Brain Serotonin Turnover Research Articles

Effects of leptophos on rat brain levels and turnover rates of biogenic amines and their metabolites

Leptophos is a potent acetylcholinesterase inhibitor which causes delayed central-peripheral neuropathy. Rats were administered multiple doses of leptophos until motor deficits were observed in rotorod performance in the highest dosage group. Doses lower than the median effective dose were then administered to other rats and alterations of brain catecholamine and serotonin levels and turnover rates were determined. Turnover rates of brain norepinephrine and dopamine were elevated in rats administered cumulative doses of 75 mg/kg leptophos over a 15-day period. Levels of the major dopamine metabolite, 3,4-dihydroxyphenylacetic acid, appeared to be slightly elevated at this dose level and levels of dopamine were also higher than controls. These observations suggest that leptophos increases brain adrenergic activity. Rats administered the same dose levels had significantly reduced serotonin turnover rates. This observation was possibly artifactual, because rats administered a cumulative dose of 225 mg/kg leptophos showed no difference from controls.

MIF-1: effects on norepinephrine, dopamine and serotonin metabolism in certain discrete brain regions.

A single injection of melanocyte-stimulating hormone inhibitory factor (MIF-1) in a dose of 3 mg/kg IP produced no significant effect on dopamine turnover. However, a dose of 5 mg/kg increased striatal tyrosine hydroxylase activity by 25% and homovanillic acid level by 27% when compared to control values. No change in either parameter was detected in olfactory tubercles. Dopamine levels also were elevated in striatum, pons-medulla and cerebral cortex in rats receiving 5 mg/kg dose of MIF-1. In olfactory tubercles, dopamine levels were however, reduced to 71% of control values taken as 100%. The concentration of norepinephrine tended to increase in several brain areas examined but, the change was statistically significant only in olfactory tubercles and cerebral cortex. The level of norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol, was lowered to 63% in whole brain of animals given MIF-1 at the dose of 5 mg/kg. These data suggest that MIF-1 enhances the turnover of dopamine and norepinephrine in the brain. However, MIF-1 treatment seemed to produce no consistent change in brain serotonin turnover. In striatum and cortex, this neuropeptide increased serotonin but elevated the level of its metabolite, 5-hydroxyindoleacetic acid indicating that the release of this brain amine was decreased in these two brain regions. The levels of 5-hydroxyindoleacetic acid were enhanced in hypothalamus and pons-medulla regardless of the dose of MIF-1 administered.

Brain serotonin and catecholamine turnover in uremic rats.

In white female Wistar rats with acute renal failure an increase in serum serotonin and tryptophan concentration was observed. Serotonin concentrations in different parts of uremic rat brains and sero

Effects of short- and long-term neuroleptic treatment on brain serotonin synthesis and turnover: Focus on the serotonin hypothesis of schizophrenia

Short-term (90 min) administration of haloperidol (2 mg/kg), or chlorpromazine (10 mg/kg) increased the activity of tryptophan hydroxylase as well as the levels of 5-hydroxytryptamine (serotonin) and 5-hydroxyindoleacetic acid in mid-brain of rats. The chronic neuroleptic treatment (21 days) produced more pronounced changes in all parameters related to serotonin synthesis and turnover. The activity of tryptophan hydroxylase in mid-brain was further augmented; the levels of 5-hydroxytryptamine and 5-hydroxyindole-acetic acid were significantly elevated not only in mid-brain, but also in several other discrete regions examined. These data suggest that neuroleptics enhance the synthesis and utilization of brain serotonin. The role of brain serotonergic neurons in the pathophysiology of schizophrenia is further considered.

Brain serotonin turnover correlates inversely with plasma adrenocorticotropin during the triphasic response to adrenalectomy in rats.

