Brain Serotonin Turnover Research Articles

Increased rate of disappearance of serum probenecid in barbital dependent rats

Rats were made barbital dependent by administration of barbital in their drinking water. Subsequently, the rats were either not withdrawn (BN) or withdrawn from barbital for 24 h (BW-24). Before sacrifice, probenecid was administered to measure brain serotonin turnover. A statistically significant decrease in 5-hydroxyindole-acetic acid (5-HIAA) accumulation was observed in the cerebral cortex, medulla pons and midbrain. Subsequently, serum levels of probenecid were also measured by gas chromatography to determine if chronic barbital consumption might affect circulating probenecid. By ninety minutes following probenecid administration, serum probenecid levels in BN and BW-24 rats were significantly lower than control while a probenecid metabolite was significantly increased. The significantly reduced accumulation of 5-HIAA in brain areas of BN and BW-24 rats is probably the result of the more rapid decline of probenecid rather than a true decrease in serotonin turnover.

Nutritionally Small-for-Dates Rats: Their Subsequent Growth, Regional Brain 5-Hydroxytryptamine Turnover, and Behavior

Rats were subjected to nutritional growth retardation either from conception to 5 postnatal days of age (fetal and neonatal restriction (FNR) group), or from 5 to 25 postnatal days of age (infantile restriction (IR) group). The FNR group may serve as a model for the human small-for-dates baby. At 20 weeks of age cerebellum, midbrain, and cerebrum were significantly reduced in weight by 4%, 5%, and 4%, respectively, in FNR animals when compared with controls. Only cerebellum and midbrain were affected in IR rats of the same age, but in both regions the percentage deficits (8% and 9%, respectively) were greater than in FNR animals. Both cerebellum and midbrain weighed significantly less in IR than in FNR rats. The timing of nutritional growth retardation appeared to be of little consequence to the regional brain turnover of 5-hydroxytryptamine in adulthood. The rate of synthesis in the hippocampus of both FNR and IR animals was significantly faster (67% and 75% respectively) than in controls. The increased turnover could perhaps represent "overactivity" of those 5-hydroxytryptaminergic neurons terminating in the hippocampus. Some differences in the behavior of the previously undernourished adult animals were also evident. On the fifth day of testing, control rats were most venturesome in the open field. Eighteen control rats left the edge zone within 2 min, whereas only 8 FNR and 11 IR rats did so. Most animals froze immediately after a 7-sex exposure to a loud electric bell. The delay before moving about again differentiated the three groups. FNR rats took longest to move out of the area in which they froze.

Influence of dieldrin on serotonin turnover and 5-hydroxyindole acetic acid efflux in mouse brain

Chronic administration of dieldrin failed to produce any alteration of brain serotonin, norepinephrine or dopamine in mice, but caused an increase in 5-hydroxyindole acetic acid levels. The turnover rate of serotonin was unaffected by dieldrin. The probenecid induced accumulation rate of 5-hydroxyindole acetic acid was considerably lowered in dieldrin-treated mice. The results suggested a possible influence of dieldrin on 5-hydroxyindole acetic acid efflux from mouse brain.

Effects of L-tryptophan and restraint stress on hypothalmic and brain serotonin turnover, and pituitary TSH and prolactin release in rats

The dose response and time course effects of L-tryptophan and restraint stress on the metabolism of serotonin and release of thyroid stimulating hormone (TSH) and prolactin (PRL) were tested in male rats. Both treatments increased serotonin turnover in the hypothalamus (H) and remaining brain tissue minus the cerebellum (brain) as determined by enhanced accumulation of serotonin following monoamine oxidase (MAO) inhibition. L-tryptophan but not restraint stress elevated levels of tryptophan in the cerebellum. Both L-tryptophan and restraint stress inhibited TSH release and stimulated PRL release. These findings indicate that enhanced rates of serotonin turnover produced by L-tryptophan and physical restraint are associated with inhibition of TSH and stimulation of PRL release from the anterior pituitary.

