Kinetics of Drug-Induced Changes in Dopamine and Serotonin Metabolite Concentrations in the CSF of the Rat

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Every 15 min, CSF dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined by direct injection of CSF into a liquid chromatographic system coupled with electrochemical detection. Mean CSF concentrations of DOPAC, HVA, and 5-HIAA were 1.29 microM, 0.88 microM, and 2.00 microM, respectively. In order to determine the turnover rates of dopamine (DA) and serotonin, experiments using monoamine oxidase (MAO) inhibition were performed. Tranylcypromine (20 mg/kg i.p.) induced a sharp exponential decrease of CSF DOPAC, HVA, and 5-HIAA, with respective half-lives of 15.60 min, 16.91 min, and 77.23 min. Their respective turnover rates were 3.74, 2.22, and 1.18 nmol X ml-1 X h-1. m-Hydroxybenzylhydrazine (NSD-1015, 100 mg/kg i.p.) and monofluoromethyl-DOPA (100 mg/kg i.p.), two decarboxylase inhibitors, induced a slow exponential decrease of all three CSF metabolites. alpha-Methyl-p-tyrosine (250 mg/kg i.p.) also induced a slow exponential decrease of DOPAC and HVA. These decreases of CSF DOPAC and HVA induced by DA synthesis inhibitors may reflect the turnover of DA in vivo. Haloperidol (0.5 mg/kg i.p.) considerably enhanced CSF DOPAC and HVA without affecting 5-HIAA, confirming that dopaminergic receptors modulate DA neurotransmission in vivo. Haloperidol administered 1.5 h after NSD-1015 did not increase DOPAC and HVA, in contrast to reserpine (5 mg/kg i.p.) injected under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Caffeine injection raises brain tryptophan level,but does not stimulate the rate of serotonin synthesis in rat brain

Acute caffeine injection (100 mg/kg) elevates brain levels of tryptophan (TRP), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA). Experiments were performed to determine if the increases in 5HT and 5HIAA result from a stimulation of the rate of 5HT synthesis. Both the rate of 5-hydroxytryptophan (5HTP) accumulation following NSD-1015 injection, and the rate of ³H-5-hydroxyindole synthesis from ³H-tryptophan were measured $\text{in vivo}$ following caffeine administration and found to be normal. Tryptophan hydroxylase activity, as measured $\text{in vitro}$ in brain homogenates, was also unaffected by caffeine. The results suggest that the elevations in brain 5HT and 5HIAA levels produced by caffeine do $\text{not}$ reflect enhanced 5HT synthesis, despite significant elevations in brain TRP level. Some other mechanism(s) must therefore be responsible for these elevations in brain 5-hydroxyindole levels.     

5-Hydroxytryptamine : A modulator of food composition but not quantity?

After a meal of protein, in contrast to a meal of carbohydrate (CHO) at 1915 hr, rats allowed to choose from high carbohydrate and high protein diets during 2000-2100 hr prefer CHO (1). Thus the hypothesis that this regulation of macronutrient selection involves brain 5-hydroxytryptamine (5-HT) metabolism was tested. Compared to three baseline days during which rats (250- 300g ) consumed 1 g CHO, rats fed tryptophan (TRP, 5-HT precursor; 15 mg in 1 g CHO) selected meals higher in protein concentration (35.4% vs 46.6%, F (1,12) = 20.05, p less than 0.001) from 10% and 60% casein diets during 2000-2100 hr. Associated with the higher protein selection was an elevated brain 5-HT turnover in rats killed 30 minutes after consuming CHO + TRP. Pretreating rats with p-chlorophenylalanine, an inhibitor of TRP hydroxylase, blocked this effect of TRP (36.3% vs 37.0%). Fenfluramine (1 and 2 mg/kg i.p. at 1945 hr), which transiently enhances neuronal 5-HT release, increased the rat's relative preference for protein from 28.8% to 37.5% (2 mg/kg, t = 3.21, p less than 0.025) during 2000-2100 hr. These rats, also exhibited a selective preference for CHO between 3-12 hrs post injection which paralleled the known subsequent depletion of 5-HT by fenfluramine. We conclude that the relative proportion of protein and carbohydrate selected in a meal is controlled, at least in part, by prior food effects on brain 5-HT metabolism.     

