Functional brain asymmetry and lymphocyte proliferation in female mice: effects of right and left cortical ablation

Brain immunomodulation may be lateralized as evidenced by two experimental approaches. Using a behavioral paradigm, we have reported an association between asymmetrical brain function and lymphocyte reactivity in mice selected for right- and left-paw preference. Left-handed mice, in comparison to right-handers, exhibit higher mitogen-induced T-lymphocyte proliferation. Using a cortical lesion paradigm in mice, it has been previously shown that each hemicortex modulates in opposite directions lymphocyte reactivity. In these experiments, the role of the brain cortex in the association between paw preference and immune reactivity was assessed by studying mitogen-induced lymphoproliferation in left- and right-handed mice after right or left-cortical ablation. The difference in T-lymphocyte responsiveness between right- and left-handed mice persisted after right lesions but was abolished after left lesions. This immunological effect of left cortical ablation is hypothesized to involve the hypothalamic dopaminergic neurons.     

Asymmetrical distribution of brain interleukin-6 depends on lateralization in mice

The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system.     

Naltrexone administration effects on regional brain monoamines in developing rats

The effects of the opioid antagonist naltrexone (NALTX) daily administration (1 mg/kg SC) from birth on the levels of dopamine (DA), serotonin (5-HT), and their respective major metabolites, in the striatum, midbrain, and hypothalamus of 7-, 14-, and 22-day-old rats were investigated. Naltrexone treatment increased the striatal HVA/DA ratio on postnatal day 7. At day 14, two subpopulations (A and B) were found among the treated animals. The subpopulation A showed decreased HVA/DA and increased DOP AC/DA ratios, whereas the subpopulation B presented a higher DA concentration. No significant effect appeared on the striatal dopaminergic system in 22-day-old pups. The serotonergic system was affected by exposure to naltrexone only from day 14. The subpopulation A showed a reduction in all the parameters measured in the three regions studied, although in the subpopulation B, lower 5-HIAA/5-HT ratios appeared in the midbrain and hypothalamus. At 22 days of age NALTX treatment elevated striatal 5-HT and 5-HIAA and the ratio of 5-HIAA/ 5-HT in the midbrain and hypothalamus. These data suggest an endogenous opioid modulation on the central aminergic systems during the neonatal period and point out the consequences of opioid plasticity on related neurotransmitter systems.     

Depressed convulsions by diazepam and its effects on brain monoamines and amino acids in E1 mice

The effect of diazepam on inbred mutant E1 mice, which develop convulsive seizures after repeated sessions of being tossed up, was examined. Acute administration of diazepam (32 mg/kg, i.p.) completely inhibited the convulsions. At that time, the dopamine level was increased in the cortex and hippocampus, and the norepinephrine level in the cerebellum was decreased. 5-Hydroxytryptamine levels were not changed. As for amino acids, the glutamine level increased and the levels of GABA, glutamic acid, aspartic acid, alanine and other amino acids were not changed.     

Asymmetric distribution of brain monoamines in left- and right-handed mice

Biogenic amine distributions analyzed in the cerebral neocortex, striatum, anterior hypothalamus, and bulbospinal region, were compared between both hemispheres of left- and right-handed mice. The handedness of mice was determined using a paw preference test. The animals were tested 5 times, once every two weeks, and the biochemical analysis was performed two weeks after the last behavioral evaluation. The results indicated that (1) asymmetrical monoaminergic concentrations exist in the mouse brain. Monoamine contents were found to be higher in the right parietal cortex and anterior hypothalamus than in the left ones; (2) besides the behavioral expression of handedness, left- and right-handed subpopulations of mice differ according to asymmetrical distributions of cortical and bulbospinal NE contents as well as DA turnover of the tuberoinfundibular system.     