Responses of Midbrain raphe neurons to local temperature.

The effect of heating and cooling in the midbrain on the unit activities of midbrain raphe neurons in the rat was observed. Out of 24 raphe units studied, 14 units responded to a rise in midbrain temperature with an increased rate of firing. The remaining 10 units did not respond to temperature changes between 34 and 41 degrees C. The result is consistent with the idea that the heat-induced increase in brain serotonin turnover is mediated by an increased firing rate of midbrain raphe neurons.

Effects of morphine on the turnover of brain catecholamines and serotonin in rats — chronic morphine administration

The turnover of brain monoamine was studied in rats in which different degrees of tolerance to and dependence on morphine were induced by pellet implantation. The degree of tolerance to morphine was assessed by measuring the increase in effective dose for an antinociceptive effect (vocalization test). The rate of depletion of brain dopamine (DA) and serotonin (5-HT) after α-methyl-p-tyrosine (AMT) or α-propyl-dopacetamide (dop-acetamide) was not changed by chronic morphine treatment. In contrast, the accumulation of brain homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) after probenecid was significantly increased, but there was no correlation between the biochemical changes and the degree of tolerance/dependence of the animals; at a very high degree of dependence 5-HIAA accumulation even became normal. In rats in which smaller amounts of morphine were repeatedly injected every 8 hr for 1 week the increased accumulation of HVA and 5-HIAA persisted in spite of complete tolerance to the antinociceptive effect. The rate of depletion of brain noradrenaline (NA) after AMT or dopacetamide was not changed and the accumulation of brain 3-methoxy-4-hydroxy-phenylglycol sulphate (MHPG-SO 4) after probenecid was not affected in most chronic morphine groups. In the group with the highest degree of tolerance/dependence NA depletion after AMT was even retarded. The results suggest that chronic morphine treatment increases the synthesis and the intraneuronal destruction of newly synthesized DA and 5-HT without changing the rate of functional utilization of the monoamines. It is unlikely that the changes in monoamine metabolism are causally related to processes leading to morphine tolerance/dependence.

Effects of morphine on the turnover of brain catecholamines and serotonin in rats — acute morphine administration

Morphine increased the rate of brain dopamine (DA) depletion when given before α-methyl-p-tyrosine (AMT) or α-propyl-dopacetamide, but not when given after AMT. No effect of morphine was found on the rate of depletion of brain noradrenaline (NA) or serotonin (5-HT) after the two synthesis inhibitors. The accumulation of homovanillic acid and 5-hydroxy-indoleacetic acid induced by probenecid was significantly increased by morphine pretreatment, whereas the accumulation of 3-methoxy-4-hydroxy-phenylglycol sulphate was not changed. These findings can be best explained by the hypothesis that morphine increases the non-functional intraneuronal catabolism of newly synthesized DA and 5-HT, without much effect on the monoamines already taken up in the synaptic vesicles. NA turnover does not seem to be changed by acute morphine administration.

Behavioral, pharmacological, and biochemical analysis of genetic differences in rats

Several strains of commercially available rats were studied which showed clear behavioral differences in activity and in shock avoidance behavior. Intensive study of two behaviorally very different strains, F-344 and Zivic-Miller, shows that their differences in shuttle box avoidance acquisition is genetic and is based on their activity response to shock stress rather than to a difference in general learning ability. Drug administration and lesion studies suggested that the behavioral differences were due to differences in brain monoamine responses to shock stress. Biochemical studies of brain serotonin, norepinephrine, and dopamine turnover following stress support this concept.

Effect of acute and chronic iprindole on serotonin turnover in mouse brain

Effect of acute and chronic iprindole on serotonin turnover in mouse brain

Effects of methergoline on central monoamine neurones. Evidence for a selective blockade of central 5-HT receptors

The effects of methargoline have been studied on brain dopamine (DA), noradrenaline (NA) and serotonin (5-HT) levels and turnover using biochemistry and quantitative microfluorimetry. Also, its actions on spinal NA and 5-HT receptor activities and telencephalic DA receptor activity have been evaluated by studies on the flexor and extensor reflex activity, respectively, and on rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending DA pathways. The results indicate that methergoline can selectively block at least some postsynaptic 5-HT receptors in the CNS and can be an important tool in the functional and biochemical analysis of central 5-HT neurones. According to the view of Andén et al. [2] it may have a therapeutic action in certain types of schizophrenia.

