Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats

Concentrations of monoamines (dopamine, DA; serotonin, 5-HT) and their major metabolites (homovanillic acid — HVA; dihydroxyphenylacetic acid — DOPAC; 5-hydroxyindolacetic acid — 5-HIAA) were measured in selected brain areas of chronically gonadectomized, steroid- or oil-treated male and female rats. Concentrations of DOPAC and HVA were markedly increased in the hypothalamus (male, female), striatum (male, female) and brainstem (male) following gonadectomy, whereas the levels of DA remained unaltered in most of the brain areas examined. Most of the changes were reversed or attenuated by chronic estradiol (EB) substitution. In contrast, chronic treatment with physiological concentrations of testosterone (TP) reduced indexes of DA turnover only in the striatum of ovariectomized (OVX) and brainstem of orchidectomized (ORDX) rats. ORDX-related increases in striatal levels of DOPAC and HVA were not reversed by either EB or TP. ORDX increased the levels of 5-HIAA (hypothalamus, striatum) and decreased those of 5-HT (hypothalamus, hippocampus). These changes were reversed by chronic treatment with either TP or EB. Brain metabolism of 5-HT remained unaltered following OVX.

Gonadectomy and chronic steroid replacement therapy appear to alter brain monoamine metabolism in a brain region and sex-dependent manner. Our data demonstrate that gonadectomy-related increases in the activity of brain monoaminergic neurons in both male and female rats was attenuated more effectively with physiological concentrations of estradiol than with testosterone. Insensitivity of monoaminergic neurons in a number of brain areas (e.g., hypothalamus, striatum) to the action of testosterone was evident in both sexes.     

Effects of morphine treatment and withdrawal on striatal and limbic monoaminergic activity and ascorbic acid oxidation in the rat

Since ascorbic acid (AA) reportedly suppresses tolerance to and dependence on morphine in humans and rodents, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), AA, dehydroascorbic acid (DHAA), uric acid, xanthine, hypoxanthine, glutamate and γ-amino-butyric acid (GABA) were determined by high-pressure liquid chromatography (HPLC) in the striatum and in the limbic forebrain of the rat following morphine treatment (single or repeated) and withdrawal. Single morphine administration (20 mg/kg s.c.) increased DOPAC + HVA/DA, 5-HIAA/5-HT and DHAA/AA ratios, uric acid levels, and decreased xanthine, hypoxanthine, glutamate and GABA levels in both regions. 3-MT levels were decreased in the striatum and increased in the limbic forebrain. After 7 days of morphine treatment, striatal DOPAC + HVA/DA and DHAA/AA ratios and uric acid levels were still higher and striatal and limbic xanthine levels still lower than in controls, while all other parameters were in the range of control values in both regions. Morphine treatment also increased the glutamate/GABA ratio in the striatum. In all morphine-treated rats, individual striatal DOPAC + HVA/DA and DHAA/AA ratio values were directly correlated. After a 48 h withdrawal period, both striatal AA oxidation and glutamate/GABA ratio further increased; limbic 3-MT levels further decreased, while all other parameters did not differ from control values. We conclude that: (i) tolerance to morphine-induced increase in hypoxanthine, xanthine and AA oxidation develops in the limbic forebrain faster than in the striatum; (ii) the morphine-induced increase in striatal and limbic AA oxidation may be considered a consequence of increased formation of reactive oxygen species due to increased DA, hypoxanthine and xanthine oxidative metabolism; (iii) a striatal excitotoxic imbalance characterizes the withdrawal state and may be taken into account to explain the further increase in striatal AA oxidation.     

Differential effects of kainic acid on dopamine and serotonin metabolism in ventral and dorsal striatal regions

The comparative effects of kainic acid (KA) on dopamine (DA) and serotonin (5-HT) metabolism in ventral and dorsal striatum were investigated. Local injection of KA into the caudate-putamen (CP) increased by 155% DOPAC (2,3-dihydrophenylacetic acid), by 114% HVA (homovanillic acid) and by 79% 5-HIAA (5-hydroxyindoleacetic acid) concentrations: with little or no effect on monoamine levels. The (DOPAC + HVA)/DA ratio increased from 0.33 ± 0.2 in vehicle-treated to 0.77 ± 0.1 in KA-treated CP. 5-HIAA/5-HT ratio increased from 2.7 ± 0.2 to 5.9 ± 0.1 after KA treatment. However, direct KA injections into the olfactory tubercle (OT), the most ventral part of the ventral striatum, did not alter significantly the levels of DA, 5-HT, DOPAC, HVA or 5-HIAA. Since KA is a neurotoxin which preferentially destroys perykaria and dendrites, leaving unchanged terminal boutons and axons of passage, the lack of effects on DA and 5-HT metabolism in OT suggests, that contrary to the CP, interneurons and projecting neurons in the OT play no role in inhibitory feedback mechanisms to control DA and 5-HT activities.     