The effect of tryptophan administration on ileum contractility and oxidant status in mice

Summary. L-Tryptophan (TRP) is the precursor amino acid for the synthesis of serotonin (5-HT). 5-HT is effective both on the food intake and gastrointestinal system contractility. The aim of this study was to search the effects of systemic TRP treatment on 5-HT levels of ileum and searching the effect of ileal contractility and oxidant status. Swiss-albino mice were divided into two groups: 1. Control, 2. TRP-treated (100 mg/kg/24 h, i.p., for 7 days). Body weights were recorded at the beginning and at the end of experiments. Acetylcholine-induced contractile responses in the isolated ileum were recorded on polygraph. Ileal tissue malondialdehyde and glutathione levels determined by spectrophotometric and ileal tissue 5-HT levels were measured by immunohistochemical methods. TRP treatment decreased body weight and increased ileal contractile response. In the TRP-treated group, ileum malondialdehyde levels increased and glutathione levels decreased. Immunohistochemical detection showed that ileal 5-HT levels were increased by TRP treatment. There is a relationship between increased oxidative stress and increased contractility in the ileal tissue of the TRP-treated animals. These effects may be related to increased ileal 5-HT synthesis.     

Effect of pentylenetetrazol on the carbaryl-induced changes of serotonin metabolism in rat-brain hypothalamus

Carbaryl (200 mg/kg or 400 mg/kg, p.o.) significantly elevated serotonin (5-HT) (57–109%) and 5-hydroxy-indoleacetic acid (5-HIAA) (60–78%) levels at 1.0 h in the hypothalamic region of adult male rat brain. Further, administration of carbaryl (200 mg/kg, p.o.) for different time intervals (0.5 h, 1.0 h, and 2.0 h) revealed that both 5-HT and 5-HIAA levels elevated maximally at 0.5 h in hypothalamus. These regional 5-HT and 5-HIAA levels were not significantly affected with pentylenetetrazol (PTZ) at any time after its treatment. But simultaneous administration of carbaryl (200 mg/kg, p.o.) and PTZ (60 mg/kg, s.c.) reduced the carbaryl-induced elevation of both 5-HT and 5-HIAA leveis. Measurement of (i) probenecid-induced (200 mg/kg, i.p.) accumulation and (ii) pargyline-induced (75 mg/kg, i.p.) depletion of hypothalamic 5-HIAA level in the absence or presence of carbaryl (200 mg/kg, p.o.) and/or PTZ (60 mg/kg, s.c.) revealed that (a) carbaryl enhanced the synthesis as well as the breakdown of 5-HT, (b) PTZ had no effect on either of these processes of 5-HT, and (c) carbaryl-induced increased catabolism of 5-HT became normal in the presence of PTZ.     

The effect of 5,6-dihydroxytryptamine on post-decapitation convulsions

Previous data (1) have shown that L-DOPA increases the duration of the clonic phase of post-decapitation convulsions (PDC) in mice. It was suggested that this effect is produced by depleting 5-hydroxytryptamine (5-HT) in the inhibitory bulbospinal pathways and thus enhancing reflex activity in the spinal cord. If this were true then L-DOPA administration should not influence clonic PDC in animals whose 5-HT pathways were destroyed. We therefore tested the effects of L-DOPA on mice 3 weeks after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5, 6-DHT) (50 μg/kg, intracerebroventricularly). All mice were given the peripheral decarboxylase inhibitor, Ro 4-4602. 5,6-DHT halved the brain 5-HT levels and significantly increased the duration of clonic PDC. The administration of L-DOPA (320 mg/kg i.p.) to 5,6 DHT treated mice did not produce any further significant increases in duration. The administration of 5-hydroxytryptophan (5-HTP) (100 mg/kg, i.v.) to 5,6-DHT treated mice, however, increased 5-HT to above control levels and reduced convulsions to control levels. Administration of both 5-HTP and L-DOPA to 5,6-DHT treated mice resulted in 5-HT levels and convulsion times which were also not significantly different from the controls. These data give additional indication that intact 5-HT nerve terminals are necessary for L-DOPA to prolong the duration of clonic PDC.     

Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice

Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are gaining growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurones. Our recent microdialysis experiment performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT neuronal function (Froger et al. 2001). The aim of the present study was to evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal raphe nucleus using in vivo microdialysis in awake, freely moving mice. The systemic or intraraphe administration of a NK1 receptor antagonist did not change basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a statistically significant increase in [5-HT]ext with a larger extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4 mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on cortical [5-HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice. When GR205171 (300 micro mol/L) was perfused by 'reverse microdialysis' into the dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5-HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a local perfusion of 1 micro mol/L of citalopram into the frontal cortex, a single dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171 (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1 receptor antagonists, when combined with a SSRI, augment 5-HT release by modulating substance P/5-HT interactions in the dorsal raphe nucleus.     

Maternal Lead Exposure Produces Long-Term Enhancement of Dopaminergic Reactivity in Rat Offspring

To determine the effect of prenatal lead exposure on brain monoaminergic systems, pregnant rats were given tap water containing 250 ppm lead acetate, for the duration of pregnancy, while tap water without lead (Pb²⁺) was substituted at birth. Control rats were derived from dams that consumed tap water during pregnancy, and had no exposure to lead afterwards. At 12 weeks after birth, Pb²⁺ content of brain cortex was increased 3- to 4-fold (P < 0.05). At this time the endogenous striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were 19% lower in Pb²⁺ exposed rats (P < 0.05), while there was no change in the striatal level of dopamine (DA), noradrenaline, 3,4-dihydroxyphenylglycol, serotonin (5-HT) and 5-hydroxyindoleacetic acid (HPLC/ED). Also there was no change in these monoamines and metabolites in the prefrontal cortex of Pb²⁺ exposed rats. However, turnover of 5-HT in prefrontal cortex, as indicated by 5-hydroxytryptophan accumulation 30 min after acute treatment with the decarboxylase inhibitor NSD-1015 (100 mg/kg IP), was lower in the Pb²⁺ exposed rats. In the striatum AMPH-induced (1 mg/kg IP) turnover of DA, evidenced as L-DOPA accumulation after NSD-1015, was increased to a lesser extent in the Pb²⁺ exposed rats (P < 0.05). The nitric oxide synthase inhibitor 7-nitroindazole (10 mg/kg IP) attenuated the latter effect, indicating that neuronal NO mediates this AMPH effect, at least in part. Moreover, DA D₂ receptor sensitivity developed in Pb²⁺ exposed rats, as evidenced by enhanced quinpirole-induced yawning activity and enhanced quinpirole-induced locomotor activity (each, P < 0.05). These findings indicate that ontogenetic exposure to lead can have consequences on monoaminergic neuronal function at an adult stage of life, generally promoting accentuated behavioral effects of direct and indirect monoaminergic agonists, and related to increased dopamine turnover in basal ganglia. Special issue dedicated to Dr. Moussa Youdim.     

Serotonergic activity of HP 184: Does spontaneous release have a role?

Examination of HP 184, [N-n-propyl)-N-(3-fluoro-4-pyridinyl)-1H-3-methylindodel-1-amine hydrochloride], in a variety of tests for serotonergic activity revealed some unique properties of this compound. We report here that 100 μM HP 184 enhanced spontaneous release of [³H]serotonin (5-HT) from rat hippocampal slices. This release was independent of the uptake carrier. In vivo assays confirmed that HP 184 (20 mg/kg, i.p.) lacked significant interactions at the norepinephrine (NE) or 5-HT uptake carrier itself. Notably, HP 184 (15 mg/kg, i.p.) reduced drinking behavior in schedule-induced polydipsic (SIP) rats. We previously reported that some selective 5-HT reuptake inhibitors decrease SIP 30–40% after a 14–21 day treatment. In the current study, HP 184 decreased SIP beginning with the first treatment, and this reduction (30%) was maintained for 28 days. We further investigated HP 184 and serotonin metabolite levels. One hour after i.p. administration of 30 mg/kg HP 184, the ratio of whole brain 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was increased, suggesting serotonergic activation. Under these conditions, the brain: plasma ratio of HP 184 was approximately 2∶1, with brain concentrations of 1.6 μg/gram. We speculate that the spontaneous release effects of HP 184 may be responsible for the behavioral effects observed.     

The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors. The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown. Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals. In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In Tg8 mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.     