Analysis of temporal and dose-dependent effects of estrogen on monoamines in brain nuclei

Levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were measured in hypothalamic and limbic nuclei of ovariectomized rats after various doses of estradiol and at various intervals after estradiol administration. Of 13 areas examined, time- and dose-dependent effects of estrogen on monoamine content were restricted to only a few, discrete areas which concentrate estradiol. Subcutaneous administration of 1-50 micrograms of estradiol benzoate (EB) and measurement of monoamines 24 h later was associated with dose-dependent increases of NE in the medial preoptic nucleus, diagonal band nucleus and periventricular area of the anterior hypothalamus, and increased levels of DA in the periventricular area of the preoptic area. No changes were found in 5-HT levels, but dose-dependent increases in the level of the 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), were measured in the lateral portion of the ventromedial nucleus. Effects of 5 micrograms of EB were evaluated at 1.5, 6, 12 and 45 h after administration. No changes were noted at 1.5 h, but 5-HIAA in the ventromedial nucleus was elevated at 6 and 12 h. NE levels were elevated at 12 and 45 h in the diagonal band and preoptic nuclei and at 45 h in the lateral septum and periventricular area of the hypothalamus. DA levels decreased in the arcuate-median eminence area 45 h after estrogen. Intravenous administration of 10 micrograms of estrogen and measurement of monoamines 1 h later was not associated with altered levels of any monoamine suggesting that the estrogen-dependent changes are consistent with the genomic model for steroid hormone action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nerve growth factor: effects on -amphetamine-induced activity and brain monoamines

Adult male rats were given 6-hydroxydopamine lesions of the nucleus accumbens, followed immediately by injections of saline or nerve growth factor (NGF; 125 B.U.) near the substantia nigra. Such lesions were previously reported to attenuate the locomotor response to -amphetamine. NGF-treated rats showed an enhanced response to -amphetamine (1.5 mg/kg) when tested 15 days postoperatively. Levels of dopamine and norepinephrine in the striatum and nucleus accumbens were equivalently depressed in the two lesion groups, indicating that the apparent recovery of the NGF-treated rats was probably not due to catecholaminergic neuronal regrowth. Intracerebral NGF administration enhanced the response to -amphetamine 15 days later in rats without lesions, and also appeared to result in increased turnover of brain norepinephrine and serotonin at 3, but not 15, days postadministration. NGF might increase dopamine turnover at 15 days, but the evidence obtained did not convincingly confirm or negate this possibility. The results show that intracerebral NGF administration can produce similar behavioral changes in brain-damaged and intact rats, and also modify the apparent turnover of brain monoamines.     

快速老化模型小鼠学习记忆行为及有关脑区单胺递质水平的增龄性变化

目的 研究快速老化模型小鼠(senescence accelerated mice，SAM)学习记忆能力及其大脑皮层、海马和下丘脑单胺递质含量的增龄性变化及它们之间的关系。方法 分别采用跳台实验和穿梭箱实验测定SAM的被动和主动回避反应能力，采用高效液相色谱电化学检测法测定脑内单胺递质的含量。结果 2月龄快速老化亚系SAM-prone/8(SAMP8)的被动和主动回避反应能力已较同龄抗快速老化亚系SAM-resistance／1(SAMR1)明显降低，且其主动回避反应能力随增龄进一步降低。同时，SAMP8大脑皮层、海马及下丘脑内单胺递质水平多明显高于同龄SAMR1，且随增龄明显增高。结论 SAMP8学习记忆能力的衰退可能与其相关脑区单胺递质的变化密切相关。     

Regulation of nestin expression after cortical ablation in adult rat brain

During embryogenesis, transient expression of nestin in proliferating neuroepithelial stem cells signals the commitment of progenitor cells to differentiate. Although adult mammalian brain contains very little nestin, significant upregulation of nestin has been reported following cerebral injury, leading to speculation that nestin may be involved in brain repair. In this study, we assessed the temporal profile of nestin expression following ablation injury of the sensory barrel cortex and investigated the influence of contralateral whisker stimulation on nestin expression. Since the adult mammalian brain contains proliferating neuronal progenitor cells that can be labeled with bromodeoxyuridine (BrdU), we also determined the association of nestin reexpression with BrdU-labeled cells. Nestin reexpression was detected predominantly in the ipsilateral cortex 3 days post-ablation. There was no significant nestin upregulation in the subcortical region. Nestin reexpression was most marked surrounding the lesion, but also extended throughout the entire lateral cortex. Nestin in the ipsilateral cortex subsided by day 7, although perilesional nestin expression was still apparent 28 days post-injury. Western blot analysis of nestin expression 3 days post-ablation confirmed a significant two-fold increase in nestin expression (p<0.05). Double immunofluorescence labeling demonstrated that the majority of nestin expression occurred in astrocytes. We were unable to detect any colocalization with neuronal makers. However, BrdU-labeled cells, which were readily detected in the subventricular zone prior to injury, were readily detected in the perilesional area 3 days post-ablation, concomitant with nestin in this area. Confocal microscopy detected several BrdU-positive cells expressing nestin. Taken together, the data support a potential role for nestin reexpression in brain repair.     