Metabolism of monoamine neurotransmitters in the evolution of infarction in ischemic striatum

Summary The time course of changes in monoamine metabolism in ischemic striatum was assessed by measurement of levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxy-indole-acetic acid (5-HIAA) 2, 4, 7 and 16 hours after irreversible unilateral carotid ligation in Mongolian gerbils with stroke. DA was reduced to 30% of the level in the contralateral non-ischemic striata by 2 hours after stroke, but DOPAC was significantly elevated (p < 0.01) to 227%, while HVA remained equal to control. At 4 hours after stroke, DOPAC was 86% of the contralateral non-ischemic striata but HVA had risen to 130%. At 7 hours after stroke, DOPAC in the ischemic striata was 148% of control, while HVA remained at 133%. By 16 hours after stroke, DA, DOPAC and HVA were depleted from the ischemic striata, corresponding to the time course for irreversible damage to the neurotransmitter uptake function of nerve terminals. 5-HT levels in the ischemic striata were 30% of control at 2 hours, 46% at 4 hours, 30% at 7 hours and 21% at 16 hours, while 5-HIAA remained equal to control throughout the time course. These studies indicate that monoamine metabolism continues in ischemic striatum for up to 8 hours after the onset of stroke following irreversible unilateral carotid ligation in the Mongolian gerbil, but metabolism of DA is disrupted by 16 hours after stroke while metabolism of 5-HT continues.     

Central monoamine metabolism in the male Brown-Norway rat in relation to aging and testosterone

Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.     

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of l-DOPA-treated monkeys

The effects of monoamine oxidase (MAO) inhibitors on the metabolism of dopamine synthesized from exogenous l-DOPA were investigated in the striatum and substantia nigra of squirrel monkeys. Administration of a single dose of l-DOPA (methyl ester, 40 mg/kg, i.p.) caused a significant increase in the levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and in the DOPAC/dopamine ratio in the putamen, caudate and substantia nigra. These changes were more pronounced in the substantia nigra than in the striatum and within the striatum of l-DOPA-treated monkeys, levels of dopamine and its metabolites were higher in the putamen than in the caudate nucleus. When l-DOPA treatment was preceded by the injection of clorgyline or deprenyl at a concentration (1 mg/kg) which selectively inhibited MAO A or MAO B, respectively, striatal dopamine was increased while the striatal DOPAC and HVA levels and DOPAC/dopamine ratio were significantly reduced as compared to the values obtained with l-DOPA alone. The two MAO inhibitors also counteracted the increase in the DOPAC and HVA levels and DOPAC/dopamine ratio induced by l-DOPA in the substantia nigra. Thus, both MAO A and MAO B contribute to the metabolism of dopamine when higher levels of this neurotransmitter are generated from l-DOPA in the squirrel monkey. The extent of reduction of dopamine catabolism (as assessed by the decrease in DOPAC and HVA levels) in the striatum and substantia nigra was similar with clorgyline and deprenyl even if the ratio MAO A/MAO B was approximately 1 to 10. This indicates that, though catalyzed by both MAO A and MAO B, dopamine deamination following treatment with l-DOPA preferentially involves MAO A.     

The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats

The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.     