After bilateral adrenalectomy in adult male rats a triphasic change occurs in the plasma concentration of radioimmunoassayable ACTH. Plasma ACTH is markedly elevated at 2 h, returns almost to normal at 20 h, and is again markedly elevated 92 h after adrenalectomy. We have examined brain serotonin (5HT) turnover during this period using two nonsteady state methods: accumulation of 5HT after monoamine oxidase inhibition with pargyline and decline of 5-hydroxyindoleacetic acid (5HIAA) after pargyline. Both endpoints demonstrated decreases in hypothalamic and brain stem 5HT turnover 2 and 92 h after adrenalectomy, but normal 5HT turnover 20 h after adrenalectomy. Thus, we demonstrated inverse relationships between 5HT turnover in both the hypothalamus and brain stem and the plasma ACTH concentration throughout the period of triphasic change after adrenalectomy. The adrenalectomy-induced increases in plasma ACTH and decreases in brain 5HT turnover both 2 and 92 h after adrenalectomy are inhibited by treatment with small doses of corticosterone. The data strongly suggest that the activity of some brain 5HT neurons changes after adrenalectomy in a triphasic pattern and, further, that these changes are related in part to glucocorticoid withdrawal. 5HT receptor antagonists blunted corticosterone inhibition of the adrenalectomy-induced decreases in brain 5HT turnover, providing further evidence for an interaction between glucocorticoids and brain 5HT neurons. The data are consistent with a role of brain 5HT neurons in the adrenalectomy-induced triphasic changes in ACTH secretion.

Accelerated metabolism of probenecid during long-term treatment of rats with anticonvulsant drugs: effect on central serotonin turnover studies

Studies were carried out in rats to determine the effects of long-term administration (once daily for 9 days) of phenytoin (50 mg kg −1), sodium phenobarbital (25 mg kg −1), primidone (50 mg kg −1), and l-5-hydroxytryptophan ( l-5-HTP; 50 mg kg −1) on probenecid metabolism and on serotonin turnover rates as estimated by probenecid-induced accumulation of 5-hydroxyindoleacetic acid (5-HIAA) in brain. Without probenecid, mean brain 5-HIAA levels were similar in control and drugtreated rats, suggesting that the turnover rate of brain serotonin was not affected by the chronic anticonvulsant drug pretreatment. But, in the rats treated with phenobarbital, the rate of accumulation of 5-HIAA in brain during the first 90 min after probenecid (200 mg kg −1) was significantly lower than the rate of accumulation in the control rats. Also, at 6 hr after probenecid, brain 5-HIAA levels were similar to pre-probenecid values in the rats pretreated with phenobarbital or primidone, while 5-HIAA levels were still increased in the rats treated with phenytoin, l-5-HTP, or vehicle. Examination of serum revealed that the concentration of probenecid in serum decreased more rapidly in rats pretreated with either primidone or phenobarbital than in rats given vehicle, l-5-HTP, or phenytoin. It is likely, therefore, that the decreased 5-HIAA accumulation in the brains from these animals were due to decreased inhibition of 5-HIAA efflux and not to a decreased rate of serotonin turnover in brain. Since a sustained inhibition of acid transport by probenecid is required, drug interactions with probenecid may be important in clinical studies using probenecid-induced accumulations of 5-HIAA in cerebrospinal fluid to estimate central serotonin turnover rates.

N, N-dimethyl- α-[2-( p-topoloxy) ethyl]benzylamine hydrochloride (LY125180) : Effects on serotonin uptake and serotonin synthesis in rat brain in vitro and in vivo

N, N-Dimethyl- α-[2-( p-tolyloxy)ethyl]benzylamine hydrochloride (LY125180) competitively inhibited the uptake of serotonin and norepinephrine by cortical synaptosomes and of dopamine by striatal synaptosomes, with K i values of 0.06, 2.2 and 2.5 μM respectively. In platelets of human plasma, LY125180 blocked serotonin uptake by 50 per cent at 22 nM. The administration of LY125180 led to a reduction of serotonin uptake by rat hypothalamic synaptosomes with an ed 50 value of 12 mg/kg, i.p., and a maximum effect within 1 hr. Prior treatment with β-diethylaminoethyl-2, 2-diphenylvalerate, HCl (SKF-525A), an inhibitor of microsomal metabolism, enhanced the potency of LY125180 by 3-fold and prolonged its action for at least 4 hr. LY125180 in vivo blocked the neurotoxic effect of p-chloroamphetamine on serotonin uptake by cortical synaptosomes but did not prevent the neurotoxic effect of 6-hydroxydopamine on norepinephrine uptake by hypothalamic synaptosomes or the accumulation of radiolabeled norepinephrine in rat heart at 50 mg/kg, i.p. A reduction in brain level of 5-hydroxyindoleacetic acid but not of serotonin and tryptophan and a decrease in the conversion of [ 3H]tryptophan to [ 3H]serotonin and [ 3H]-5-hydroxyindoleacetic acid after the administration of LY125180 suggest a decrease of serotonin turnover in rat brain. These data are consistent with the conclusion that LY125180 is effective and selective in the blockade of the serotonin pump in vitro as well as in vivo. Except for a much shorter duration of action in vivo, LY125180 exhibits properties similar to the earlier reported selective serotonin uptake inhibitor, fluoxetine.

