Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain

Biogenic amines (norepinephrine, dopamine, homovanillic acid, serotonin and 5-hyroxyindole acetic acid) were measured by HPLC method in adult F1 generation rats’ brain regions (brainstem, hypothalamus, hippocampus, striatum and frontal cortex), whose mothers (P generation) were treated with vitamin A or vitamin D neonatally (hormonal imprinting). Many significant differences were found, related to the maternally untreated controls. In the earlier studied P generation females, vitamin A consistently influenced the serotonerg system (5HIAA), while vitamin D the dopaminerg system (DA or HVA). Vitamin A imprinting always resulted in reduced, while that by vitamin D always in increased tissue levels. In the present case (directly untreated F1 generation) the transgenerational effect was not unidirectional, however biogenic amine tissue levels were strongly disturbed and brain-area dependent. The results call attention to the transgenerational effect of hormonal imprinting in the case of receptor level acting vitamins which are frequently used in the most imprinting-sensitive period (perinatally) of human life and suggests that caution is warranted.     

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.     

Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases

The effects of ketamine on the levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were examined in discrete brain regions in mice. A high dose of ketamine (150 mg/kg, i.p.) did not change DA metabolism in the frontal cortex, nucleus accumbens, striatum and hippocampus, but did decrease it in the brainstem during anesthesia. In contrast, during recovery from the ketamine anesthesia, the high dose increased the level of homovanillic acid (HVA) in all brain regions. A low subanesthetic dose of ketamine (30 mg/kg, i.p.) increased the concentrations of both 3,4-dihydroxyphenylacetic acid (DOPAC) and HVA only in the nucleus accumbens. The DA level was not affected by any ketamine treatment. During ketamine anesthesia, the content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) was decreased in the brainstem, whereas during recovery from anesthesia, the MHPG level was increased in the frontal cortex, nucleus accumbens and brainstem. The NE content was not altered in any region by ketamine treatment. The concentration of 5-hydroxyindoleacetic acid (5-HIAA) was reduced in the frontal cortex, striatum, hippocampus and brainstem during ketamine anesthesia. The 5-HT level was unaltered in all regions except the brainstem where it was reduced. In contrast, after anesthesia, the concentrations of both 5-HT and 5-HIAA were increased in the striatum. During the subanesthetic phase, however, the levels of NE, 5-HT and their metabolites were unchanged. These neurochemical results are consistent with the electrophysiological findings that a high dose of ketamine does not change the basal firing rates of nigrostriatal DA neurons during anesthesia, while low subanesthetic doses significantly increase those of ventral tegmental DA neurons.     

Ethanol alters monoamines in specific mouse brain regions.

Ethanol (3.5 g/kg 60 min post-IP injection) produced the following changes in regional brain monoamine levels and in the respective metabolite/neurotransmitter ratios: for the noradrenergic system, MHPG was decreased in the amygdala and increased in the hypothalamus, while the MHPG/NE ratio was increased in the prefrontal cortex and the hypothalamus. For the dopaminergic system, DA was decreased in the olfactory tubercle, DOPAC was increased in the prefrontal cortex and septum, and DOPAC/DA was increased in the prefrontal cortex, septum, striatum, and hypothalamus. HVA was increased in the prefrontal cortex and septum, while HVA/DA was increased in the same regions plus the olfactory bulb. 3MT was decreased in the olfactory tubercle and striatum. The serotonergic system was not altered. The results demonstrate that ETOH produces selective regional changes in the concentration and utilization of monoamines in mouse brain with a predominant influence on dopaminergic systems and a lesser effect on noradrenergic activity.     

Monoaminergic activities in Lewy Body dementia: Relation to hallucinosis and extrapyramidal features

Summary Serotonergic (5-HT) and dopaminergic activities have been examined in Lewy Body Dementia (LBD) and compared with Parkinson's disease (PD) and Alzheimer's disease (AD). In the neocortex the LBD subgroup experiencing hallucinations was distinguised from the other categories by an increase in the 5HIAA:5HT ratio measured in frontal cortex and by the serotonergic (5-HIAA or 5-HIAA:5-HT): cholinergic (choline acetyltransferase) ratio in frontal and temporal cortex. In the neostriatum (caudate nucleus), loss of dopamine and increased HVA: dopamine ratio correlated with the reduction in substantia nigra neurons in LBD but not PD, despite the greater loss of neurones and dopamine and the higher dopamine turnover ratio in PD. LBD patients experiencing severe Parkinsonism as a result of neuroleptic treatment tended to have lower neuron counts, in combination with higher turnover ratios, than the remainder. Qualitative differences between LBD and PD included decreased cortical 5-HT turnover in PD compared with the increase in LBD. There were no significant changes in any parameter in AD, with the exception of a reduction in temporal cortex 5HIAA. The results suggest that although the neurochemical pathology of LBD and PD involves similar systems, the nature of the derangements differs sufficiently between the diseases to account for differences in symptomatology.     