Suppressive effect of nantenine,isolated from Nandina domestica Thunberg,on the 5-hydroxy-L-tryptophan plus clorgyline-induced head-twitch response in mice

We investigated the effects of nantenine (9,10-Methylenedioxy-1,2 dimethoxyaporphine), a major alkaloid isolated from the fruit of Nandina domestica Thunb (Berberidaceae), on the 5-HT2A receptor-mediated head-twitch response (HTR) in mice. Intraperitoneal (i.p.) injection of nantenine (13.3, 20 and 30 mg/kg) as well as the 5-HT2A receptor antagonist ketanserin (0.0625, 0.25 and 1 mg/kg) inhibited the 5-hydroxy-L-tryptophan (l-5-HTP; 75 mg/kg, i.p.) plus monoamine oxidase inhibitor, clorgyline (1 mg/kg, i.p.)-induced HTR in a dose-dependent manner. In contrast, neither l-5-HTP plus clorgyline nor 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 5 microg/mouse, i.c.v.)-induced head weaving was affected by nantenine or ketanserin. Furthermore, neither nantenine (up to 30 mg/kg) nor ketanserin (up to 1 mg/kg) affect on the locomotor activity. In the receptor binding studies, nantenine showed affinity to the 5-HT2A receptors (Ki = 0.4 microM), while it had less affinity toward alpha1-adrenergic (Ki = 2.1 microM) and D2-dopaminergic (Ki = 1.7 microM) receptors of the mouse brain. These results suggest that nantenine inhibits l-5-HTP plus clorgyline-induced head- twitch response by blocking 5-HT2A receptors in the central nervous system.     

DEPENDENCE OF BRAIN TRYPTAMINE FORMATION ON TRYPTOPHAN AVAILABILITY

Abstract— The dependence of rat brain tryptamine (TA) formation on tryptophan availability was investigated. Rat brain TA was found to accumulate linearly with respect to time over 90min following pargyline (75 mg/kg. i.p.). The in vivo rate of brain TA appearance was estimated to be 0.1 nmol/g/h. After tryptophan loading the accumulation of brain TA and 5-HT in pargyline-pretreated rats was linearly related to both brain and plasma tryptophan concentrations. Low doses of tryptophan (5–10 mg/kg. i.p.) produced statistically significant increments in brain TA formation. The findings of this study indicate that the in vivo formation of TA in rat brain is directly dependent upon brain and plasma tryptophan concentrations.     

Turnover of Dopamine and Serotonin and Their Metabolites in the Striatum of Aged Rats

Turnover of dopamine (DA), serotonin [5-hydroxytryptamine (5-HT)], and their metabolites has been measured in adult and aged rats. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxy-3-indoleacetic acid (5-HIAA) have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase (MAO) and from the accumulation rates by probenecid inhibition of the probenecid-sensitive transport system. DA and 5-HT turnover rates have been measured as accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015) and as accumulation rates of DA and 5-HT after pargyline inhibition of MAO. The DA turnover rate after NSD-1015 was 23.9% lower in aged rats than in adults, whereas after pargyline there was no significant difference between the two age groups. The HVA fractional rate constant and turnover after pargyline were lower in aged rats than in adults, and HVA turnover after probenecid was higher in aged rats than in adults. The DOPAC-HVA pathway seems to be reinforced at the expense of DOPAC conjugation. In aged and adult rats whose 5-HT steady-state levels were not statistically different, the 5-HT turnover rate after pargyline and NSD-1015 treatment was lower in aged rats than in adults. An increase of 5-HIAA levels after pargyline and probenecid treatment in aged rats could be due to the handling stress.     

Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study

Plant flavonoids are emerging as potent therapeutic drugs effective against a wide range of free radical-mediated diseases. Morin (3,5,7,2′,4′-pentahydroxyflavone), a member of flavonols, is an important bioactive compound by interacting with nucleic acids, enzymes and protein. In this study, we found that morin (30 mg/kg body weight) by oral administration offers protection against hyperammonemia by means of reducing blood ammonia, oxidative stress and enhancing antioxidant status in ammonium chloride-induced (100 mg/kg body weight; i.p) hyperammonemic rats. Enhanced blood ammonia, plasma urea, lipid peroxidation in circulation and tissues (liver and brain) of ammonium chloride-treated rats was accompanied by a significant decrease in the tissues levels of superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione peroxidase (GPx). Morin administered rats showed a significant reduction in ammonia, urea, lipid peroxidation with a simultaneous elevation in antioxidant levels. Cotreatment with morin prevented the elevation of liver marker enzymes induced by ammonium chloride. The body weight of the animals decreased significantly on ammonium chloride administration when compared with control group. However, cotreatment with morin significantly prevented the decrease of the body weight caused by ammonium chloride. Hyperammonemic rats show liver fibrosis, steatosis, sinusoidal dilatation, etc., along with necrosis, microcystic degeneration in brain. All these changes were reduced in hyperammonemic rats treated with Morin, which too correlated with the biochemical observations. In conclusion, these findings indicate that morin exert antioxidant potential and offer protection against ammonium chloride-induced hyperammonemia. But the exact underlying mechanism needs to be elucidated.     

