Long-lasting changes in regional brain amino acids and monoamines in recovered pyrithiamine treated rats

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine +a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were signifciantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.     

Morphine tolerance in arthritic rats and serotonergic system

To understand whether chronic inflammation alters the development of morphine tolerance, the tail-flick test was used to evaluate the analgesic effect of morphine (75 mg tablet, s.c.) in the arthritic rats at the day 9-12 after the inoculation with Freund's adjuvant. Spinal cord monoamines and amino acid neurotransmitters were concomitantly measured. Chronic inflammation attenuated the antinociceptive effect of morphine as tolerance developed faster in the arthritic rats compared to the vehicle-treated controls. In addition, ratio of 5-hydroxyindole-3-acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) increased in the lumbar spinal cord of arthritic rats without any change in the concentrations of norepinephrine, glutamate, aspartate or GABA. Interestingly, increased serotonin turnover in the spinal cord was observed in both control and arthritic rats 24 hours after morphine treatment. Overall, the results suggest a significant role of serotonin up-regulation in the spinal cord during chronic pain and the development of morphine tolerance.     

Effects of p,p''-DDT on the Rat Brain Concentrations of Biogenic Amine and Amino Acid Neurotransmitters and Their Association with p,p''-DDT-Induced Tremor and Hyperthermia

Male, Fischer strain 344 adult rats were given various doses (25-100 mg/kg) of p,p'-DDT by oral gavage, and levels of biogenic amines, their metabolites, and amino acid neurotransmitters, tremor activity, and rectal temperature were measured at several intervals (2, 5, 12, and 24 h) after dosing. Dose-related increases in rectal temperature and in tremor activity were observed at 50-100 mg/kg 12 h after dosing. Tremorigenic doses of DDT increased the 5-hydroxyindoleacetic acid (5-HIAA) level in hypothalamus, brainstem, and striatum, whereas doses of 75 and 100 mg/kg increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level in hypothalamus and brainstem and the 3,4-dihydroxyphenylacetic acid level in striatum. Six amino acids were assayed in the brainstem, hypothalamus, and striatum; aspartate and glutamate levels were increased only in brainstem at 25-100 mg/kg. No consistent changes in concentrations of taurine, glutamine, glycine, or gamma-aminobutyric acid were observed in any of the regions assayed. Time-related increases in rectal temperature were seen 2-12 h after dosing, and the presence of tremor was observed 5-12 h after dosing; for both the time of peak effect was at 12 h. The DDT-induced hyperthermia and tremor were associated with dose- and time-related increases in levels of 5-HIAA, MHPG, aspartate, and glutamate. It is suggested that an increase in the turnover rate of 5-hydroxytryptamine (5-HT) may be responsible for the DDT-induced hyperthermia, whereas increases in the metabolism of 5-HT and norepinephrine may be involved in the tremor.     

Possible role of glutamate, aspartate, glutamine, GABA or taurine on cadmium toxicity on the hypothalamic pituitary axis activity in adult male rats

This work was designed to evaluate the possible changes in glutamate, aspartate, glutamine, GABA and taurine within various hypothalamic areas the striatum and prefrontal cortex after oral cadmium exposure in adult male rats, and if these changes are related to pituitary hormone secretion. The contents of glutamine, glutamate, aspartate, GABA and taurine in the median eminence, anterior, mediobasal and posterior hypothalamus, and in prefrontal cortex in adult male rats exposed to 272.7 mol l^–1 of cadmium chloride (CdCl₂) in the drinking water for one month. Cadmium diminished the content of glutamine, glutamate and aspartate in anterior hypothalamus as compared to the values found in the untreated group. Besides, there is a decrease in the content of glutamate, aspartate and taurine in the prefrontal cortex. The amino acids studied did not change in median eminence, mediobasal and posterior hypothalamus or the striatum by cadmium treatment. Plasma prolactin and LH levels decreased in rats exposed to the metal. These results suggest that (1) cadmium differentially affects amino acid content within the brain region studied and (2) the inhibitory effect of cadmium on prolactin and LH secretion may be partially explained by a decrease in the content of both glutamate and aspartate in anterior hypothalamus, but not through changes in GABA and taurine.     

