Effect of intrastriatal injection of soman on acetylcholine, dopamine and serotonin metabolism

Intrastriatal injection of soman (14.85 nmol) inhibits cholinesterase (ChE) activity in the striatum with much smaller decreases in ChE activity in other brain areas of the rat. As would be expected, there is a substantial increase in striatal acetylcholine (ACh) content shortly after soman injection. However, this increase is no longer significant 1 h following intrastriatal injection. There is no change in striatal KACh 20 min, 1 h or 24 h following soman injection. ACh content is not affected in the parietal cortex, hippocampus, or medulla/pons following intrastriatal soman injection. However, KACh and/or ACh turnover are reduced in these brain areas following soman injection. There is no consistent effect on dopamine (DA) metabolism in any of the brain areas studied. However, serotonin (5-HT) metabolism appears to be affected in the cortex, hippocampus and medulla/pons following intrastriatal injection of soman. Possible mechanisms of the actions of local injection of soman on brain Ach and 5-HT metabolism are discussed, as well as the differences observed between the effects of local and peripheral administration of soman on DA metabolism in the striatum.     

Effects of Repeated Low-Dose Exposure of the Nerve Agent VX on Monoamine Levels in Different Brain Structures in Mice

In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD₅₀ of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30 % inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.     

Peripheral ChE Inhibition Modulates Brain Monoamines Levels and <Emphasis Type="Italic">c-fos</Emphasis> Oncogene in Mice Subjected to a Stress Situation

The present study examined, in mice, whether regional patterns of brain monoamines concentrations (DA, 5-HT and their metabolites) and expression of c-Fos protein, that may represent a prolonged functional change in neurons, could be changed after a combined exposure to stress and the peripheral cholinesterase reversible inhibitor pyridostigmine (PYR). Animals were subjected every day to a random combination of mild unescapable electric footshocks and immobilization over a 12-day period, resulting in a significant increase of glucocorticoids levels and an activation of c-fos in hippocampus, thalamus and piriform cortex. This stress protocol induced a significant increase of 5-HT levels in striatum, hippocampus and ponto mesencephalic area (PMA) but failed to induce any DA activation. When PYR (0.2 mg/kg s.c. inducing 19–35% inhibition of the plasmatic ChE activity) was administered twice a day during the last 5 days of the stress session, 5-HIAA levels and expression of c-fos oncogene were significantly increased in the most of the brain areas studied. DA levels were also enhanced in striatum/hippocampus as a result of a possible activation of mesolimbic and nigrostriatal dopamine systems. Taken together, these results suggest that a combined exposure to certain stress conditions and PYR leads, in mice, to functional changes in neurons and may affect centrally controlled functions. The mechanisms underlying these modifications and their behavioral implications remain to be further investigated.     

Effect of Soman and Sarin on Phosphatidylcholine Asymmetry in the Electroplax from the Electric Eel

Some effects of organophosphorus anticholinesterase compounds that are unrelated to cholinesterase inhibition and that are sometimes long lasting may be due to alterations at the cellular membrane level. Phosphatidylcholine exchange protein was used to assess the effects of sarin and soman on phosphatidylcholine asymmetry in the inner and outer leaflets of the plasma membrane bilayer of the electroplax. Exposure of electroplax (30 min in vitro) to soman (10(-4), 10(-6) M) or sarin (10(-4), 10(-6), 5 x 10(-9) M) increased the percentage of phosphatidylcholine in the outer monolayer of the innervated plasma membrane bilayer and decreased the percentage in the inner monolayer. These changes by sarin were observed at concentrations that produced 100% cholinesterase inhibition (10(-4), 10(-6) M) and at a concentration (5 x 10(-9) M) where no inhibition occurred, suggesting that these effects are not directly due to cholinesterase inhibition. A 1-week exposure of live eels to soman (10(-8) M) in vivo caused an increase in phosphatidylcholine labeling in the outer monolayer of the innervated and noninnervated surfaces of the electroplax. Two weeks after stopping exposure to soman, increased labeling was still observed, suggesting that this may be a long-term effect. Because the organophosphates did not increase the permeability of the electroplax, all of these changes in labeling appear to be due to a redistribution of phosphatidylcholine from the inner to the outer monolayer of the plasma membrane bilayer.     