Dopaminergic and serotonergic correlates of stimulation-induced circling

Rotation induced by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus was associated with increases in dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum ipsilateral to the site of stimulation (i.e. contralateral to direction of turning). The concentrations of DA, DOPAC and HVA within the nucleus accumbens (NAS) were not altered. In the olfactory tubercle (OT), concentrations of DA and both metabolites were, in general, elevated ipsilateral to the electrode. However, relative to non-stimulated controls, HVA concentrations were increased bilaterally in rats exhibiting circling. Stimulation-induced circling also resulted in a bilateral enhancement of striatal serotonin (5-HT) metabolism as indicated by elevated 5-hydroxyindoleacetic acid: 5-HT ratios. No changes in 5-HT metabolism were observed in the NAS. The utilization of 5-HT was elevated in the OT ipsilateral to the electrode in rats that exhibited stimulation-induced rotation. While most subjects that exhibited contraversive rotation in response to the stimulation demonstrated enhanced DA activity, the neurochemical changes were not observed in all subjects. As such, it is concluded that while stimulation of the mesotelencephalic DA system can be associated with stimulation-induced rotation it is not necessary for its elicitation.     

Effect of anoxia on striatal monoamine metabolism in immature rat brain compared with that of hypoxia: an in vivo microdialysis study

We examined in 5-day-old rats the effects of either anoxia or 8% hypoxia on extracellular monoamines such as dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) using in vivo microdialysis and subsequent HPLC. After stabilization 64 animals were exposed to 100% nitrogen for 16 min and 40 animals to 8% oxygen for 128 min. Both anoxia and hypoxia produced acute increase in the striatal extracellular DA (anoxia: P < 0.001, hypoxia: P < 0.01). Especially in anoxia, DA levels increased transiently to 2000-times the basal levels and 6-times higher than those in hypoxia. NE also increased in both anoxia and hypoxia. DOPAC and HVA decreased during hypoxia ( P < 0.01 and P < 0.001, respectively), while those in anoxia were unchanged. In anoxia, decrease tendency of their levels were in short duration and that of 5-HIAA was followed by gradual increase ( P < 0.001). These data demonstrated that brief exposure to anoxia or hypoxia had significant influence on striatal monoamine metabolism in immature brain and the pattern of change of monoamine in anoxia was different from that in hypoxia.     

Effect of a selective MAO-A inhibitor (Ro 41-1049) on striatal L-dopa and dopamine metabolism: An in vivo study

Summary We administered Ro 41-1049, an inhibitor of the enzyme monoamine oxidase type A (MAO-A) to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal (IP) administration of a bolus of L-dopa. Acute administration of Ro 41-1049 (1–50 mg/kg IP) produced a dose-dependent decrease in basal levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and an increase in basal levels of dopamine. In rats treated with Ro 41-1049 (20 mg/kg IP), L-dopa administration (100 mg/kg IP) produced a greater increase in striatal levels of dopamine than it did in controls, while DOPAC and HVA formation was attenuated. We conclude that inhibition of central MAO-A activity promotes synaptic accumulation of dopamine following administration of pharmacological doses of L-dopa.     

Regional changes in central monoamine and metabolite levels during the hibernation cycle in the golden-mantled ground squirrel.

We assayed various brain regions for levels of monoamines and their metabolites throughout the hibernation cycle of the golden-mantled ground squirrel Spermophilus lateralis. The tissue concentrations of serotonin, dopamine, norepinephrine and their metabolites were determined in the parietal cortex, striatum, midbrain, hippocampus, hypothalamus, and pons. Telencephalic regions exhibited the most significant variations in biogenic amine content. Cortical serotonin (5-HT) levels increased significantly at entrance (P less than 0.0001) relative to other periods of the hibernation cycle, suggesting a role for 5-HT in the initiation of hibernation. Among striatal dopamine (DA) metabolites, 3-methoxytyramine was detectable only during euthermia and arousal; from entrance through arousal, homovanillic acid (HVA) levels were half that found during euthermia (P = 0.0001); and dihydroxyphenylacetic acid (DOPAC) levels increased during day 1 of hibernation (P less than 0.0005). Midbrain DA (P = 0.0295) and hippocampal HVA (P = 0.0194) levels also changed significantly across the hibernation bout. The absence of a consistent change in any monoamine or metabolite throughout the brain precludes the possibility of preferential temperature-dependent impairment of an enzyme involved in biogenic amine synthesis or degradation and suggests that the levels observed reflect changes in neural activity specific to each brain region. Together with previous studies of brain 2-deoxyglucose uptake throughout the hibernation cycle, these data indicate that a transient change in afferent monoaminergic metabolism and neurotransmission in the forebrain is a necessary component for the entrance to hibernation.     

