Association between the levels of biogenic amines and superoxide anion production in brain regions of rats after subchronic exposure to TCDD

The effects of TCDD on the distribution of biogenic amines and production of superoxide anion (SA) in different brain regions of rats have been studied after subchronic exposure. Groups of females Sprague-Dawley rats were administered daily dose of 46ng TCDD/(kgday) (treated groups), or the vehicle used to dissolve TCDD (control group), for 90 days. The rats were sacrificed at the end of the exposure period and their brains were dissected into different regions including, hippocampus (H), cerebral cortex (Cc), cerebellum (C), and brain stem (Bs). The levels of different biogenic amines and some of their metabolites, including, norepinephrine (NE), dopamine (DA), 3,4-dihydroxy phenyl acetic acid (DOPAC), 4-hydroxy-3-methoxy-phenyl acetic acid (HVA), 5-hydroxy tryptamine (5-HT), and 5-hydroxy indole 3-acetic acid (5-HIAA), were determined in those brain regions, using a high performance liquid chromatography (HPLC) system with an electrochemical detector. SA production was also determined in those regions, using the cytochrome c reduction method. Results of analyses indicate significant increases in the levels of DA, NE and DOPAC in H, NE and HVA in Cc, NE and DA in Bs and NE in C. SA production was significantly increased in H and Cc, but not in Bs or C. The results also indicated strong correlations between DA and DOPAC, and SA and NE in all of the brain regions, and also between SA and 5-HT/HIAA in H and Cc. These results may indicate the contribution of biogenic amines, especially NE and 5-HT/HIAA to SA overproduction in some brain regions and may also indicate the potential of long term neurotoxic effects of those biogenic amines, in response to subchronic exposure to TCDD.     

Subclinical effects of groundwater contaminants. IV. Effects of repeated oral exposure to combinations of benzene and toluene on regional brain monoamine metabolism in mice

Benzene and toluene are known neurotoxicants that may interact in vivo. The effect of combined treatment with benzene and toluene on the endogenous concentrations of the catecholamines norepinephrine (NE) and dopamine (DA), the catecholamine metabolites vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the indoleamine serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), were investigated in six discrete brain regions of CD-1 mice. Groups of male, adult mice were continuously exposed to benzene (166 mg/l), toluene (80 and 325 mg/l), and combinations of benzene + toluene (80 or 325 mg/l) in drinking water for 4 weeks. Benzene produced increases of NE in the hypothalamus, cortex, midbrain and medulla oblongata, DA in the hypothalamus and corpus striatum, and 5-HT in all dissected brain regions except cerebellum. Elevated levels of various monoamine metabolites were also observed in these brain areas. Toluene ingestion alone also significantly increased the concentrations of NE, DA, 5-HT, and their metabolites in several brain regions. Mice given the combined treatments exhibited raised regional neurochemical levels when compared to the untreated controls. Increased concentrations of biogenic amine metabolites in several brain regions were greater in the combined exposures of benzene and toluene than when either chemical was used alone. The findings were different from those observed on immune parameters using similar treatment protocols, where simultaneous exposure to toluene prevented the immunotoxic effects of benzene.     

Methyl bromide alters catecholamine and metabolite concentrations in rat brain

The effects of inhalation exposure of rats methyl bromide (MB) on dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA) concentrations of various brain regions (striatum, hypothalamus, frontal cortex, midbrain, and medulla oblongata) were investigated. Rats received a single 8 hr exposure to MB, and amines and metabolites were separated by a reverse-phase HPLC, and were quantified via native fluorescence. An exposure to 100 ppm MB decreased tissue levels of DA and NE in all brain areas at 0 or 2 hr following exposure. HVA and MHPG contents were significantly increased in almost all brain regions. In a second study, rats were exposed to four concentrations of MB ranging from 31-250 ppm, and monoamine and metabolite levels in brain regions measured immediately after the exposure. Again, there were dose-dependent decreases of DA and NE, and increases in HVA and MHPG. Less clear changes in 5 HT and 5HIAA contents were observed. These data suggest that alterations of catecholamine metabolism may be a factor in MB-induced neurotoxicity.     