Nerve growth factor: effects on D-amphetamine-induced activity and brain monoamines.

Adult male rats were given 6-hydroxydopamine lesions of the nucleus accumbens, followed immediately by injections of saline or nerve growth factor (NGF; 125 B.U.) near the substantia nigra. Such lesions were previously reported to attenuate the locomotor response to D-amphetamine. NGF-treated rats showed an enhanced response to D-amphetamine (1.5 mg/kg) when tested 15 days postoperatively. Levels of dopamine and norepinephrine in the striatum and nucleus accumbens were equivalently depressed in the two lesion groups, indicating that the apparent recovery of the NGF-treated rats was probably not due to catecholaminergic neuronal regrowth. Intracerebral NGF administeration enhanced the response to D-amphetamine 15 days later in rats without lesions, and also appeared to result in increased turnover of brain norepinephrine and serotonin at 3, but not 15, days postadministration. NGF might increase dopamine turnover at 15 days, but the evidence obtained did not convincingly confirm or negate this possibility. The results in brain-damaged and intact rats, and also modify the apparent turnover of brain monoamines.     

Influence of cerebral embolism on brain monoamines

In baboons the right cerebral hemisphere was embolised by a shower of microemboli, immediately followed by one large embolus designed to occlude the middle cerebral artery (MCA). One hour after embolism a significant, though small, reduction in blood flow and oxygen consumption of the embolised hemisphere was recorded, at which time the animals were killed and brain monoamines measured. Dopamine was reduced in the ipsilateral caudate nucleus, the reported site of maximal ischaemic damage in this model. Dopamine levels were increased in frontal and occipital grey matter sampled from areas surrounding the occluded MCA territory and in similar brain areas of the opposite non-embolised hemisphere. Noradrenaline was increased in grey matter from both cerebral hemispheres, as well as subcortical structures bilaterally. Brain 5-hydroxytryptamine levels were unaltered, but increased 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid suggested transient alteration in 5-hydroxytryptamine metabolism after embolism. The effects of cerebral embolism on brain monoamine metabolism appear to be different from the effects of permanent surgical occlusion of major cerebral vessels. The bilaterality of effects after unilateral hemispheric embolism might be related to diaschisis. The mechanisms of the observed changes, as well as their relevance to the progression of cerebral ischaemia and the complications associated with cerebral embolism, still require to be established.     

Changes in tissue-plasminogen activator mRNA expression following cortical ablation in the rat brain

Tissue plasminogen activator (tPA) has been used to treat acute thrombotic lesions. Roles other than the activation of fibrinolytic pathways have been suggested for tPA in the mature brain. We used the in situ hybridization technique to investigate the changes in tPA mRNA expression within the brain after cortical ablation. We found that expression of tPA mRNA started to increase diffusely in the cortex ipsilateral to the injury 6 h after ablation. This increase had become prominent 24 h after ablation. On d 5, the expression of tPA mRNA had returned to that of the control animals except for the area near the injury. We also found that administration of MK-801 before injury suppressed the increase of tPA mRNA in the ipsilateral cortex. These results suggest that the increase in tPA mRNA is likely to be mediated via activation of NMDA receptors.     