Effects of hypoxia-ischemia on monoamine metabolism in the immature brain

We measured acute changes in monoamine metabolites in corpus striatum of immature rat pups exposed to hypoxia-ischemia, hypoxia alone, or total global ischemia. Carotid ligations and two hours of 8% oxygen environment in 7-day-old pups led to asymmetrical turning behavior, a 70% decrease in endogenous striatal dopamine levels, and a 125% increase in homovanillic acid (HVA) concentrations on the side of ligation. In contrast, hypoxia alone and total global ischemia alone were not associated with HVA level elevation. Elevation of HVA level with hypoxia-ischemia showed a threshold effect between 1 and 1.5 hours, and this time course paralleled that for production of gross morphological changes in rats raised to maturity. The data suggest that dopamine release from striatal nerve terminals is associated with events causing brain injury during perinatal hypoxia-ischemia. Tissue HVA in the animal model appears to be a quantitative marker for the effects of the insult on a population of nerve terminals.     

Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 micrograms/0.5 microliter in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 micrograms/0.5 microliter). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.     

Reproductive experience increases striatal and hypothalamic dopamine levels in pregnant rats

The effects of parity on the dopaminergic function of rats were studied. Striatal and hypothalamic levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) as well as serum prolactin (PRL) levels of 7-days primigravid and multigravid rats were compared. Brains and trunk blood were collected from 1200–1400 h on day 7 of pregnancy and assayed for monoamines and their metabolites, and prolactin, respectively. Multigravid rats showed a significant increase in striatal and hypothalamic dopamine levels. A tendency to increase in striatal DOPAC levels was also observed in multigravid rats. Levels of other neurotransmitters and metabolites were not statistically different. Haloperidol (1 mg/kg) treatment induced a significant increase in multigravid 5-HT striatal levels. There was no statistical difference among primigravid and multigravid serum PRL levels after either saline or haloperidol treatment. These data suggest that prior parity produces a shift in dopaminergic activity in multigravid rats.     

Effect of acute levodopa on brain catecholamines after selective MAO and COMT inhibition in male rats

Summary Interactions between a selective catechol-O-methyltransferase (COMT) inhibitor OR-462 and a monoamine oxidase (MAO)-A inhibitor clorgyline were studied measuring concentrations of L-dopa, dopamine and their metabolites in the rat hypothalamus and striatum after administration of levodopa/carbidopa (15/30 mg/kg i.p.). Part of the experiments were performed in rats pretreated with 6-OH-dopamine (6-OHDA) intracerebroventricularly (i.c.v.) to determine whether changes in dopamine metabolism occurred inside or outside catecholaminergic neurons. OR-462 was an effective COMT inhibitor at the doses 3 and 30 mg/kg i.p. Inhibition of 3-O-methyldopa (3-OMD) formation from L-dopa was reflected in the hypothalamus (45–81% decrease) and striatum (87–88% decrease), since 3-OMD penetrates the blood-brain barrier. Homovanillic acid (HVA) was decreased only in the striatum at 30 mg/kg of OR-462. Clorgyline (8 and 32 mg/kg i.p.) decreased 3,4-dihydroxyphenylacetic acid (DOPAC) formation in the hypothalamus and striatum by 61–91%. When given together, OR-462 and clorgyline elevated hypothalamic dopamine levels 3.2–4.6-fold, but striatal dopamine only 1.3–1.9-fold. The formation of 3-OMD and DOPAC remained suppressed and even brain HVA levels were decreased by 51–97%. 6-OHDA treatment decresed striatal and hypothalamic dopamine by 50% and noradrenaline by 75%. In these animals levodopa/carbidopa increased brain L-dopa 2.4–4-fold, those of 3-OMD 1.2–1.7-fold compared to intact animals, but the synthesis and metabolism of dopamine and the effects of COMT and MAO inhibitors were not significantly changed. Levodopa/carbidopa treatment decreased significantly prolactin and thyrotropin levels in serum but none of the additional treatments changed this action.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Evidence for different sites of monoamine oxidase and catechol-O-methyltransferase in the striatum

Wistar rats were implanted with a probe for brain microdialysis in the striatum, and measured for two major dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal chlorpromazine (5 mg/kg) increased the concentrations of both metabolites in the dialysate when the determinations were carried out before 90 min after the administration. An apparent difference between the declines in concentrations of DOPAC and HVA was observed. Although the concentration of HVA maintained higher levels for over 6 h after the administration, DOPAC underwent a decrease in its concentration after the maximum level, which occurred at 90 min after the administration. These results are discussed in terms of the different distributions of two enzymes related to the metabolism of dopamine, catechol-O-methyltransferase and monoamine oxidase.     