巴曲酶对脑缺血再灌注细胞外液单胺类及其代谢产物的影响——微透析研究

目的巴曲酶对脑缺血再灌流损伤的保护机理。方法采用脑内微透析技术结合高灵敏度的高压液相色谱－电化学检测手段（ＨＰＬＣ－ＥＤ），测定前脑缺血３０ｍｉｎ再灌注１２０ｍｉｎ时的纹状体细胞外液（ＥＣＦ）的ＤＡ、５－ＨＴ和ＮＥ及其代谢产物（５－ＨＩＡＡ）和ＨＶＡ的变化和巴曲酶的影响。结果显示脑缺血时，ＥＣＦＤＡ、ＮＥ及５－ＨＴ明显升高，巴曲酶能显著地降低脑缺血时ＥＣＦＤＡ及再灌注时ＥＣＦＨＶＡ和５－ＨＩＡＡ的水平。结论巴曲酶影响单胺神经递质是对脑缺血再灌注损伤起保护作用的机理之一     

The effects of himantane and cycloprolylglycine on the enzymatic linkage of monoamine synthesis in the rat brain

Using HPLC we studied the effects of new substances with antiparkinsonian activities, viz., himantane and cycloprolylglycine (CPG), on the contents of monoamines and their metabolites in the brain structures of Wistar rats under conditions of the inhibition of tyrosine and tryptophan hydroxylases. It was shown that 70 min after administration himantane induces a significant decrease in the level of noradrenaline in the nucleus accumbens (NA) and striatum. At 70 min after administration of CPG, we observed an increase in the DOPAC/DA ratio in the NA and the level of 5-HIAA in the striatum. At 24 h after CPG administration, we observed an increase in the HVA content and HVA/DA ratio in the hypothalamus and striatum. We found a decrease in 5-HIAA in all brain structures we studied at 24 h after administration of CPG, which was absent at 70 min after injection of the substance; the magnitude of 5-HIAA/5-HT decreased in the hypothalamus, nucleus accumbens, and hippocampus. Our results suggest that both substances we studied influence serotonergic transmission by inhibition of the MAO B enzyme.     

Effects of nefiracetam,a novel pyrrolidone derivative,on brain monoamine metabolisms in mice

Summary The effects of acute and chronic administration of nefiracetam, a pyrrolidone derivative, on monoaminergic neurotransmitter systems in the mouse hippocampus, frontal cortex, hypothalamus, and striatum were studied. The levels of monoamines and of their metabolites were measured by high performance liquid chromatography with electrochemical detection on the first, 7th, and 14th days after nefiracetam was given. The neurochemical effects of nefiracetam were compared with those of oxiracetam and indeloxazine.Acute administration of nefiracetam (10 mg/kg, po) and oxiracetam (10 mg/ kg, po) had no effect on the levels of noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT), or on the levels of their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in any of the regions examined. In contrast, a single dose of indeloxazine (10 mg/kg, po) decreased the levels of MHPG, DOPAC, and 5-HIAA in all regions examined.After chronic administration of nefiracetam (10 mg/kg, po, once daily), the levels of MHPG, DOPAC, and 5-HIAA were higher than control in all regions on the 14 th day only. Oxiracetam (10 mg/kg, po, once daily) similarly increased the levels of MHPG, DOPAC, and 5-HIAA in the hippocampus, frontal cortex, and striatum, but not in the hypothalamus. Conversely, indeloxazine (10 mg/ kg, po, once daily) decreased the levels of MHPG and 5-HIAA in all regions and the levels of DOPAC and HVA in the hippocampus and striatum as measured on the 7 th and 14 th days.These results show that nefiracetam has a delayed effect on brain monoaminergic metabolism, and that its effects are similar to those of oxiracetam, but clearly different from those of indeloxazine.     

Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging

This study examines the age-associated changes in noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), serotonin (5-HT) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in different brain areas of rats. DA and DOPAC concentrations in striatum increased at third month of age, remaining without significant variations until 12th month of age, and decreasing in 24-month-old rats. DA concentration dropped in hippocampus, amygdala and brainstem of 24-month-old-rats, whereas DOPAC levels decreased only in hippocampus. These changes suggest an age-dependent deficit of the dopaminergic system, presumably related to a reduced number/activity of DA nigrostriatal and mesolimbic neurons. An age-induced decline in NA content was found in the pons-medulla, the area containing NA neuronal bodies. Concentrations of 5-HT were reduced with aging in frontal cortex, showing a tendency to decrease in all brain areas examined. The increased 5-HIAA/5-HT ratio found in frontal cortex, amygdala and striatum suggests an age-related decreased synthesis and an accelerated 5-HT metabolism. The 5-HIAA content decreased in brainstem of the oldest rats. These findings point to a selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas reductions in NA were restricted to cell bodies region and 5-HT showed changes of different extent in areas of terminals and neuronal cell bodies.     

The brain 5HTergic response to an acute sound stress in rats with generalized (absence and audiogenic) epilepsy

The brain serotoninergic (5HTergic) system of epileptic subjects can influence their vulnerability to stress. We studied the putative dependency of 5HT neurotransmission parameters on emotional stress, and the presence, types and severity of seizures using rats with genetic generalized (absence and/or audiogenic) epilepsy, of WAG/Rij and Wistar strains. The animals were stressed by exposure to a short aversive noise or left without sound stimulation. Tissue concentrations of 5HT, tryptophan (TRT) and 5-hydroxyindolacetic acid (5HIAA) were assessed by HPLC. The stressor activated the 5HTergic system within thalamus (5HIAA elevated), frontal cortex (5HT, TRT elevated), hypothalamus (increased TRT) in all rats. However, the normal (non-epileptic) rats displayed the highest response in the frontal cortex and the lowest one in the thalamus, as compared to the epileptic rats. Absence-epileptic rats exhibited higher thalamic 5HIAA increase than their controls. Significant correlations existed between propensity of absence epilepsy and 5HTergic parameters measured in the cortex and hypothalamus of absence-epileptic rats. No major difference was found between groups with and without audiogenic epilepsy. The results imply that the stress response depends on the presence of epileptic pathology and the seizure type and severity. The brain 5HT may be involved in the control of the paroxysms and behaviour in absence-epileptic subjects.     

Effect of perinatal stress on the biogenic amine neurotransmitter level of the adult rat's brain

The amount of biogenic amines (dopamine and serotonin) and their metabolites (DOPAC, HVA, 5-HIAA, and 5-HTOL) in five regions of the brain (frontal cortex, hypothalamus, hippocampus, striatum, and brainstem) was studied in the male and female offspring of control and perinatally (48 h before birth or 48 h after birth) food and water deprived dams, when they were three months old, by using HPLC-EC determination. The increase of amine or metabolite level was dominant (19 values increased and 10 decreased related to control). Before-birth stress caused increase in 9 case and only 2 decreased, while in the case of after-birth stress 10 increased and 8 decreased. However, though there is no possibility to decide an exact tendency of direction, the after-birth stress (transmitted by milk) has more expressed effect. Striatum and brainstem were the most touched regions. There was a gender dependence with the dominance of males, except striatum. Blood plasma nociceptin level was also studied and there was a significant elevation in males after pre- and postnatal deprivation, while in females only after postnatal deprivation. The importance of the results in correlation with other stress effects is discussed.     

Evidence for acute tolerance to the behavioral effects of lindane: concomitant changes in regional monoamine status.

The effects of the organochlorine insecticide lindane on plus-maze ((+)-maze) behavior of rats and on regional monoamine status were studied at two time points, 30 min and 24 hr post-dosing. Animals were given lindane, 20 mg/kg, 30 min before (L1/2 group), or 40 mg/kg, 24 hr before (L24 group), experimental time; these schedules allowed the study of animals with equivalent brain concentration of lindane at two different time points after administration. The (+)-maze results indicated a reduction in the number of entries into the arms of the maze 30 min after administration of lindane that was not present 24 hr later, suggesting the development of an acute tolerance to the behavioral effects of the chemical. In a parallel group of animals, concentrations of noradrenaline (NA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were determined by HPLC in seven brain regions. Significant decreases in NA concentrations were found in L1/2 animals in hippocampus and cerebral cortex and also in the L24 group in the latter region. 5HT/5HIAA ratios increased in several brain regions in the L24 rats but not in the L1/2 rats, thus showing an inverse relationship with behavioral effects. DOPAC/DA and HVA/DA ratios in hypothalamus and cerebral cortex were, by contrast, increased in both groups of treated animals. In conclusion, it appears that an acute tolerance can develop to the behavioral effects of lindane, and that there are modifications produced in central monoaminergic systems by lindane that show brain region and and treatment schedule specificity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regional and kinetics effects of piribedil and bromocriptine on dopamine metabolites: a brain microdialysis study in freely moving rats