Alterations in Regional Brain Neurotransmitters by Silymarin,a Natural Antioxidant Flavonoid Mixture,in BALB/c Mice

Silymarin, a natural antioxidant flavonoid mixture, exerts anti-inflammatory effects in the liver and hinders tumor formation. The effect of this flavonoid mixture on the central nervous system is unknown, although antioxidants are considered beneficial. Brain amines and metabolites were studied after a short-term silymarin treatment. BALB/c mice were intraperitoneally treated with 0, 10, 50, or 250 mg/kg of silymarin per day for 5 days. High-performance liquid chromatography coupled with electrochemical detection was performed to determine concentrations of norepinephrine (NE), dopamine (DA), dioxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid (5-HIAA) in discrete brain regions. Analyses showed increased 5-HT levels in the cortex and increased DA and NE levels in the cerebellum in the highest dose group. Results indicated lack of general adverse effect on the brain amine metabolism and suggest that silymarin may have marginal serotonergic, dopaminergic, and noradrenergic effects.     

Naloxone-precipitated changes in biogenic amines and their metabolites in various brain regions of butorphanol-dependent rats

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a μ/δ/κ mixed opioid receptor agonist; 26 nmol/μl/h) or morphine (a μ-opioid receptor agonist; 26 nmol/μl/h) was investigated using highperformance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.     

Effect of formamidines on 5-hydroxytryptamine uptake and biogenic amine levels in rat platelets

Uptake of radioactive 5-hydroxytryptamine (5-HT) by platelets from rats treated intraperitoneally with the insecticide/acaricide chlordimeform (CDF) at 25 mg/kg was not significantly influenced at 1 h; however, uptake of this amine by platelets from rats treated with its N- monodemethyl metabolite (DMC) at the same dosage was significantly inhibited (37%). Two reversed phase high performance liquid chromatographic systems with electrochemical detection were developed with a capacity to separate 11 biogenic amines and related compounds. Only 5-HT, norepinephrine (NE), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were consistently detected in platelets and plasma samples. At 1 h and/or 24 h postinjection, CDF effected significant decreases in platelet levels of 5-HT, NE, and DA and plasma levels of 5-HT, whereas platelet and plasma levels of DOPAC were significantly increased. DMC effected significant decreases in both platelet and plasma levels of 5-HT. These in vivo studies confirmed previous in vitro experiments which demonstrated that formamidines inhibited uptake of 5-HT by platelets and released endogenous stores of amines from platelets.     

Evaluation of Acrylamide Treatment on Levels of Major Brain Biogenic Amines, Their Turnover Rates, and Metabolites

Evaluation of Acrylamide Treatment on Levels of Major BrainBiogenic Amines, Their Turnover Rates, and Metabolites. Aldous,C.N., Fair, C.H. and Sharma, R.P. (1983). Fundam. Appl. Toxicol.3:182-186. Acrylamide, a widely used and chemically active substance,has caused delayed distal neuropathy in man and in experimentalanimals. Male rats administered 50 mg/kg/ day acrylamide for5 days demonstrated ataxia in preliminary rotorod experiments.Additional groups of rats were dosed with 5, 15 or 50 mg/kg/dayacrylamide for 5 days, then sacrificed on day 6 at various timeintervals after iv injections of tritiated tyrosine (Tyr) ortryptophan (Trp). Brain levels of Tyr, Trp, norepinephrine(NE),dopamine(DA), serotonin(5-HT), and respective metabolites, 3-methoxy-4-hydroxyphenylethyleneglycolsulfate (MOPEG-sulfate), 3,4-dihydroxyphenylacetic acid (DOPAC),and 5-hydroxyindoleacetic acid (5-HIAA) were assayed fluorometrically.Turnover rates of NE, DA and 5-HT were estimated by evaluatingthe rates of specific activity changes in neurotransmittersand precursor amino acids over time. A slight reduction of wholebrain NE content was observed in rats administered 50 mg/kg/dayacrylamide. Other neurotransmitter levels were not affectedby acrylamide levels administered, nor were turnover rates affected.Levels of MOPEG-sulfate and DOPAC were unchanged at any dosetested. Increased levels of 5-HIAA were observed in rats receiving15 and 50 mg/kg/day acrylamide. Results suggest that acrylamideneurotoxicity does not entail widespread damage to the neuronsassociated with these biogenic amines; however, the acid metaoliteefflux from brain was significantly inhibited.     