Effects of chronic oral nicotine treatment and its withdrawal on locomotor activity and brain monoamines in mice

The effects of chronic nicotine and its withdrawal on locomotor activity and brain monoamines were studied using a new animal model of administering nicotine in the drinking water to male NMRI mice as the sole source of fluid. Locomotor activity as well as cerebral concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) were measured post mortem on the 50th day of nicotine administration or at 12-14 or 23-25 h after withdrawal. On the 50th day of drug administration the chronically nicotine-treated mice were more active than the control mice drinking tap water and after withdrawal from nicotine the locomotor activity dropped to the level of the controls. In chronically nicotine-treated mice the striatal concentrations of DOPAC, HVA and 5-HIAA, hypothalamic 5-HIAA and NA as well as cortical NA were elevated. The concentrations of DOPAC, HVA and 5-HIAA reversed to control levels within 23-25 h after withdrawal from nicotine. The nicotine-induced elevation of the hypothalamic NA concentration was still significant at 23-25 h after withdrawal. At 12-14 h after withdrawal the hypothalamic concentration of MOPEG was increased. In conclusion, our findings on locomotor activity suggest that administration of nicotine in the drinking water to mice for several weeks seems to be a relevant method to study nicotine dependence. Furthermore, the alterations found in cerebral DA, NA and 5-HT metabolism during chronic nicotine administration indicate that all three cerebral transmitter monoamines might be involved in nicotine dependence and withdrawal.     

Pineal melatonin and brain transmitter monoamines in CBA mice during chronic oral nicotine administration

The effects of chronic oral nicotine administration on the pineal melatonin and brain transmitter monoamines were studied in male CBA mice, which possess a clear daily rhythm of melatonin secretion. On the 50th day of nicotine administration, pineal melatonin as well as cerebral dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined at various times. The chronic nicotine treatment did not alter the timing of the pineal melatonin peak, which occurred at 10 h after the light offset. However, in mice drinking nicotine solution, the nocturnal pineal melatonin levels were lower than in control mice drinking tap water. The chronic nicotine treatment increased the striatal DA, DOPAC, HVA and 5-HIAA levels, the hypothalamic NE, MHPG and 5-HIAA and the cortical MHPG. Most prominent effects of nicotine were found at 8 h after the light offset, when the striatal levels of DA and HVA, hypothalamic NE and MHPG as well as cortical MHPG were significantly elevated in the nicotine-treated mice compared with the control mice. No direct correlation between nicotine's effects on brain transmitter monoamines and on pineal melatonin levels was apparent. The results suggest that chronic nicotine treatment slightly suppresses the melatonin production but does not alter the daily rhythm of pineal melatonin in mice maintained on a light-dark cycle. However, the results indicate that nicotinic receptors might be involved in the regulation of pineal function.     

Effects of intraventricular dynorphin treatment on brain monoamines

Dynorphin was administered into the lateral cerebral ventricle of rats and its effects were measured 60 min later on the noradrenaline (NA), dopamine (DA) and serotonin (5-HT) contents of various brain regions. Dynorphin decreased the NA, DA and 5-HT contents of the hypothalamus as well as the 5-HT content of the caudate nucleus. These effects were not manifested after naloxone pretreatment. In the frontal cortex and in the septum, dynorphin caused a naloxone-insensitive increase in the 5-HT content, and the increased caudate DA content was not antagonized by the opiate receptor antagonist either. The data suggest that dynorphin affects cerebral monoaminergic neurotransmission. The changes of the largest magnitude occured in the hypothalamus. Only some of these effects were antagonized by naloxone, suggesting that the CNS effects of dynorphin are only partly mediated by endogenous opioid binding sites.     

Distribution of monoamines in human brain: evidence for neurochemical heterogeneity in subcortical as well as in cortical areas

Norepinephrine, epinephrine, dopamine, serotonin and their major metabolites were measured by high-performance liquid chromatography with electrochemical detection in 49 regions of the human brain. The regional distribution of the different monoamines in the subcortical areas was similar to previous reports. We report here the distribution pattern of the 4 monoamines observed in the cerebral cortex. Regional differences in concentration were observed for norepinephrine, epinephrine and serotonin, with high concentrations in the frontal and parietal regions. However, no regional difference in dopamine concentrations was detected. The possible role of norepinephrine and serotonin as conventional transmitters, and of dopamine and epinephrine as neurotransmission modulators is discussed.