The effect of yohimbine on the turnover of brain catecholamines and serotonin

Yohimbine moderately increased the depletion of brain dopamine (DA) after α-methyl-p-tyrosine (AMT) only when the two drugs were given at the same time; the baseline concentration of brain homovanillic acid (HVA) and its accumulation after probenecid were strongly increased by yohimbine. Yohimbine markedly decreased the concentration of brain noradrenaline (NA), both when given alone and before or at the same time as AMT; when it was given at an increasing interval after AMT, the effect became progressively smaller. The baseline concentration of brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate and its accumulation after probenecid were increased by yohimbine; this effect was not as marked as that on HVA and was proportional to the quantity of NA depleted in the AMT method. The accumulation of brain 5-hydroxyindoleacetic acid after probenecid was decreased by yohimbine pretreatment.

Inhibtion of the transport of 5-hydroxyindoleacetic acid from brain by ethanol.

Abstract—The injection of ethanol in mice produced a transient rise in 5‐hydroxyindoleacetic acid (5‐HIAA) levels in brain. However, no concomitant changes in serotonin (5‐HT) levels were noted. In an attempt to explain the biochemical mechanism by which ethanol produced this effect, uptake of tryptophan by brain, serotonin turnover in brain, and transport of 5‐HIAA from brain were investigated. No changes in tryptophan levels or uptake into brain of ethanol‐treated mice were noted. Ethanol 3 g/kg was found to decrease serotonin turnover. Ethanol was also demonstrated to inhibit the removal of 5‐HIAA from the central nervous system, and was found to be an inhibitor of 5‐HIAA uptake by isolated choroid plexus. The inhibition of biogenic acid transport was noted even at sub‐hypnotic levels of ethanol.

Effect of acutely administered analgesic drugs on rat brain serotonin turnover

Rat brain 5-HT levels were unaltered by all four analgesics. Levels of 5-HAA in the rat brain were increased by morphine and decreased by pethidine. The effect of morphine, but not pethidine, on 5-HIAA levels was antagonized by naloxone pretreatment. Rat brain 5-HT turnover was measured by two non-isotopic techniques. Of morphine, pentazocine, methadone and pethidine only morphine increased brain 5-HT turnover. Furthermore, morphine increased brain tryptophan levels. The ability of morphine to increase both 5-HT turnover and tryptophan levels was antagonized by naloxone pretreatment. Pethidine also increased brain tryptophan levels but this effect was not antagonized by naloxone. It is concluded that the ability of morphine to increase rat brain 5-HT turnover is not possessed by pentazocine, methadone and pethidine.

Regional Brain 5-Hydroxytryptamine Turnover in Adult Rats Growth Retarded in Early Life

Regional Brain 5-Hydroxytryptamine Turnover in Adult Rats Growth Retarded in Early Life

Biochemical and behavioral effects of lesions of raphe nuclei in aggressive mice

A decrease of brain 5-hydroxytryptamine turnover was described to be present in mice made aggressive by prolonged isolation. The lesion of brain serotoninergic pathways decreases both 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels in the forebrain and completely abolishes the aggressive behavior in previously fully aggressive mice. No change of aggressive behavior or of serotonin levels was observed in aggressive mice submitted to lesions of other areas.