Long-Term Effects of Portacaval Anastomosis on the 5-Hydroxytryptamine, Histamine, and Catecholamine Neurotransmitter Systems in Rat Brain

Abstract: Portacaval anastomosis (PCA) in the rat is used as a model for portal systemic encephalopathy. Changes in the serotonergic, histaminergic, and catecholaminergic neurotransmitter systems are often found shortly after PCA. We have examined the long-term effects of PCA on the aminergic systems in brains of male Wistar rats, which 8 months previously had been subjected to PCA. Precursors, amines, and metabolites were assayed by HPLC. Eight months after PCA, the catecholamine levels were unchanged in all brain regions. In contrast, tryptophan was evenly increased throughout the brain. The accumulation of 5-hydroxytryptophan after decarboxylase inhibition (NSD-1015; 100 mg/kg i.p.) and the endogenous levels of 5-hydroxyindoleacetic acid were significantly higher in PCA rats, particularly in the hypothalamus and midbrain, whereas 5-hydroxytryptamine concentrations were unchanged. Histamine levels were elevated throughout the brain with the greatest increase found in the hypothalamus and in the striatum. tele -Methylhistamine levels were significantly elevated in cortex and hypothalamus. We conclude that 8 months after PCA, catecholaminergic systems had reestablished their homeostasis, whereas serotonergic and histaminergic systems still show profound disturbances in their function. With histamine, this is reflected as an increase in the amounts of both transmitter and metabolite; serotonergic neurons respond by increasing only the level of the metabolite.     

Effects of Long-Term Low Dietary Tryptophan Intake on Determinants of 5-Hydroxytryptamine Metabolisn in the Brains of Young Rats

Abstract: The relationship between plasma and brain tryptophan (TRP) concentrations and brain 5-hydroxytryptamine (5-HT) metabolism was studied in weanling rats fed diets containing either 0.4 g or 1.45 g TRP/ 100 g casein hydrolysate. Both groups gained weight comparably though food intakes were generally higher in the low-TRP group. Severe depletion of plasma total and free TRP and of brain TRP, 5-HT, and 5-hydrox-yindoleacetic acid (5-HIAA) occurred within 1 day of feeding the 0.4% TRP diet. Levels became stable after 7 days. The decreased brain TRP concentration of the rats on the 0.4% TRP diet did not cause a compensatory rise of the tryptophan hydroxylase (TRP OHase) activity in vitro. In the low-TRP group, neither plasma free TRP nor total TRP correlated significantly with brain TRP and although plasma TRP/large neutral amino acid (NAA) ratios (TRP/NAA) correlated significantly ( P < 0.05) with the time course of brain TRP, this statistical relationship depended almost completely on the variation of the TRP values alone. In the higher TRP group none of these correlations were significant. A plot of mean plasma free TRP versus brain TRP gave two distinct regression lines with similar slopes and corresponding to values before and after 7 days on the diet. The time course of brain 5-hydroxyindole concentrations did not parallel those of brain TRP and suggested that changes of TRP OHase activity also had an influence on 5-HT synthesis.     

Dose-dependent action of corticosteroids on brain serotonin content and passive avoidance behavior.