BW 1370U87, a new monoamine oxidase-A inhibitor: Effects on biogenic amine neurotransmitter and metabolite levels in rat brain

Monoamine oxidase (MAO) inhibitors increase brain concentrations of biogenic amines and decrease concentrations of the acidic metabolites of biogenic amines. It has been suggested that the magnitude of these effects is an indicator of MAO inhibition. Oral doses of BW 1370U87, moclobemide, and brofaromine were given to rats at doses previously shown to induce brain MAO-A inhibition by at least 80%. The effects on brain biogenic amines and their metabolites were quantified 2 and 4 hr after oral dosing using HPLC with electrochemical detection. Moclobemide and BW 1370U87 induced larger increases in 5HT, NE, and DA and larger decreases in DOPAC, 5HIAA, and HVA than did brofaromine at the doses tested. At 8 hr post-dose the effects of BW 1370U87 on 5HT, NE, DOPAC, and HVA were still significant (P≤0.05), and the time course was similar to that seen following moclobemide and brofaromine treatment. Only BW 1370U87 increased brain concentrations of biogenic amines at a dose that does not significantly potentiate pressor effects of orally administered tyramine.     

Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems

The cerebral content of the biogenic amines, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their catabolites 30 min after CRF or saline injections was determined using HPLC with electrochemical detection. Injection of CRF (1.0 micrograms) into the lateral ventricles (ICV) of mice produced a behavioral activation in which their motor movements appeared as bursts of activity followed by periods of immobility. CRF administration (ICV or SC) did not alter the concentrations of DA, NE, tryptophan, 5-HT, or 5-hydroxyindoleacetic acid (5-HIAA) in any brain region measured. ICV CRF increased the concentrations of dihydroxyphenylacetic acid (DOPAC), the major catabolite of DA, and of 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of NE, in several brain regions. DOPAC:DA ratios were consistently increased in prefrontal cortex, septum, hypothalamus, and brain stem relative to animals injected with saline. MHPG:NE ratios were also increased in the prefrontal cortex and hypothalamus, with a marginal effect (p = 0.06) in brain stem. SC CRF significantly increased DOPAC:DA in prefrontal cortex, and MHPG:NE in prefrontal cortex, hypothalamus and brain stem. Pretreatment with naloxone did not prevent any of the neurochemical responses to ICV CRF, but naloxone alone increased DOPAC:DA in medial profrontal cortex, and decreased MHPG:NE in nucleus accumbens in CRF-injected mice. These results suggest that administration of CRF either centrally or peripherally induces an activation of both dopaminergic and noradrenergic systems in several regions of mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reuptake of biogenic amines by brain slices: Effect of hydrocortisone

Biogenic amines and steroid hormones are postulated to play an important role in human and animal behavior. Steroids may exert some control over amine activity by influencing one or more aspects of amine metabolism. The brain slice technique offers a useful in vitro system for determining biogenic amine reuptake, a major control mechanism for regulating the amount of physiologically available amine. Using this technique the effect of hydrocortisone (HC) upon the reuptake of norepinephrine (NE), serotonin (5-HT) and dopamine (DA) was studied. HC had no detectable effect upon the reuptake of NE, 5-HT, or DA by hypothalamic tissue slices.     

Influence of formamidines on biogenic amine levels in rat brain and plasma

Biogenic amine levels in samples of whole brain and plasma following treatment of rats with chlordimeform (CDF), its two N-demethyl metabolites (DMC and DDC), p-chloroamphetamine (PCA), and harmaline were separated by high performance liquid chromatography equipped with fluorescence or electrochemical detection systems. At 1 hr following s.c. injection, CDF (200 mg/kg) caused a reduction in levels of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and tyramine (TRM), an increase in dopamine (DA), and no change in levels of beta-phenethylamine (PEA) in samples of whole rat brain, whereas DMC (100 mg/kg) and DDC (25 mg/kg) effected reductions of brain levels of NE, 5-HT, TRM, and PEA with no change in DA. The effect of DMC (100 mg/kg) on NE and DA levels in brain was followed periodically for 24 hr. Following a significant decrease at 1 hr, NE levels increased to a maximum at 12 hr and remained higher than controls throughout the remainder of the 24 hr test period. DA levels increased during the initial 12 hr and remained significantly higher than controls for the remaining 12 hr. The influence of s.c. vs i.p. administration of DMC (100 mg/kg) on brain amine levels was examined. Intraperitoneal treatment generally resulted in lower amine levels in DMC and vehicle treated animals. Differences in treatment effects were similar for all amines except for 5-HT in which s.c. injection produced a slight reduction, while i.p. injection resulted in a two-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurobiochemical alterations induced by the artificial sweetener aspartame (NutraSweet)