Change in serotonin metabolism in the rat brain in response to the repeated stimulus presentation

The content of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase (MAO) activity and kinetic parameters (K(m) and Vmax) for the reaction of 5-HT deamination, were examined in various regions of the rat brain after repeated presentation of a contextual stimulus. Habituation to the stimulus was accompanied by an increase of 5-HT metabolism and active transport of 5-HIAA in the amygdala, striatum and midbrain, while these changes were not found in the prefrontal cortex and hippocampus. Kinetic studies have revealed that the enhancement of 5-HT deamination by MAO in the brain structures was mediated by different catalytic mechanisms. A significant decrease in K(m) value for 5-HT deamination in the amygdala indicated an increase in the affinity of enzyme towards 5-HT. In the striatum the enhanced MAO activity was provided by increasing maximal rate of 5-HT deamination. It is concluded that an activation of presynaptic mechanisms of the serotonergic transmission in the amygdala and striatum is involved in the inhibition of biological significance and attention to repeated presentation of stimulus.     

RELATIONSHIP BETWEEN CHOLINE AVAILABILITY AND ACETYLCHOLINE SYNTHESIS IN DISCRETE REGIONS OF RAT BRAIN

Abstract— The relationship between choline availability and the synthesis of acetylcholine in discrete brain regions was studied in animals treated with the organophosphorus cholinesterase inhibitor paraoxon. Administration of paraoxon (0.23 mg/kg) inhibited acetylcholinesterase activity by approx 90% in the striatum, hippocampus and cerebral cortex and increased acetylcholine levels to 149%, 124% and 152% of control values, respectively. Free choline levels were unaltered by paraoxon in the hippocampus and cerebral cortex, but were significantly decreased in the striatum to 74% of control. When animals were injected with choline chloride (60 mg/kg), 60 min prior to the administration of paraoxon, the paraoxon-induced choline depletion in the striatum was prevented and the paraoxon-induced acetylcholine increase was potentiated from 149% to 177% of control values. Choline pretreatment had no significant effect in either the hippocampus or cerebral cortex, brain regions that did not exhibit a decrease in free choline levels after paraoxon administration. Results indicate that choline administration, which had no significant effect on acetylcholine levels by itself, increased acetylcholine synthesis in the striatum in the presence of acetylcholinesterase inhibition. However, this effect was not apparent in either the hippocampus or the cerebral cortex at similar levels of enzyme inhibition. It appears that choline generated from the hydrolysis of acetylcholine may play a significant role in the regulation of neurotransmitter synthesis in the striatum, but not in the other brain areas studied. The evidence supports the concept that the regulatory mechanisms controlling the synthesis of acetylcholine in striatal interneurons may differ from those in other brain regions.     

Regionally specific effects of diazepam on brain serotonin metabolism in rats: Sustained effects following repeated administration

The effects of single (1mg/kg) and repeated (1mg/kg 2¹ daily for 4 days) diazepam administration are investigated on brain regional 5-hydroxytryptamine (5-HT; serotonin) and 5-hydroxy indoleacetic acid (5-HIAA) concentration in rats. Daily treatment decreased food intakes but body weights did not decrease. Administration of diazepam (1mg/kg) to 4 day sahne injected rats on the 5th day decreased 5-HT levels in the hippocampus and increased it in the hypothalamus. 5-HIAA levels were increased in the striatum and decreased in the hypothalamus. 4 day diazepam injected rats injected with sahne on the 5th day also exhibited silmilar changes of 5-HT and 5-HIAA. Cortical levels of 5-HIAA were also smaller in these rats. Administration of diazepam to 4 day diazepam injected rats again decreased 5-HT in the hippocampus and 5-HIAA in the hypothalamus. 5-HT and 5-HIAA were both decreased in the striatum. Regionally specific effects of diazepam on brain serotonin metabolism are discussed in relation to their possible functions.     