Asymmetrical development of the monoamine systems in 2,4-dichlorophenoxyacetic acid treated rats

The purpose of this study was to determine whether the regional brain biogenic amine levels in adult rats were altered by pre- and post-natal exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). Pregnant rats were daily orally exposed to 70 mg/kg per day of 2,4-D from gestation day (GD) 16 to post-partum day (PPD) 23. After weaning, the pups were assigned to one of two subgroups: T1 fed with untreated diet up to post-natal day (PND) 90 and T2 (maintained with 2,4-D diet up to PND 90). In addition, we wanted to know the effect of 2,4-D on lateralization in the monoamine systems of the basal ganglia of these adult rats and whether there was any correlation with the behavioral developmental pattern previously reported by us. In this study the content of noradrenaline (NA) was significantly increased in substantia nigra (SN) while it decreased in cerebellum in male and female rats of T2 group. The decreased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovallinic acid (HVA) contents in cerebellum, midbrain, ventral tegmental area (VTA) and prefrontal cortex (PFc) showed an alteration in the mesocorticolimbic system. However, an increase of DA in SN and of DOPAC and HVA in nucleus accumbens (NAc) in both sexes and of DA and DOPAC (only in females) in striatum was detected. The contents of serotonin (5-hydroxytryptamine, 5-HT) were significantly increased in both sexes in PFc, striatum (St), midbrain, SN and cerebellum. Variations of any monoamine levels in NAc and VTA were determined. T1 rats were irreversibly altered: a diminution in DA and/or DOPAC levels in PFc, midbrain, VTA and cerebellum was determined. Indolamines of these rats were increased in both sexes in PFc and St. There was also a large increase in 5-HT levels in midbrain of male rats. Although no changes in the dopaminergic system with respect to their control values in any side of these brain structures were observed, DA and DOPAC levels were found to be decreased in the right side with respect to the left side in striata and accumbens nuclei in T2 female rats supporting the behavioral rotation previously registered by us in these rats. In addition, the increased 5-HT content detected in both the right and left striata observed in this study could be the answer to the behaviors observed and to the early alterations in dopamine in basal ganglia by 2,4-D in neonatal exposed rats, mediated by a serotonergic modulation on the dopaminergic system.     

Sertraline induced parkinsonim. A case report and an in-vivo study of the effect of sertraline on dopamine metabolism

Summary. We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft?), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, IP) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome. Received October 3, 1997 / Accepted December 20, 1997     

Central and peripheral neurochemical alterations and immune effects of prenatal ethanol exposure in rats

In contrast to the well known effects of prenatal ethanol exposure on the central nervous system, data about its peripheral effects are scarce. Here, Sprague-Dawley rats were fed a liquid diet (gestational days 0–20) containing 36% ethanol-derived calories (EDCs, group H) or were pair-fed with 18% EDCs (group L) or 0% EDCs (group C. On postnatal day 20, one male and one female from each of 10 litters per group were killed. Norepinephrine (NE) was analyzed in the frontal cortex, spleen and thymus, and dopamine, 5-hydroxytryptamine (serotonin, 5-HT) and their metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in the striatum by high-performance liquid chromatography with electrochemical detection. Lymphocyte subpopulations in the spleen and thymus were also assessed in half of these litters. Significant decreases in splenic NE concentration were seen in both sexes of group H (males 27%, females 28%). Decreases in striatal 5-HT and 5-HIAA of group H subjects appeared to be sex specific (only females were significantly affected: 23% decrease in 5-HT, 37% decrease in 5-HIAA). Pronounced, dose-dependent reductions in T cell percentages were observed in both the thymus and spleen. Splenic CD8⁺ and CD4⁺ cell percentages were positively correlated with the splenic NE concentrations. It is concluded that the decreases seen in splenic T cell percentages subsequent to prenatal ethanol exposure may be caused, at least partially, by impaired noradrenergic control of this organ.