Effect of thiamine deficiency on brain serotonin turnover

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in the medulla-pons, hypothalamus and cerebral cortex. [14C]5-HT levels were normal in all of the brain areas except the cerebral cortex which had an increase of 58%. The ratio of [14C]5-HIAA/[14C]5-HT was significantly increased in every brain region of PT-treated rats except the cerebral cortex. Part of this increase in [14C]5-HIAA was shown to be due to impairment of active transport of this 5-HT metabolite out of the brain. However, increased 5-HT synthesis in the cerebellum, hypothalamus, striatum, hippocampus and cerebral cortex was demonstrated by measurement of 5-HT accumulation after inhibition of brain monoamine oxidase. PT-induced increase in endogenous 5-HIAA in the medulla-pons occurred simultaneously with the onset of neurological signs and both parameters were reversible by thiamine administration. These results suggest that acute thiamine deficiency, induced by PT, both increases brain 5-HT synthesis and impairs 5-HIAA efflux from the brain. There is a close correlation between neurological manifestations and changes in brain 5-HT metabolism in acute thiamine deficiency.

Nerve growth factor: effects on d-amphetamine-induced activity and brain monoamines

Adult male rats were given 6-hydroxydopamine lesions of the nucleus accumbens, followed immediately by injections of saline or nerve growth factor (NGF; 125 B.U.) near the substantia nigra. Such lesions were previously reported to attenuate the locomotor response to d-amphetamine. NGF-treated rats showed an enhanced response to d-amphetamine (1.5 mg/kg) when tested 15 days postoperatively. Levels of dopamine and norepinephrine in the striatum and nucleus accumbens were equivalently depressed in the two lesion groups, indicating that the apparent recovery of the NGF-treated rats was probably not due to catecholaminergic neuronal regrowth. Intracerebral NGF administration enhanced the response to d-amphetamine 15 days later in rats without lesions, and also appeared to result in increased turnover of brain norepinephrine and serotonin at 3, but not 15, days postadministration. NGF might increase dopamine turnover at 15 days, but the evidence obtained did not convincingly confirm or negate this possibility. The results show that intracerebral NGF administration can produce similar behavioral changes in brain-damaged and intact rats, and also modify the apparent turnover of brain monoamines.

THE EFFECT OF ?9-TETRAHYDROCANNABINOL (?9-THC) ON THE TURNOVER RATE OF BRAIN SEROTONIN OF THE RAT

1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of delta 9-tetrahydrocannabinol (delta 9-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by delta 9-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid from the rise of serotonin following pargyline. 3. delta 9-THC did not alter serotonin turnover rate when it was calculated from the conversion of 3H-tryptophan to 3H-serotonin. 4. The serotonin turnover rate was significantly increased by delta 9-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that delta 9-THC does not alter the turnover of rat brain serotonin. The previously reported delta 9-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by delta 9-THC of the vesicular binding of serotonin.

Effect of 1-(m-trifluoromethylphenyl)-piperazine on 3H-serotonin binding to membranes from rat brain in vitro and on serotonin turnover in rat brain in vivo

1-(m-Trifluoromethylphenyl)-piperazine inhibited the specific binding of tritiated serotonin to membranes from rat brain in vitro at lower concentrations than did quipazine or MK-212 (6-chloro-2-[1-piperazinyk]-pyrazine). In rats 1-(m-trifluoromethylphenyl)-piperazine decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) without altering the concentration of serotonin in whole brain. The decrease in 5-HIAA was apparently due to a decrease in serotonin turnover, since 1-(m-trifluoromethylphenyl)-piperazine caused a slower decline in serotonin concentration after synthesis inhibition by α-propyldopacetamide and a slower accumulation of 5-HIAA after probenecid injection to block its efflux from brain. The decrease in serotonin turnover is an expected result of stimulating serotonin receptors in brain and has earlier been reported to occur with quipazine. Thus all of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.