Pharmacological effects of GABA on serotonin metabolism in the rat brain

The pharmacological effects of GABA-related drugs were studied on the serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA) contents of various regions of the rat brain. These effects were examined in the nuclei raphe dorsalis, magnus and centralis and in structures receiving a dense serotonin innervation such as the habenula complex and subcommissural organ. The GABA agonist, muscimol, increased the 5-HT contents and reduced 5-HIAA levels in structures containing serotoninergic terminals suggesting an inhibitory effect of GABA on the firing of serotoninergic neurons with concomitant reduction of 5-HT utilisation. In contrast, the GABA antagonist, bicuculline, probably stimulated 5-HT turnover since its intraperitoneally administration produced significant increase of 5-HT and/or 5-HIAA levels in the same brain regions. These data are in agreement with a transsynaptic inhibitory control of GABA on serotoninergic neurons. Drugs which inhibit the GABA catabolism such as amino-oxyacetic acid or gamma-vinyl-GABA and which should elevate GABA levels in the synaptic gap were capable of increasing or decreasing the 5-HT and the 5-HIAA levels depending on the experimental conditions. These results suggest that several processes are probably involved in the control of serotoninergic neurons by GABA in the rat brain. Among them, an intracellular effect of GABA on 5-HT metabolism might well occur in cells containing both GABA and 5-HT.     

Turnover rates of amino acid neurotransmitters in regions of rat cerebellum

The turnover rates of aspartate, gamma-aminobutyric acid (GABA), glutamate, glutamine, alanine, serine, and glycine were measured in five regions of rat cerebellum. Turnover rates of the putative neurotransmitters (aspartate, glutamate, and GABA) were 2-20-fold higher than those of alanine and serine, and generally consistent with the proposed neurotransmitter functions for these amino acids. However, glutamate turnover was high and similar in magnitude in the deep nuclei and granule layer, suggesting possible release, not only from parallel fibers, but from mossy fibers as well. The differential distribution of turnover rates for GABA supports its neuronal release by Purkinje, stellate, basket, and Golgi cells, whereas aspartate may be released by both climbing and mossy fibers. The distribution of glycine turnover rates is consistent with release from Golgi cells, whereas alanine may be released from granule cell parallel fibers. Turnover rates measured in two other motor areas, the striatum and motor cortex, indicated that utilization of these amino acid neurotransmitters is differentially distributed in brain motor regions. The data indicate that turnover rate measurements may be useful in identifying neurotransmitter function where content measurements alone are insufficient.     

Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum

This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.     

Neurochemical asymmetries in the albino rat's cortex, striatum, and nucleus accumbens

The concentrations of dopamine (DA), norepinephrine (NE), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the right and left cortex, striatum, and nucleus accumbens of adult Purdue-Wistar rats. There was more DA in the right cortex and accumbens and a greater concentration of NE in the left striatum. There is more 5-HT in the left striatum and right accumbens, more 5-HIAA in the left cortex, as well as a greater 5-HT turnover in the left accumbens. These results are considered in the light of previous findings concerning the relationship of neurochemical asymmetries and behavioral lateralization.     

Alternate cadmium exposure differentially affects amino acid metabolism within the hypothalamus, median eminence, striatum and prefrontal cortex of male rats.

This work was designed to analyze the possible changes in glutamate, aspartate and glutamine content induced by cadmium exposure in the hypothalamus, striatum and prefrontal cortex of rats, using an alternate schedule of metal administration. Pubertal-adult differences were also evaluated. In adult control rats, glutamate and aspartate contents in the anterior hypothalamus decreased as compared to pubertal controls. After cadmium administration from day 30 to 60 of life, the content of anterior hypothalamic glutamate and aspartate diminished. In adult control animals, the glutamine content increased in mediobasal hypothalamus as compared to pubertal controls. After cadmium exposure from day 30 to 60 of life, the mediobasal glutamine content increased, and after cadmium treatment from day 60 to 90 of life, the mediobasal aspartate content decreased. In adult control rats the content of glutamine, glutamate and aspartate of the posterior hypothalamus decreased significantly. After cadmium administration in pubertal animals, posterior hypothalamic contents of glutamine, glutamate and aspartate diminished. Cadmium treatment of adult animals caused a decrease in glutamine content, as compared to controls. In adult control rats, only glutamate and aspartate content increased in the prefrontal cortex as compared to the values found in pubertal controls. When cadmium was administered to adult animals, only the aspartate content decreased. In the striatum, cadmium decreased the glutamine and aspartate contents when administered from day 60 to 90 of life. These data suggest that cadmium differentially affects amino acid metabolism in the hypothalamus, striatum and prefrontal cortex. Age-dependent effects of cadmium on these brain areas appeared to have occurred.     

Effects of chronic administration of bilobalide on amino acid levels in mouse brain.