Summary Brain microdialysis coupled to HPLC was applied to freely moving rats to investigate the regional kinetics of piribedil and bromocriptine on the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatum, nucleus accumbens, and frontal cortex. Both D2 agonists (20 mg/kg i.p.) decreased DOPAC and HVA in the three brain regions. The responsiveness of frontal cortex to both compounds was greater than those previously reported with other dopaminergic drugs. Regional and temporal differences were observed under piribedil: DOPAC and HVA levels decreased more in the nucleus accumbens than in striatum or frontal cortex but increased over basal values from the 5th hour in the frontal cortex suggesting a late stimulatory effect of piribedil on dopamine synthesis in this area. Such regional effects differentiate piribedil from most other D2 agonists and could explain some behavioural and therapeutic actions possibly related to involvement of nucleus accumbens or/and frontal cortex.     

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.     

Time course of changes in serotonin and noradrenaline in rat brain after predictable or unpredictable shock

The effects of predictable and unpredictable shock on concentrations of serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP) and noradrenaline (NA) have been studied in 7 regions of rat brain. Two separate experiments have been carried out determining these substances both at 30 min and 2 h after the stress session. Unpredictable shock depleted NA levels in all brain regions except the striatum. However, at 2 h poststress NA in these regions increased significantly in comparison with both controls and predictably shocked rats. Predictable shock also decreased NA in locus coeruleus, brainstem and hypothalamus, which was not observed 2 h later. Both predictable and unpredictable shock decreased 5-HT in brainstem and hypothalamus. At 2 h poststress, 5-HT levels in these regions were still decreased in predictably shocked rats, but had attained control values in unpredictably shocked rats. 5-HT metabolism expressed as the 5-HIAA/5-HT ratio, was significantly increased 30 min after predictable shock in all regions except the locus coeruleus and hippocampus. Unpredictable shock produced a much more marked increase in 5-HIAA/5-HT ratio. At 2 h poststress 5-HT metabolism returned to control values in most of the brain regions of predictably shocked animals, but it remained high after unpredictable shock. The activation of serotonergic metabolism following each type of shock is different according to the nucleus in which the 5-HT nerve endings originate. Only slight increases in tryptophan were observed after both types of shock. Our results suggest that unpredictable shock is perceived as a more anxiogenic situation and that under this condition both 5-HT and NA levels are more effectively normalized with time.     

Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy

Changes in the cholinergic, serotonergic, noradrenergic, dopaminergic, GABAergic and somatostatinergic neurons were investigated to determine their roles in Alzheimer's disease (AD). Markers for these systems were analyzed in postmortem brain samples from 20 patients with AD and 14 controls. In the CSF study, markers for the cholinergic neurons (choline esterase, ChE) and for the somatostatinergic neurons (somatostatin-like immunoreactivity, SLI) were assayed for 93 and 75 probable AD patients and 29 and 19 controls, respectively. Activity of choline acetyltransferase (CAT) was decreased by 50-85% in four cortical areas and hippocampus in patients with AD, but not in other areas of the brain, indicating a profound deficit in the function of cholinergic projections ascending from the nucleus basalis to the cerebral cortex and hippocampus in AD. Muscarinic receptor binding was reduced by 18% in the frontal cortex but not in other areas of the brain in AD. Serotonin (5HT) concentrations were reduced (by 21-37%) in hippocampal cortex, hippocampus and striatum; and 5HT metabolite levels were lowered (by 39-54%) in three cortical areas, thalamus and putamen in AD patients. Concentrations of noradrenaline (NA) were reduced (18-36%) in frontal and temporal cortex and putamen. These data imply that serotonergic and noradrenergic projections are also affected in AD but less than the cholinergic neurons. Dopamine (DA) concentrations in AD patients were reduced by 18-27% in temporal and hippocampal cortex and hippocampus, while HVA, the metabolite of DA, was unaltered. Glutamic acid decarboxylase activity was not altered in AD. SLI was decreased (28-42%) in frontal, temporal and parietal cortex, but not in thalamus and putamen in patients with AD. Frontal tangle scores correlated most strongly with cortical CAT activity reduction and less so with decreases of 5HT, NA and DA, indicating a closer correlation with the cholinergic changes and severity of AD than with other neurotransmitter deficiencies. ChE activity and SLI were reduced by 20% and 35%, respectively, in CSF of the whole group of AD patients as compared to the controls. Comparison of CSF findings between four subgroups of dementia severity indicated that the SLI was already reduced in the group of mildest AD (-31%), while ChE activity was not. Although ChE activity in CSF declined in relation to dementia severity, however, the maximal reduction was only modest (-30%). On the other hand, SLI in CSF showed only a slight further reduction (up to -41%) as the dementia become more severe.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential pulse voltammetry: simultaneous in vivo measurement of ascorbic acid, catechols and 5-hydroxyindoles in the rat striatum