Seasonal changes in the levels and the turnover of brain serotonin and noradrenaline in the European hamster kept under constant environment.

Seasonal changes in the content and the turnover of noradrenaline and serotonin are shown in various parts of the brain of the European hamster kept under constant conditions of light and temperature.

Possible role of brain serotonin in the central effects of ketamine

Ketamine increased serotonin turnover in the rat brain. This effect persisted for several hours after the anaesthetic effect of ketamine had terminated. Pretreatment with para-chlorophenyl-alanine, an inhibitor of serotonin synthesis, or with methergoline, a serotonin receptor blocker, potentiated the anaesthetic and analgesic effect of ketamine.

Brain serotonin turnover in the hypophysectomized rat

Brain serotonin turnover, as measured from the rate of decline of 5-hydroxyindoleacetic acid after pargyline administration, was higher in hypophysectomized rats than in intact age-matched controls. As a consequence brain 5-HIAA concentrations were also increased after hypophysectomy. The increased brain 5-HT turnover was neither dependent on the duration of hormonal deprivation nor it was related to the extent of sexual maturation of the animal when the pituitary ablation was performed. The finding that hypophysectomy markedly affected the disposal of tryptophan both in the plasma and the brain suggest that the increased brain 5-HT turnover found in hypophysectomized rats may be ascribed to an enhanced availability of this amino acid by brain 5-HT neurons.

Behavioral and neurochemical effects of prenatal halothane.

Permanent neurobehavioral toxicological effects have been theorized to occur at the lowest doses of a toxic agent if exposure occurs during early development compared to exposure during adulthood. Data are reviewed showing the exposure to 10 ppm of halothane from conception to day 60 of life post-partum led to adult rats (>/= 135 days of age) which were hyperalgesic to electric footshock and which committed 30% more errors learning a light-dark discrimination to escape footshock, or learning the shortest path to a food reward in a maze. Exposure only during adulthood to 10 ppm of halothane (from day 60 of life onwards) had no effects. To determine prenatal periods sensitive to halothane, rats were exposed to 12,500 ppm of halothane (with 35% oxygen) on day 3, 10, or 17 of gestation. As adults (>/= 75 days of age) day 3- and day 10-exposed rats, but not day 17-exposed rats, were hyperalgesic and committed 40% more errors in learning a visual discrimination to escape footshock. Food and water consumption, body weight, and running wheel activity were unaffected. Finally, adult rats exposed to 10, 50, or 100 ppm of halothane from conception to day 28 postpartum had 15% less 5-hydroxyindoleacetic acid in brain, but normal 5-hydroxytryptophan, noradrenalin, and dopamine. The possibility is discussed that the hyperalgesia noted above results from a permanently reduced turnover of brain serotonin produced by halothane present in brain at days 10-15 of gestation.

Dissociation of increased 5-hydroxyindoleacetic acid levels and physical dependence: the effects of naloxone.

1. A slow release emulsion of naloxone (naloxone SR) was administered subcutaneously to rats in an attempt to induce physical dependence of the morphine type. 2. Naltrexone (2.5 mg/kg), injected i.p., failed to elicit an abstinence syndrome in rats treated with 75, 100 or 150 mg/kg naloxone SR for 24, 48, or 72 h. 3. Naloxone SR had no effect on the whole brain levels of noradrenaline, dopamine, homovanillic acid or serotonin. 4. Naloxone SR caused an apparent dose-related increase in the brain levels of 5-hydroxyindoleacetic acid. 5. These results show that while naloxone does not induce physical dependence of the morphine type, it may, like morphine, increase the brain serotonin turnover rate. 6. It is proposed that the increase in brain serotonin turnover rate may not be causally related to physical dependence on morphine-like drugs but may be a property of drugs containing the basic opiate molecular structure.