We have previously demonstrated that 4-day-treatment of mice with bilobalide, a sesquiterpene of Ginkgo biloba L., increases GABA levels in mouse brain, but, effects of chronic treatment with it are not clear. To study effects of chronic treatment of mice with bilobalide on amino acid levels in the brain, we determined the levels of aspartate, glutamate, serine, glutamine, glycine, taurine and GABA in the hippocampus, striatum and cortex. Bilobalide (3 mg/kg/day) was administered orally to 4-week-old mice for 40 days. Bilobalide treatment resulted in a significant increase in the levels of glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine in the hippocampus of mice compared with the control. An increased level of glycine after bilobalide treatment was also detected in the striatum. In the cortex, bilobalide increased the GABA level, whereas it decreased the level of aspartate. These changes in the levels of various amino acids may be involved in the broad spectrum of pharmacological activities of the extract of Ginkgo biloba on the central nervous system.     

NEURONAL-GLIAL CONTRIBUTIONS TO TRANSMITTER AMINO ACID METABOLISM: STUDIES WITH KAINIC ACID-INDUCED LESIONS OF RAT STRIATUM

Abstract– Various aspects of amino acid metabolism were studied in striatum of rats with unilateral, kainic acid-induced lesions. Tissue slices were prepared from the lesioned and the contralateral, unlesioned, striatum. The preparations were incubated with a mixture of d -[2-¹⁴C]glucose and [³H]acetate in a Krebs-Ringer bicarbonate medium to evaluate oxidative metabolism. Glutamate and aspartate levels were decreased in the slices prepared from the lesioned striata by 35-40% and that of GABA by 75% compared to the levels found in the slices from the contralateral striata; glutamine levels were not different in the two preparations. Glucose utilization was decreased 60% in the slices from the lesioned striatum; this was caused not only by decreased levels of glutamate, aspartate and GABA but also by a decreased rate of labelling of glutamate and aspartate. On the other hand, the metabolism of [³H]acetate was greatly increased. The specific activities of glutamate and aspartate were 4-5-fold higher in the slices from kainic acid-lesioned striata; those of glutamine and GABA were unchanged. Thus, there was a 6-7-fold increase in the ratio of ³H to ¹⁴C in the specific activities of glutamate, aspartate and GABA with no change in this ratio in glutamine. The labelling of glutamine relative to that of glutamate, especially from [³H]acetate, suggested that the compartmentation of the glutamate-glutamine system was greatly altered in the kainate-lesioned striatum which now more closely resembled a single compartment system. The activities of lactate dehydrogenase, glutamate dehydrogenase, GABA transaminase and ‘cytoplasmic’ aspartate aminotransferase were decreased in homogenates of lesioned striatum. Succinate dehydrogenase, glutaminase (phosphate-activated) and ‘mitochondrial’ aspartate aminotransferase activities were unchanged whilst that of glutamine synthetase was increased. The results are consistent with hypotheses concerning the assignment of labelled acetate metabolism to glial cells as well as the distribution of the above enzymes between glia, neurones and nerve endings.     

Additive effects of apomorphine and clonidine on serotonin neurons in the dorsal raphe

Effects of apomorphine (APO) and clonidine (CLON) on the mesostriatal and mesolimbic serotonergic systems were examined in the present study. Both drugs selectively elevated serotonin (5-HT) concentrations in the dorsal raphe and the striatum without significantly altering 5-HT measures in the median raphe and the hippocampus. Apomorphine also increased tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) levels in the dorsal raphe and 5-HIAA level in the striatum. Clonidine did not markedly alter tryptophan and 5-HIAA measures, while it decreased 5-HT turnover rate in both region, as indicated by the ratio of 5-HIAA/5-HT levels. Co-administration of APO and CLON, at doses of each drug exerted maximum effects on 5-HT alone, produced an additive effect on 5-HT in the dorsal raphe, while their effects on 5-HT and 5-HIAA in the striatum were counteracting each other. Effects of APO on 5-HT and 5-HIAA were attributed to the elevation of 5-HT precursor tryptophan, while effects of CLON on 5-HT and 5-HIAA were due to a decreased rate of 5-HT turnover. Therefore, the present results support the hypothesis that the additive effects of APO and CLON on dorsal raphe 5-HT are mediated through different receptors and neuropharmacological mechanisms.     

Effects of Cyclohexanonic Long-Chain Fatty Alcohol, tCFA15 on Amino Acids in Diabetic Rat Brain: A Preliminary Study

The aim of this study was to evaluate the effects of streptozotocin-induced type 1diabetes and a subchronic treatment with cyclohexanonic long-chain fatty alcohol, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (tCFA15) on contents of amino acids including aspartate, glutamate, glutamine, GABA, glycine, taurine, alanine, serine, threonine, and arginine in the prefrontal cortex, hippocampus and striatum. Levels of glutamate, threonine, taurine, alanine, arginine, and the ratio of glutamate/glutamine were altered region-differently in the brain of diabetic rats. However, tCFA15 region-specifically antagonized the changes in taurine and arginine levels and the ratio of glutamate/glutamine. The alteration in glutamate/glutamine ratio may indicate that experimental models of type 1 diabetes have abnormalities of neuron-gria interaction in brain.     