The dipeptide aspartame (NutraSweet) is a newly approved and widely used artificial sweetener in foods and beverages. Consumption of aspartame (ASM) has been reported to be responsible for neurologic and behavioral disturbances in sensitive individuals. Unfasted male CD-1 mice were dosed orally with 13, 130, or 650 mg/kg ASM in corn oil, while control animals received corn oil alone. Three hours after dosing, the animals were killed, and the concentrations of the catecholamines norepinephrine (NE) and dopamine (DA), catecholamine metabolites 3-methoxy-4-hydroxymandelic acid (VMA), homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC), the indoleamine serotonin (5-HT), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined by electrochemical high-performance liquid chromatography in six brain regions. ASM exerted its primary effect on adrenergic neurotransmitters in various brain regions. In the hypothalamus, the region richest in NE, increases in NE concentrations of 12, 49, and 47% were found in the low, medium, and high dose groups, respectively, relative to control. Significant increases of NE in the medulla oblongata and corpus striatum were also observed. Increases of the catecholamine DA and catecholamine metabolites VMA, HVA, and DOPAC were seen in various regions. The indoleamine serotonin and its metabolite 5-HIAA were unaffected by ASM treatment. These findings are consistent with ASM-induced increases in the brain catecholamine precursor amino acids phenylalanine and tyrosine, as reported earlier. Such observed alterations in brain neurotransmitter concentrations may be responsible for the reported clinical and behavioral effects associated with ASM ingestion.     

ACUTE EFFECTS OF A BICYCLOPHOSPHATE NEUROCONVULSANT ON MONOAMINE NEUROTRANSMITTER AND METABOLITE LEVELS IN THE RAT BRAIN

Naive male Sprague-Dawley rats were injected intraperitoneally (ip) with the bicyclophosphate convulsant trimethylolpropane phosphate (TMPP) at dose levels from 0.2 to 0.6 mg/kg. Rats were observed for convulsive activity, and were sacrificed 15 min posttreatment. Levels of the monoamine neurotransmitters norepinephrine (NE), epinephrine (EPI), dopamine (DA) , and serotonin (5-HT) and the major metabolites 3,4- dihydroxyphenylacetic acid ( DOPAC) , homovanillic acid ( HVA) , and 5-hydroxyindoleacetic acid ( 5-HIAA) were assayed in forebrain, midbrain, hindbrain, cerebellum and brainstem regions. Neurotransmitter and metabolite levels were compared between control rats and rats that did and did not experience seizures. TMPP administration induced significant decreases in levels of measured neurotransmitters that varied as a function of brain region, dose, and expression of the seizure activity. These results show that tonic or tonic-clonic seizures induced by TMPP administration (0.6 mg/ kg) are reliably associated with regional decreases in serotonin, dopamine, and norepinephrine. Convulsive activity resulting from lower dose administrations (0.2-0.4 mg/kg) of TMPP result only in decreased regional levels of serotonin.     

Selective depleting effect of syrosingopine on brain catecholamine levels with relation to morphine analgesia in the rat.

Reserpine was the most potent, rescinnamine the next and syrosingopine the weakest in the depleting effects on brain amines of rauwolfia alkaloids. After syrosingopine, brain dopamine (DA) was decreased to a smaller degree and with a shorter duration as compared with norepinephrine (NE) and serotonin (5-HT), whereas reserpine elicited a marked and long lasting reduction in these amines. Accordingly, syrosingopine induced a depletion of brain NE and 5-HT without alteration in brain DA content 2-4 days after administration. Repeated administrations of syrosingopine, 2 mg/kg daily for 2 or 4 days, resulted in similar alterations in brain amine levels. This selective depleting effect of syrosingopine on brain amines was potentiated by combined treatment with disulfiram or fusaric acid, a dopamine beta-hydroxylase inhibitor. Under the condition of selective depletion of brain amines induced by repeated administrations of syrosingopine, 2 mg/kg daily for 2 days, the analgesic action of morphine was not affected, whereas reserpine and tetrabenazine antagonized morphine analgesia, concomitant with inducing a depletion of all brain amines. The results suggest that brain DA may be more important than brain NE or 5-HT with regard to the mechanisms by which morpine produces analgesia.     

Biogenic amines distribution in the brain of nervous and normal pointer dogs. A genetic animal model of anxiety.