n-3 polyunsaturated fatty acid supplementation reverses stress-induced modifications on brain monoamine levels in mice

The aim of this study was to examine the effects of supplementation with n-3 polyunsaturated fatty acids (PUFAs) on stress responses in mice subjected to an unpredictable chronic mild stress (UCMS) procedure. Stress-induced modifications in coat and aggressiveness were evaluated, and phospholipid PUFA profiles and monoamine levels were analyzed in the frontal cortex, hippocampus, and striatum. The results showed that repeated exposure to mild stressors induced degradation in the physical state of the coat, lowered body weight gain, and increased aggressiveness, without any effect of n-3 PUFA supplementation. The UCMS induced a significant decrease in the levels of norepinephrine in the frontal cortex and striatum, and a nonsignificant decrease in the hippocampus. The tissue levels of serotonin (5-HT) were 40% to 65% decreased in the three brain regions studied. Interestingly, the n-3 PUFA supplementation reversed this stress-induced reduction in 5-HT levels. These findings showed that supplementation in n-3 long-chain PUFAs might reverse certain effects of UCMS in cerebral structures involved in stress-related behaviors.     

Neuropathy target esterase in hens after sarin and soman

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.     

Distinctions in metabolism of serotonin and dopamine in rat brain during latent inhibition

Latent inhibition (LI) is a behavioral phenomenon, in which repeated presenting of a non-reinforced stimulus retards conditioning to this stimulus when it is coupled with a reinforcer. In order to find specific serotonin (5-HT- and dopamine (DA) changes mediating the LI, the 5-HT and DA metabolism was investigated in certain brain regions. Oxidative deamination of 5-HT and DA by monoamine oxidase (MAO) was determined in the prefrontal cortex, striatim, amygdala, and hippocampus at preexposure and testing stages of the LI using the passive avoidance procedure in rats. Preexposed animals demonstrated high MAO activity for 5-HT deamination in the amygdala and striatum and lower MAO activity for DA deamination in the amygdala and hippocampus. After testing the LI, a high level of 5-HT deamination by MAO was revealed in the amygdala, white the lower level of 5-HT deamination by MAO was shown in the prefrontal cortex. At the same time, no changes in DA metabolism were found in all the brain regions studied. Thus, the role of dopaminergic system in the LI effect may be limited by the preexposure stage. The obtained evidence suggests that the enhanced 5-HT activity in the amygdala and striatum induced by the preexposed stimulus is a principal biochemical mechanism underlying the LI.     

Involvement of striatal serotonin in fluoxetine effects on adrenocortical function and behaviour

Treatment of the adult rats with selective serotonin (5-HT) reuptake inhibitor: fluoxetine and its complexes with glycyrrizhinic acid during 2 weeks (25 mg/kg/day) significantly increased plasma corticosterone levels that were measured after 5-min plus-maze. All the drugs decreased the content of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum as well as 5-HT in the hippocampus. There was a significant negative correlation between 5-HT in the striatum and corticosterone levels. These data suggest that fluoxetine induces serotoninergic changes in the striatum that might be related to neuroendocrine and behavioural effects of the drug.     

Effect of acute and chronic cholinesterase inhibition on biogenic amines in rat brain

The effects of five cholinesterase inhibitors on forebrain monoamine and their metabolite levels, and on forebrain and plasma cholinesterase (ChE) activity in rat were studied in acute and chronic conditions. Acute tetrahydroaminoacridine (THA) dosing caused lower brain (68%) and higher plasma (90%) ChE inhibition than the other drugs studied increased levels of brain dihydroxyphenylacetic acid (DOPAC) (236%), homovanillic acid (HVA) (197%) and 5-hydroxyindolaecetic acid (5-HIAA) (130%). Acute physostigmine (PHY) administration caused a 215% increase in brain DOPAC content. Despite high brain ChE inhibition induced by metrifonate (MTF), dichlorvos (DDVP) or naled no changes in brain noradrenaline (NA), dopamine (DA) or serotonin (5-HT) occurred due to treatment with the study drugs in the acute study. In the chronic 10-day study THA or PHY caused no substantial ChE inhibition in brain when measured 18 hours after the last dose, whereas MTF induced 74% ChE inhibition. Long-term treatment with THA or MTF caused no changes in monoamine levels, but PHY treatment resulted in slightly increased 5-HT values. These results suggest that MTF, DDVP and naled seem to act solely by cholinergic mechanisms. However, the central neuropharmacological mechanism of action of THA and PHY may involve changes in cholinergic as well as dopaminergic and serotoninergic systems.     