Compartmentation of TCA cycle metabolism in cultured neocortical neurons revealed by 13C MR spectroscopy

Cultured neocortical neurons were incubated in medium containing [U-13C]glucose (0.5 mM) and in some cases unlabeled glutamine (0.5 mM). Subsequently the cells were "superfused" for investigation of the effect of depolarization by 55 mM K+. Cell extracts were analyzed by 13C magnetic resonance spectroscopy and gas chromatography/mass spectrometry to determine incorporation of 13C in glutamate, GABA, aspartate and fumarate. The importance of the tricarboxylic acid (TCA) cycle for conversion of the carbon skeleton of glutamine to GABA was evident from the effect of glutamine on the labeling pattern of GABA and glutamate. Moreover, analysis of the labeling patterns of glutamate in particular indicated a depolarization induced increased oxidative metabolism. This effect was only observed in glutamate and not in neurotransmitter GABA. Based on this a hypothesis of mitochondrial compartmentation may be proposed in which mitochondria associated with neurotransmitter synthesis are distinct from those aimed at energy production and influenced by depolarization. The hypothesis of mitochondrial compartmentation was further supported by the finding that the total percent labeling of fumarate and aspartate differed significantly from each other. This can only be explained by the existence of multiple TCA cycles with different turnover rates.     

Excitatory and inhibitory amino acid changes in ischemic brain regions in spontaneously hypertensive rats

Excitatory (glutamate, aspartate) or inhibitory amino acids (-aminobutyric acid: GABA, taurine) and glutamine contents were examined in acutely induced cerebral ischemia in spontaneously hypertensive rats. At 20 min ischemia most of these amino acids remained unchanged, but glutamine significantly decreased by 14% in the CA3 hippocampal subfield. At 60 min ischemia glutamate significantly decreased by 14% in the CA3, aspartate by 17–26% in the CA3, cingulate cortex, septum and striatum. In contrast, GABA significantly increased by 48–106% in the cortices (frontal, parietal and cingulate), striatum and nucleus accumbens, but insignificantly in hippocampal subrïelds. Likewise, taurine increased in the parietal cortex and nucleus accumbens. Glutamine showed heterogeneous changes (increase in the nucleus accumbens and decrease in the CA3). Amino acid levels change during ischemia, but their changes are varied in each area, implying that different reaction of amino acids may explain the selective vulnerability to cerebral ischemia.     

Serotonin and γ-Aminobutyric Acid Turnover After Injection into the Median Raphe of Substance P and D-Ala-Met-Enkephalin Amide

The raphe nuclei [which contain serotonin (5-HT) cell bodies] are also known to contain axons that store substance P, met-enkephalin, and gamma-aminobutyric acid (GABA). We have previously shown that GABA has a tonic inhibitory action on 5-HT turnover. To examine other possible interactions of these neuronal systems, we assessed the effect on 5-HT turnover of injecting substance P and 2-D-ala-met-enkephalin into the median raphe nucleus, and the effects of substance P on GABA turnover. Serotonin turnover was increased by 30% in the hippocampus after the injection of substance P (4 micrograms) into the median raphe, indicating an excitatory effect of substance P on the raphe-hippocampal system. Local injection of the metabolically stable metenkephalin analog 2-D-ala-met-enkephalin amide (10 micrograms) increased the hippocampal steady state content of 5-hydroxyindoleacetic acid (5-HIAA) by 60%. The data suggest an excitatory effect of met-enkephalin within the raphe nucleus. We attempted to estimate GABA turnover from the rate of disappearance of GABA after inhibition of glutamic acid decarboxylase by isoniazid and by the rate of accumulation of GABA after inhibition of GABA transaminase by gabaculine. Isoniazid, which is a competitive inhibitor, had too short and incomplete an action to be of use when injected intranuclearly. Gabaculine, which is an irreversible inhibitor, induced a rapid-onset increase in GABA content. This accumulation was linear up to 90 min. The injection fo gabaculine (80 ng) into the raphe increased GABA content by five times the control values, but hippocampal 5-HT and 5-HIAA contents were not significantly changed. Substance P injection increased the GABA turnover by 30%. Gabaculine seems a promising tool for detecting changes in GABA turnover.     