Nervous pointer dogs have been suggested as an animal model for pathological anxiety. In order to study possible disturbances in neurotransmitter functions in this animal model, we measured brain biogenic amines (norepinephrine, dopamine, and serotonin) and their metabolites in both nervous and normal dogs. Eight nervous and six normal dogs were behaviorally tested and later anesthetized and killed. Brains were removed and dissected while frozen using a punch technique. Samples were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. The nervous dogs had higher [NE] in the reticular formation and lower serotonin, and its metabolite 5-hydroxyindoleacetic acid, in the septal nuclei, indicating possible important differences in noradrenergic and serotonergic functions in the nervous dogs. There was a trend for lower [HVA] and [DOPAC] levels and a significantly lower [DOPAC]/[DA] ratio in the nervous dogs, suggesting decreased dopaminergic function.     

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359

Levels of monoamines and their metabolites were determined in the cortex, hippocampus, and striatum of rats killed by microwave irradiation. Moclobemide (20 mg/kg, p.o.) and clorgyline (10 mg/kg, p.o.), type A monoamine oxidase (MAO-A) inhibitors, increased the levels of normetanephrine (NM) and 3-methoxytyramine (3MT) and decreased those of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) in almost all three regions. Deprenyl (10 mg/kg, p.o.), a type B monoamine oxidase inhibitor, however, little affected monoamine and metabolite levels in all regions. The maximum effects of RS-8359 (10 mg/kg, p.o.) were obtained at 2 to 6 hr after administration, when the levels of norepinephrine (NE), NM, 3MT, and serotonin (5HT) in all regions and dopamine (DA) in the striatum increased, while DOPAC and HVA levels decreased. The levels of monoamines and metabolites had returned to normal by 20 hr after administration. Dose-dependency of the effects of RS-8359 on monoamine metabolites was observed at doses up to 30 mg/kg (p.o.) at 1 and 6 hr after administration. In conclusion, NE, DA, and 5HT are exclusively or preferentially deaminated by MAO-A in the cortex, hippocampus, and striatum of rats, and RS-8359 exhibits a reversible MAO-A inhibitory action in all three regions tested in vivo.     

Alteration of brain noradrenaline, dopamine and 5-hydroxytryptamine levels during vanadium poisoning

Effects of subacute and chronic intoxication with vanadium on the levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were examined. It was shown that subacute as well as chronic intoxication caused changes in levels of biogenic amines in the rat brain. NA concentration decreased whereas DA and 5-HT levels significantly increased. Vanadium in concentrations of 10(-3) and 10(-4) M inhibited the uptake of 3H-NA by cerebral cortex slices in vitro.     

Effect of repeated dietary exposure of aflatoxin B1 on brain biogenic amines and metabolites in the rat

Male Sprague-Dawley rats were treated po twice weekly for 3 weeks with a low (32.8 micrograms/kg) and high dose (327.9 micrograms/kg) of aflatoxin B1 (AFB1) in corn oil. A control group received corn oil only. At the end of the experiment the rats were killed, and the concentrations of the brain catecholamines, norepinephrine (NE) and dopamine (DA), catecholamine metabolites, 3-methoxy-4-hydroxymandelic acid (VMA), homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC), and the indoleamine serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined by high-pressure liquid chromatography in five brain regions. The major effects were found in striatal dopamine and serotonin concentrations, with decreases of 37 and 29%, respectively. A corresponding decline was observed in the dopamine metabolites, homovanillic acid (44%) and dihydroxyphenylacetic acid (30%). Concentrations of these neurotransmitters and metabolites were only marginally altered in cerebral cortex, cerebellum, hypothalamus, and medulla oblongata. It appears that a major effect of AFB1 is on dopaminergic pathways, possible by selectively perturbing the conversion of tyrosine to biogenic catecholamine neurotransmitters.     

Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats

The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5-HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved.     

Changes of serotonin and catecholamines are related to pharmacokinetic alterations of clomipramine in rat brain.

When rats received a single i.p. injection of clomipramine (20 mg/kg), clomipramine and desmethylclomipramine were rapidly distributed into the brain and their concentrations were markedly higher in the brain than in the serum, while the concentration of the metabolite in the brain was much lower than that of clomipramine. Chronic administration of clomipramine gradually increased the concentrations of the metabolite in both serum and brain, but did not significantly change those of clomipramine. The levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the brain were compared with the concentrations of clomipramine and desmethylclomipramine at different times. The levels of 5-HT, NE, DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain did not appear to be affected by changes in the concentrations of the drug and metabolite. The level of 5-hydroxyindole acetic acid (5-HIAA) was reduced following clomipramine injection and the reduced level was maintained during chronic treatment. Chronic treatment for more than 7 days increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level with no alteration of NE level. This elevation appeared to be induced by desmethylclomipramine.