic schizophrenic patients taking haloperidol for a short or long period, chronological changes of blood 5HT, PRL and HGH were measured after an oral loading dose of L-5hydroxytryptophan (L-5HTP), a precursor of 5HT. The subjects consisted of 8 male patients with chronic schizophrenia, who were divided into the following two groups. The 1st group--4 patients taking haloperidol (5.6 mg/day) for 8 months on an average (short-term treatment). The 2nd group--4 patients taking haloperidol (4.8 mg/day) for 7.5 years on an average (long-term treatment). The control group was made up of 9 healthy male volunteers. As a result, the basal level of blood 5HT in the 1st group was significantly higher than that in the control group. The blood 5HT levels in the 1st and 2nd groups showed an equally remarkable increase as compared with the control group. The basal level of plasma PRL in the 2nd group was significantly lowe than that in the control group. Moreover, in the 2nd group, an increase in the plasma PRL level after the loading was suppressed, but it showed less suppression in the 1st group. There was no significant difference in the basal HGH levels among the control, 1st and 2nd groups. After the loading, an increase in the plasma HGH was suppressed in the 2nd group, but the suppression was less in the 1st group.(ABSTRACT TRUNCATED AT 250 WORDS)

The uptake and metabolism of 5-hydroxytryptamine by tissue slices of the cestode Hymenolepis diminuta

1. The in vitro uptake of [ 3H]5HT was investigated in tissue slices of the cestode Hymenolepis diminuta. 2. A concentrative, sodium sensitive, high affinity uptake mechanism ( K m 1.43 × 10 −6M; V max 222 fmoles/mg wet wt/min), together with a sodium insensitive component (linear up to 5 × 10 −6 M) were present. 3. In the presence of 2-nitroimipramine the sodium sensitive component was significantly suppressed ( V max 33 fmoles/mg/wet wt/min) although the K m (1.37 × 10 −6M) was not affected. Nitroimipramine showed an IC 50 of ∼2 × 10 −6 M. The sodium insensitive component was not affected by nitroimipramine. 4. Biogenic amines and related indoleamines were weak inhibitors of the sodium sensitive and sodium insensitive components of 5HT uptake. The tricyclic antidepressants and fluoxetine were effective inhibitors of the sodium sensitive component of 5-HT uptake; receptor ligands were weak inhibitors or without effect. 5. The metabolism of [ 3H]5HT in tissue slices of H. diminuta was examined by HPLC. 6. The role of the sodium sensitive uptake and metabolism of 5HT in terms of inactivation and recycling of neurally released 5HT and the possible importance of exogenous recruitment of 5HT are discussed.

Stimulation of serotonin synthesis in rat brain after antiepilepsirine, an antiepileptic piperine derivative

Piperine and two of its derivatives, antiepilepsirine (AE or 3,4,methylendioxycynna-moylpiperine) and compound 7448 ( N-isopropyl 3 (4 chloro-phenyl) propenoylamide) are very effective in stimulating serotonin (5HT) synthesis. AE raises the ratio of free-to-bound tryptophan (TP) in plasma and induces a long-lasting increase of this aminoacid in brain. At the same time in striatum and limbic area it causes a lasting increase in 5 hydroxyindolacetic acid (5HIAA) a 5HT metabolite and to a lesser extent, an increase in the levels of the monoamine itself. Together with this action on 5HT metabolism we found that AE caused release of 3H-5HT from an in vitro synaptosomal preparation. It thus appears that piperine and its derivatives AE and compound 7148 affect the central serotonergic system.

Regional changes in monoamine metabolism in the aging constant estrous rat

Studies were undertaken to determine levels of monoamines and their metabolites in brain regions in young (3–4 months) normally cycling and old (25–26 month) constant estrous female rats. Dopamine (DA) concentrations were reduced in old rats in the median eminence (ME), medial basal hypothalamus (MBH), preoptic area-anterior hypothalamus (POA-AH) and the striatum. Similarly, concentrations of dihydroxyphenylacetic acid (DOPAC), the major acid metabolite of DA, were reduced significantly in all 4 regions. In the ME, a strong positive correlation was observed between DA and DOPAC concentrations in both young and old rats. Concentrations of norepinephrine (NE) were reduced in old rats in the MBH and POA-AH but not in the ME or striatum. Concentrations of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA) were generally unchanged with age in all of the regions examined. These studies indicate the age-related regional alterations in DA and 5HT metabolism can be monitored by methods which quantitate monoamines and their metabolites.

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.