This paper describes carbon fibre electrodes that can simultaneously monitor changes in ascorbic acid, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in vivo in the rat striatum using differential pulse voltammetry. The separation between DOPAC and 5HIAA oxidation is improved and the size of the 5HIAA peak decreased by the removal of uric acid using the enzyme uricase indicating that uric acid oxidation may contribute to the oxidation peak at + 300 mV. Haloperidol (0.5 mg/kg) decreased ascorbic acid and 5HIAA but increased DOPAC and HVA while D-amphetamine (3 mg/kg) increased ascorbic acid, decreased DOPAC and HVA but had no effect on 5HIAA. These electrodes should be a useful means of investigating interactions between dopamine and serotoninergic systems in vivo.     

MONOAMINES (SEROTONIN AND CATECHOLAMINES) AND THEIR DERIVATIVES IN INFANTILE AUTISM: AGE-RELATED CHANGES AND DRUG EFFECTS

Levels of dopamine (DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3MT) and norepinephrine+epinephrine (NE + E), and serotonin (5HT) and its derivative 5-hydroxyindolacetic acid (5HIAA) were determined from the urine of 156 autistic children aged two to 12 years 6 months, and compared with those of age-matched mentally retarded non-autistic and normal controls. Very significant group and age effects were found for DA, HVA, 3MT, NE + E and 5HT. High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children. The results are discussed in relation to the hypothesis of a maturation defect of monoaminergic systems in autism.     

Serotonin depletion attenuates AY-9944-mediated atypical absence seizures

Summary: Purpose: To test the hypothesis that serotonin (5‐HT) plays a role in the modulation of experimental atypical absence seizures. Methods: Male Long‐Evans hooded rats were treated from postnatal day (P) 2 to P20 with the cholesterol inhibitor AY‐9944 (AY). Epidural electrodes were implanted for electrocorticography (ECoG) followed by serotonin depletion by using para‐cholorophenylalanine (PCPA). High‐performance liquid chromatography (HPLC) was used to measure the levels of serotonin and its metabolite (5‐HIAA) in various brain regions. Serotonin metabolism was computed by using the 5‐HIAA/5‐HT ratio and used to ascertain differences between groups. Results: PCPA treatment was associated with a significant decrease in the total slow spike‐and‐wave discharge (SSWD) duration in AY‐treated rats compared with controls (p < 0.01). HPLC data confirmed the PCPA depletion of 5‐HT and 5‐HIAA in cortex, thalamus, hippocampus, and brainstem compared with naïve rats. AY‐treated rats showed higher levels of 5‐HIAA and 5‐HT in the same brain regions, with a concomitant decrease in rates of serotonin turnover. Conclusions: The data indicate that serotonin depletion protects against experimental atypical absence seizures. The increased levels of 5‐HIAA and 5‐HT and altered rates of serotonin turnover suggest that the serotonergic neurotransmission may be perturbed in the AY rat.     

肿瘤坏死因子对睡眠的影响及其机制分析

本研究采用两种动物模型观察了肿瘤坏死因子（TNF）对睡眠的影响，并对其机制进行了初步的探讨。结果表明TNF可使小鼠自主活动明显减少，明显延长成巴比妥钠诱导的小鼠睡眠时间；TNF经静脉注射或脑室内注射均可延长家兔睡眠时间，其中以延长深睡眠为主，作用可持续12小时。为揭示TNF促进睡眠的机制，观察了TNF对脑内单胺神经递质的影响，结果表明，TNF可使小鼠脑内5－HT及其代谢产物5－HIAA含且明显增高；TNF还可使大鼠皮层5－HT、5—HIAA含量增高；使海马及下丘脑的5－HIAA含量增加，但5－HT的含量无明显变化；用优降宁阻断5一HT降解后，TNF可使小鼠脑内5—HT的合成速率增加。这些结果提示，TNF可能是通过促进5—HT的合成而影响睡眠的。