Modification by physostigmine of the cardiovascular responses to intracerebroventricular administration of 5-hydroxytryptamine in rats

In rats the effect of inhibition of the brain cholinesterase activity on the pressor and heart rate responses to 5-hydroxytryptamine (5-HT), administered into the lateral cerebral ventricle (l.c.v.) was examined. After administration of physostigmine (twice in a small dose of 2.5 micrograms l.c.v., 20 and 15 min before the second injection of 5-HT), the pressor effect of 5-HT (5 micrograms) was strongly reduced or almost abolished, its pure tachycardia was reduced or reversed into a bradycardia and its pure bradycardia was diminished or reversed into a tachycardia. The type of the cardiovascular response to ACh (5 micrograms l.c.v., 20 min after the second administration of 5-HT) indicates that the modification of the cardiovascular response to 5-HT was accompanied by inhibition of the brain cholinesterase activity. Thus, it seems that a functionally competent cholinesterase in the brain is necessary for the generation of the 5-HT-induced pressor response. The present experiments provide further evidence that there is a cholinergic link in the pathway by which serotonergic mechanisms in the preoptic-anterior hypothalamic area rise blood pressure and support the idea that the same link exists in the pathway(s) mediating the heart rate responses to intracerebroventricular administration of 5-HT.     

Neurotransmitter Changes in Guinea-Pig Brain Regions Following Soman Intoxication

The effects of the organophosphate acetylcholinesterase (AChE) inhibitor soman (31.2 micrograms/kg s.c.) on guinea-pig brain AChE, transmitter, and metabolite levels were investigated. Concentrations of acetylcholine (ACh) and choline (Ch), noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites, and six putative amino acid transmitters were determined concurrently in six brain regions. The brain AChE activity was maximally inhibited by 90%. The ACh content was elevated in most brain areas by 15 min, remaining at this level throughout the study. This increase reached statistical significance in the cortex, hippocampus, and striatum. The Ch level was significantly elevated in most areas by 60-120 min. In all regions, levels of NA were reduced, and levels of DA were maintained, but those of its metabolites increased. 5-HT levels were unchanged, but those of its metabolites showed a small increase. Changes in levels of amino acids were restricted to those areas where ACh levels were significantly raised: Aspartate levels fell, whereas gamma-aminobutyric acid levels rose. These findings are consistent with an initial increase in ACh content, resulting in secondary changes in DA and 5-HT turnover and release of NA and excitatory and inhibitory amino acid transmitters. This study can be used as a basis to investigate the effect of toxic agents and their treatments on the different transmitter systems.     

Differences in the in vivo dynamics of neurotransmitter release and serotonin uptake after acute para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine revealed by chronoamperometry