Corticosterone, 1.0 and 5.0 mg/kg, improved passive avoidance behavior based on fear versus thirst-conflict situation. Corticosterone, 1.0 mg/kg, increased the serotonin (5-HT) content in the hypothalamus and mesencephalon; 5.0 mg/kg of corticosterone had no effect. Plasma corticosterone level increased in a dosedependent manner after corticosterone treatment. dl-Parachlorophenylalanine (PCPA) impaired passive avoidance behavior and decreased the hypothalamic and mesencephalic 5-HT level. After PCPA treatment, the plasma corticosterone level was slightly increased. PCPA pretreatment was able to prevent the action of 1.0 and 5.0 mg/kg of corticosterone on behavior as well as on brain 5-HT level. Corticosterone, 10.0 mg/kg, impaired passive avoidance behavior, decreased the hypothalamic and mesencephalic 5-HT content, and increased the plasma corticosterone level.Monoamine oxidase inhibitor (nialamide) treatment improved the passive avoidance behavior and increased the 5-HT level in the hypothalamus and mesencephalon. The plasma corticosterone level did not change significantly. Nialamide pretreatment abolished the behavioral action of 10.0 mg/kg of corticosterone as well as its action on brain 5-HT level. A large dose of corticosterone (25.0 mg/kg) and 2.5 mg/kg of 6-dehydro-16-methylenhydrocortisone (6DH) had a similar action on passive avoidance behavior and on brain serotonin level as 10.0 mg/kg of corticosterone; however, the plasma corticosterone level was increased only in corticosterone-treated animals and was significantly decreased after 6DH. 11-Deoxycorticosterone (DOC) at a dose of 25.0 mg/kg was ineffective on passive avoidance behavior and on brain serotonin content, whereas it slightly decreased the plasma corticosterone level. Data suggest that the corticosterone has dosedependent dual action on passive avoidance behavior, and its action is, at least partly, mediated via changed brain serotonin metabolism. The action seems to be a glucocorticoid-specific one since mineralocorticoid (DOC) is ineffective on this behavioral pattern.     

Acute effects of caffeine injection on neutral amino acids and brain monoamine levels in rats

The injection of caffeine (100 mg/kg, i.p.) into male rats acutely increased brain levels of trytophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). Blood levels of glucose, nonesterified fatty acids (NEFA) and insulin also increased, while those of the aromatic and branched-chain amino acids fell. Serum tryptophan levels either did not fall, or increased. Consequently, the serum ratio of trypthopahn to the sum of other large neutral amino acids (LNAA) increased. Less consistently noted were increases in serum free tryptophan levels. Brain tyrosine levels were not appreciably altered by caffeine, nor was the serum tyrosine ratio. In dose-response studies, 25 mg/kg of caffeine was the minimal effective dose needed to raise brain tryptophan, but only the 100 mg/kg dose elevated all three indoles in brain. In no experiments did caffeine, at any time or dose, alter brain levels of dopamine or norepinephrine. Caffeine thus probably raises brain tryptophan levels by causing insulin secretion, and thereby changing plasma amino acid levels to favor increased tryptophan uptake into brain. The rises in brain 5-HT and 5-HIAA may follow from the increase in brain tryptophan, although further data are required clearly to establish such a mechanism.     

Effects of drugs on brain neurotransmitter and pituitary-testicular function in male rats.

The effects of different drugs influencing brain neurotransmitter contents have been tested on the pituitary-testicular function in male rats. L-dopa (200 mg/kg body weight, i.p.) increased the dopamine and noradrenaline contents of the hypothalamus, amygdala, striatum and mesencephalon, but it was ineffective as regards the 5-hydroxytryptamine contents of the same brain areas, and increased the plasma testosterone level. alpha-Methyl-p-tyrosine (250 mg/kg b.w., i.p.) decreased the dopamine and noradrenaline contents of these brain areas, but it was ineffective to 5-hydroxytryptamine, and decreased the plasma testosterone level. Diethyldithiocarbamate (400 mg/kg b.w., i.p. twice a day) increased the dopamine levels in the hypothalamus, amygdala, striatum and mesencephalon, decreased the noradrenaline contents in the same brain regions but had no effect on the 5-hydroxytryptamine contents of these brain areas or on the testosterone level in the peripheral blood. p-Chlorophenylalanine (300 mg/kg b.w., i.p.) decreased the 5-hydroxytryptamine contents of the different brain areas, while it had no effect on the dopamine and noradrenaline levels or on the plasma testosterone level. 5-Hydroxytryptophan (200 mg/kg b.w., i.p.) increased the 5-hydroxytryptamine contents of all brain areas studied, but was without effect on the dopamine and noradrenaline contents or the plasma testosterone level. The data suggest that both dopamine and noradrenaline may be involved in the regulation of the pituitary-testicular function, and the ratio of the two transmitters might be more important that their actual levels in definite brain areas.