Brain serotonin turnover and morphine tolerance-dependence induced by multiple injections in the rat

Tolerance to and physical dependence on morphine in the rat was induced by injecting increasing doses of morphine sulfate (M.S.) administered i.p. twice daily for 14 days. The last dose of M.S. was 200 mg/kg. This procedure produced a 4-fold tolerance to morphine as evidenced by the increased dose of morphine required to produce analgesia. The degree of dependence was quantified by determining the naloxone ED 50 for the stereotyped withdrawal jumping response. Body weight loss and hypothermic responses during abrupt and naloxone-induced withdrawal were also measured. The degree of tolerance and dependence produced by multiple injection procedure was comparable to that produced by 2 pellets containing 75 mg of morphine base implanted for 3 days. The level and turnover of brain serotonin, determined 6 or 12 h after the last morphine sulfate injection did not differ significantly from that of saline injected control animals. These data indicate that multiple injection technique produces a mild degree of tolerance to, and physical dependence on, morphine which was not related to changes in brain serotonin level or turnover.

Brain serotonin turnover in chronically uremic rats.

Brain serotonin turnover was investigated in chronically uremic and sham-operated pair-fed control rats. Animals were injected ip with 100 mg/kg body wt of pargyline HCl, a nonreversible monoamine oxidase inhibitor, and decapitated 0, 30 and 60 min later. The level of total tryptophan in plasma was decreased, and that of free tryptophan was increased in the uremic group. Uremic and control rats had similar concentrations of tryptophan and serotonin at 0 and 30 min after pargyline administration. However, the brain serotonin concentration was elevated in the uremic group 60 min after pargyline treatment. The brain serotonin turnover rate was higher and serotonin turnover time was lower in the uremic group. These results indicate that uremic stress, in addition to altering plasma tryptophan levels, also affects brain serotonin turnover.

Cadmium alters behaviour and the biosynthetic capacity for catecholamines and serotonin in neonatal rat brain.

Abstract— Daily exposure to cadmium (10 μg/100g) for 30 days since birth significantly increased spontaneous locomotor activity as well as striatal tyrosine hydroxylase and mid‐brain tryptophan hydroxylase. The endogenous levels of norepinephrine, dopamine and serotonin failed to change in various brain regions of cadmium‐treated rats. In contrast, the concentration of 5‐hydroxyindoleacetic acid tended to rise but was significantly different from controls only in the mid‐brain region. The data suggest that cadmium treatment in early life increased the synthesis and physiological utilization of these putative transmitters which in turn probably altered locomotor performance.Increasing the dose of cadmium to 100 μg/100 g for 30 days decreased body weight (by 19%) and produced slight increases in the turnover of brain amines. However, the rise was not dose‐dependent. Furthermore, the locomotor activity remained the same as that seen in rats treated with the low dose of cadmium. The levels of dopamine in hypothalamus and that of norepinephrine in several brain regions examined were enhanced. This could in part, be attributed to decreased (12%) activity of catechol‐O‐methyl transferase enzyme. Administration of the high dose of cadmium produced significant increases in 5‐hydroxyindoleacetic acid level. Data suggest that cadmium acts at some step in the sequence of intracellular events that leads to increased synthesis and presumably turnover of brain catecholamines and serotonin. Since high dosage of this heavy metal failed to produce a dose‐dependent change in locomotor activity, it is not possible to impute any casual role for these amines in the production of hyperactivity seen in cadmium‐treated rats.

Effects of 4-(3-indolyl-alkyl) piperidine derivatives on brain 5-hydroxytryptamine turnover and on cardiac and brain noradrenaline or 5-hydroxytryptamine depletion induced by 6-hydroxydopamine, H [formula omitted] and 4-chloroamphetamine

4-(3-Indolyl-alkyl)piperidine derivatives (LM 5005, LM 5008 and LM 5015), like clomipramine, had no or little effects on brain 5-HT but reduced brain 5-HIAA levels and 5-HT turnover, after single or chronic treatment. Brain tryptophan levels remained unaffected by clomipramine, were slightly decreased by LM 5008 and increased by LM 5005 and LM 5015. The piperidine derivatives counteracted brain 5-HT depletion induced by H 75 12 and 4-chloroamphetamine more effectively than clomipramine, after i.p. or p.o. administration. On the contrary clomipramine was more effective in inhibiting cardiac NA depletion induced by 6-OH-dopamine than LM 5015; LM 5008 and LM 5005 were ineffective. The potential therapeutic effects of such compounds in mental diseases are discussed.