EFFECTS OF METABOLIC INHIBITORS ON AMINO ACID METABOLISM IN RAT RETINA: A COMPARISON OF AMINO-OXYACETIC ACID AND ETHANOLAMINE-O-SULPHATE

Abstract— The abilities of AOAA and EOS to modify the utilisation of radioactively labelled glucose, acetate, glutamine and GABA were studied in isolated rat retina. AOAA inhibited the activities of GAD and GABA-T, while EOS inhibited GABA-T but not GAD. AOAA lowered the free amino acid contents of incubated retinae and suppressed the outflow of amino acids into the incubation medium, while EOS had no effect on either parameter. AOAA strongly inhibited the incorporation of ¹⁴C from labelled glucose, acetate and glutamine into GABA, and also suppressed the labelling of glutamate, aspartate and glutamine. These effects were qualitatively similar but quantitatively smaller with EOS. Both compounds markedly decreased the syntheses of aspartate and glutamate from exogenous GABA, while the passage of carbon from GABA to glutamine was much less affected. It is suggested that AOAA and EOS may act predominantly on neurones. It appears that inhibition of GABA-T alone does not cause a profound disturbance of the metabolism of other amino acids. Other metabolic inhibitors such as ouabain, malonate and fluoroacetate did not greatly affect the metabolism of GABA in rat retina.     

Regulation of Transmitter γ-Aminobutyric Acid (GABA) Synthesis and Metabolism Illustrated by the Effect of γ-Vinyl GABA and Hypoglycemia

The effect of different treatments on amino acid levels in neostriatum was studied to throw some light on the synthesis and metabolism of gamma-aminobutyric acid (GABA). Irreversible inhibition of GABA transaminase by microinjection of gamma-vinyl GABA (GVG) led to a decrease in aspartate, glutamate, and glutamine levels and an increase in the GABA level, such that the nitrogen pool remained constant. The results indicate that a large part of brain glutamine is derived from GABA. Hypoglycemia led to an increase in the aspartate level and a decrease in glutamate, glutamine, and GABA levels. The total amino acid pool was decreased compared with amino acid levels in normoglycemic rats. GVG treatment of hypoglycemic rats led to a decrease in the aspartate level and a further reduction in glutamate and glutamine levels. In this case, GABA accumulation continued, although the glutamine pool was almost depleted. The GABA level increased postmortem, but there were no detectable changes in levels of the other amino acids. Pretreatment of the rats with hypoglycemia reduced both glutamate and glutamine levels with a subsequent decreased postmortem GABA accumulation. The half-maximal GABA synthesis rate was obtained when the glutamate level was reduced by 50% and the glutamine level was reduced by 80%.     

Effects of an N-methyl-d-aspartate receptor agonist and its antagonist CPP on the levels of dopamine and serotonin metabolites in rat striatum collected in vivo by using a brain dialysis technique

3-((±)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) is an antagonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In the present study, levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) were measured after intracerebroventricular injection of NMDA, CPP or both in rat striatum using a brain dialysis method. The injection of NMDA produced a significant increase in DOPAC level. HVA level was also increased by NMDA injection. The level of 5-HIAA was not affected by NMDA injection. The injection of CPP had no effect on DOPAC, HVA and 5-HIAA levels. The injection of CPP restrained the increase of DOPAC and HVA levels induced by NMDA injection. The results suggest that intracerebral injection of NMDA may increase dopamine release from rat striatum, but have no effect on serotonin release. Furthermore, CPP inhibits NMDA induced release of dopamine.     

Dose-dependent dual effect of corticosterone on cerebral 5-HT metabolism

The action of 1.0 and 10.0 mg/kg (i.p.) of corticosterone on serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents and on serotonin turnover, measured by an MAO-inhibitor method, was studied at 30 and 120 min after administration. A 1.0 mg/kg dose of corticosterone increased the serotonin content and turnover in the hypothalamus and mesencephalon 30 min after administration; however, it was ineffective on dorsal hippocampus and frontal and parietal cortex. 5-HIAA content did not change significantly in any of the brain areas studied. A 10.0 mg/kg dose of corticosterone decreased the serotonin content and turnover in the hypothalamus and mesencephalon; it was ineffective in other brain areas investigated. 5-HIAA content significantly decreased in the hypothalamus while it increased in the mesencephalon and dorsal hippocampus. In the parietal and frontal cortex, 5-HIAA content did not change following administration of 10.0 mg/kg of corticosterone. At 120 min after corticosterone administration, neither 5-HT content and turnover nor 5-HIAA content showed any change in the brain areas investigated. The results suggest that corticosteroids might change the activity of the brain serotoninergic system in a dose- and time-dependent manner, and in this way the serotoninergic system might play an important role in mediation of the corticosteroid effect exerted on brain function.