Illicit use of p-methoxyamphetamine (PMA) is rapidly increasing. However, little is known about the acute effects of PMA on neurotransmission in vivo. High-speed chronoamperometry was used to monitor neurotransmitter release and clearance in anesthetized rats after local application of PMA or 3,4-methylenedioxymethamphetamine (MDMA). In striatum, PMA caused less neurotransmitter release than MDMA. PMA-evoked release could be partially blocked by pre-treatment with a serotonin (5-HT) reuptake inhibitor, suggesting that evoked 5-HT release contributed to the electrochemical signal and was mediated by the 5-HT transporter (SERT). MDMA-evoked release was not blocked by a SERT inhibitor, suggesting that primarily DA was released. To study the effect of these amphetamines on clearance of 5-HT mediated specifically by the SERT, clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus. In contrast to the striatum where 5-HT is cleared by both the SERT and the dopamine transporter (DAT), 5-HT is cleared primarily by the SERT in the CA3 region. This is also a region where neither PMA nor MDMA evoked release of neurotransmitter. The maximal inhibition of 5-HT clearance was greater after PMA than MDMA. These data demonstrate in vivo (1) brain region variability in the ability of PMA and MDMA to evoke release of neurotransmitter; (2) that clearance of 5-HT in the striatum is mediated by both the SERT and the DAT; (3) distinct differences in the amount and nature of neurotransmitter released in the striatum after local application of PMA and MDMA and (4) that PMA is a more efficacious inhibitor of 5-HT clearance in the hippocampus than MDMA. These fundamental differences may account for the more severe adverse reactions seen clinically after PMA, compared to MDMA.     

Neurochemical consequence of steroid abuse: stanozolol-induced monoaminergic changes

An extensive literature has documented adverse effects on mental health in anabolic androgenic steroids (AAS) abusers. Depression seems a common adverse reaction in AAS abusers. Recently it has been reported that in a rat model of AAS abuse stanozolol induces behavioural and biochemical changes related to the pathophysiology of major depressive disorder. In the present study, we used the model of AAS abuse to examine possible changes in the monoaminergic system, a neurobiological substrate of depression, in different brain areas of stanozolol-treated animals. Wistar rats received repeated injections of stanozolol (5mg/kg, s.c.), or vehicle (propylene glycol, 1ml/kg) once daily for 4weeks. Twenty-four hours after last injection, changes of dopamine (DA) and relative metabolite levels, homovanilic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC), serotonin (5-HT) and its metabolite levels, 5-hydroxy indolacetic acid (5-HIAA), and noradrenaline (NA) amount were investigated in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (STR) and hippocampus (HIPP). The analysis of data showed that after chronic stanozolol, DA levels were increased in the HIPP and decreased in the PFC. No significant changes were observed in the STR or in the NAC. 5-HT and 5-HIAA levels were decreased in all brain areas investigated after stanozolol exposure; however, the 5-HIAA/5-HT ratio was not altered. Taken together, our data indicate that chronic use of stanozolol significantly affects brain monoamines leading to neurochemical modifications possibly involved in depression and stress-related states.     

Choline Transport and Metabolism in Soman-or Sarin-Intoxicated Brain

The metabolism and blood-brain transport of choline (Ch) were investigated in perfused canine brain under control conditions and for 60 min after inhibition of brain cholinesterases by the organophosphorus (OP) compounds soman (pinacolylmethylphosphonofluoridate). Ch and acetylcholine (ACh) in blood and brain samples were analyzed using gas chromatography-mass spectrometry methods. Net transport of Ch was determined by Ch analysis in arterial and venous samples. Unidirectional transport of [3H]Ch was determined using the indicator dilution method. During control perfusion periods of 90 min, net efflux of brain Ch occurred at a rate of 1.6 +/- 0.4 nmol/g/min, and the Ch content of the recirculated perfusate increased 10-fold to approximately 8 microM. Brain Ch content increased in proportion to the increase in perfusate Ch level, but brain ACh was unaltered. Rapid administration of soman (100 micrograms) or sarin (400 micrograms) into the arterial perfusate after a 40-min control period resulted in a greater than 10-fold increase in ACh content in cerebral cortex, brainstem, and hippocampus. The ACh content of cerebellum increased only slightly. The Ch level in all four brain regions studied also increased two- to fourfold above control levels. Ch efflux from brain, however, decreased to 0.2 +/- 0.1 nmol/g/min during the 60 min after OP exposure. Unidirectional influx of [3H]Ch was 0.49 +/- 0.07 nmol/g/min before and did not change significantly 10 or 40 min after OP exposure, thus indicating that the Ch transporter of the brain endothelial cell is not directly inhibited.2+ Based on these results, it is proposed that (a) efflux of brain Ch occurs from the extracellular compartment, which becomes depleted when ACh breakdown is inhibited;(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional cholinesterase activity in white-throated sparrow brain is differentially affected by acephate (orthene®)