Long-term effects of 4-chloroamphetamine on brain 5-hydroxyindole metabolism in rats

Four weeks after a single intraperitoneal injection of 4-chloroamphetamine hydrochloride (0·1 mmol/kg) into rats, brain serotonin and 5-hydroxyindoleacetic acid levels were still depressed to approximately half the control values, though tryptophan levels in brain were normal. Serotonin turnover in brain was likewise depressed to about half of the control rate as measured by (a) the rate of serotonin accumulation after monoamine oxidase inhibition and (b) the rate of 5-hydroxyindoleacetic acid accumulation after probenecid administration to block its efflux. Despite this decreased turnover rate, the capacity of the brain to synthesize 5-hydroxyindoles, as indicated by the increases in serotonin and 5-hydroxyindoleacetic acid after the injection of various doses of l-tryptophan, was not altered.

Effect of acute and chronic ethanol administration on serotonin turnover in rat brain.

In rats treated acutely and chronically with ethanol, brain serotonin (5-HT) turnover was determined by measuring in the same animals the rate of accumulation of 5-HT and the rate of decline of 5-hydroxyindoleacetic acid (5-HIAA) in the brain after administration of the MAO inhibitor pargyline-HCl. In the acute study, 5-HT turnover was not altered after a single 4 g/kg oral dose of ethanol. In two separate studies, it was shown that chronic administration of ethanol in the form of a liquid diet for 32 days also did not alter brain 5-HT turnover, even when the rats had developed a significant degree of tolerance to the motor-impairing effects of ethanol. These results suggest that tolerance to ethanol is unrelated to any change in brain 5-HT turnover.

Modification of serotonin metabolism in rat brain after acute or chronic administration of morphine

The steady state concentration of 5-hydroxyindoleacetic acid (5-HIAA) was elevated in rat brain for at least 4 hr after administration of a single dose of morphine sulfate (30 mg/kg, s.c.), and for more than 40 hr after subcutaneous implantation of pellets of morphine alkaloid. The concentration of 5-HIAA returned to normal 3 days after pellet implantation at a rate that paralleled the development of tolerance to the analgesic and other overt actions of morphine. Morphine did not modify the steady state concentration of serotonin under any of the treatment conditions. The turnover of brain serotonin was increased significantly during the 90-min period following a single injection of morphine sulfate (30 mg/kg, s.c.), as indicated by an increased rate of accumulation of 5-HIAA after blockade of efflux of 5-HIAA by probenecid in morphinetreated animals. As judged either by the rate of accumulation of 5-HIAA after administration of probenecid, or by the rate of accumulation of serotonin after treatment with pargyline, an increase in turnover of serotonin was evident in brains of tolerant rats 72 hr after pellet implantation. The rate of efflux of 5-HIAA from the brain was the same in control and morphine-tolerant rats. These results indicate that changes in brain serotonin metabolism are associated with both the acute effects of morphine and with morphine tolerance.

Effect of high oxygen pressure on brain norepinephrine and serotonin turnover

The effect of high oxygen pressure on the in vivo turnover of NE in mouse and rat brain, and the turnover of 5-HT in mouse brain was investigated. Turnover of NE and 5-HT was determined by steady-state kinetic methods. In mice, synthesis of NE was inhibited by the administration of α-MPT. In rats NE turnover was determined from the decline in intracisternally administered H 3NE. Steady-state kinetic methods also were used to determine 5-HT turnover in mice, utilizing probenecid to block the transport of 5-HIAA. In these studies, 100% oxygen at 1 and 3 atmospheres had no effect on either NE turnover in mice and rats or 5-HT turnover in mice. These studies suggest that changes in NE and 5-HT turnover do not appear to be implicated in the onset of oxygen-induced convulsions.

Behavioral and neurochemical effects of caffeine in normal and aggressive mice

Caffeine is known to exert psychostimulant effects both in man and in animals and it has been shown to modify the levels of brain neurotransmitters. In normal and isolated-aggressive mice, caffeine induces modifications of both the level and the turnover of brain serotonin. Such modifications are however more evident in normal than in aggressive mice. Moreover, caffeine shows an antiaggressive effect and increases the exploratory activity of aggressive mice, without altering the performance of normal animals. It seems possible to conclude that the biochemical and behavioral effects of this drug differ in extent and intensity depending upon the emotional baseline on which it acts.