Effects of a 14-day dietary exposure to an organophosphorus pesticide, acephate (acetylphosphoramidothioic acid O,S-dimethyl ester), were determined on cholinesterase activity in three regions (basal ganglia, hippocampus, and hypothalamus) of the white-throated sparrow, Zonotrichia albicollis, brain. All three regions experienced depressed cholinesterase activity between 0.5–2 ppm acephate. The regions exhibited cholinesterase recovery at 2–16 ppm acephate; however, cholinesterase activity dropped and showed no recovery at higher dietary levels (>16 ppm acephate). Evidence indicates that the recovery is initiated by the magnitude of depression, not the duration. In general, as acephate concentration increased, differences in ChE activity among brain regions decreased. Three terms are introduced to describe ChE response to acephate exposure: 1) ChE resistance threshold, 2) ChE compensation threshold, and 3) ChE depression threshold. It is hypothesized that adverse effects to birds in the field may occur at pesticide exposure levels customarily considered negligible.     

合欢花对慢性应激大鼠生长和脑单胺类神经递质含量的影响

为探讨合欢花对慢性应激大鼠生长和脑单胺类神经递质的影响,采用15只大鼠,设置了对照组、应激组和合欢花组3组实验。应激组和合欢花组均接受7天的应激刺激,之后合欢花组再灌胃合欢花10天。实验结束后,取3组大鼠的脑组织,用高效液相色谱法测定高香草酸(HVA)、去甲肾上腺素(NE)、多巴胺(DA)和5-羟色胺(5-HT)的含量。结果表明,应激组大鼠日增重显著低于对照组(P=0.011);而合欢花组大鼠的日增重极显著高于应激组(P=0.002)。应激组大鼠海马、纹状体和前额叶中的HVA含量与对照组相比,虽有升高的趋势,但无显著差异;两组间的NE、DA和5-HT也无显著差异。合欢花组大鼠海马中的HVA、DA含量明显高于应激组,而前额叶中的多巴胺和5-羟色胺,以及纹状体中的5-羟色胺均明显低于应激组。这表明合欢花对慢性应激引起的大鼠生长受抑有缓解作用,对其脑内单胺类神经递质有调节作用。     

In Vivo Tryptophan Hydroxylase Activity in Rat Major Cerebral Arteries Is Decreased by Dorsal Raphe Nucleus Lesions

Abstract: The in vivo presence of tryptophan hydroxylase activity in rat major cerebral arteries as well as the possible origin of the structure containing it were explored. Enzyme activity was appraised by accumulation of 5-hydroxytryptophan after inhibition of aromatic l -amino acid decarboxylase. Decarboxylase inhibition evoked a significant increase in 5-hydroxytryptophan levels in rat cerebral arteries, striatum, hippocampus, hypothalamus, and plasma but had no effect on aorta. p -Chlorophenylalanine reduced 5-hydroxytryptophan accumulation in the cerebral vessels and brain nuclei, whereas α-methyltyrosine did not modify it except in hypothalamus, where it was enhanced. α-Methyltyrosine significantly reduced noradrenaline levels in cerebral arteries and l -dopa accumulation after inhibition of the decarboxylase in striatum. Dorsal raphe nucleus lesioning significantly diminished 5-hydroxytryptophan formation in cerebral arteries, striatum, and hypothalamus, without affecting it in hippocampus. Lesion of median raphe nucleus reduced 5-hydroxytryptophan accumulation in hippocampus and in hypothalamus but not in cerebral blood vessels or striatum. Superior cervical ganglia removal decreased noradrenaline levels in cerebral blood vessels without affecting 5-hydroxytryptophan accumulation. These results indicate the presence of a functionally active tryptophan hydroxylase in rat cerebral arteries associated with fibers originating from dorsal raphe nucleus. This supports that rat major cerebral arteries receive serotonergic innervation from central origin.