Galactolipid fatty acids in brain of pyridoxine-deficient young rats

Summary The non-hydroxy fatty acids of the galactolipid fraction of brain lipids of pyridoxine-deficient rats have been analyzed. The results suggest an impairment in the pathway for the synthesis of very long chain fatty acids in the brain of pyridoxine-deficient rats.     

Sex differences in long-term gonadectomized rats: monoamine levels and [3H]nitroimipramine binding in brain nuclei

Summary The levels of norepinephrine, dopamine, serotonin and the serotonin metabolite 5-hydroxyindoleacetic acid were measured in microdissected brain nuclei from long-term gonadectomized male and female rats. Females had 50 and 120% higher levels of serotonin in the anterior hypothalamic nucleus (AH) and arcuate-median eminence (AR-ME), respectively. No significant differences in norepinephrine, dopamine or 5-hydroxyindoline acetic acid were found in any of the brain nuclei sampled. The differences in serotonin content do not appear to result from a sexually dimorphic distribution of serotonin nerve terminals since quantitative autoradiography of ³H-nitroimipramine revealed no differences in binding between the sexes in the AH or AR-ME.Supported by USPHS grant HD12011 to V.N. Luine and USPHS postdoctoral grant HD06368 to K.J. Renner     

赛庚啶对大鼠脑损伤脑皮质和脑微血管中5—HT含量的影响

采用高效液相色谱－电化学检测器检测大鼠（１８０只）脑损伤后脑皮质及脑微血管中５－ＨＴ含量变化，并选用５－ＨＴ受体阻断剂赛庚啶治疗，观察其对脑损伤后脑皮质及脑微血管５－ＨＴ水平变化的影响。结果表明：脑损伤后５－ＨＴ水平显著升高，神经细胞和脑微血管内皮病理变化与５－ＨＴ代谢改变有密切关系，赛庚啶可显著降低脑皮质及脑微血管中５－ＨＴ含量，并减轻脑继发性损害。     

Chronic administration of electroconvulsive shock effects on mouse-killing activity and brain monoamines in rats

Mouse-killing by rats is blocked by chronic administration of electroconvulsive shock. Antidepressive drugs also block mouse-killing by rats. Thus, mouse-killing by rats may be under the control of mechanisms analogous to human depression. Whole brain concentrations of norepinephrine were higher in rats that received ECS.     

Age-related changes in fear behavior and regional brain monoamines distribution in rats

Differences in fear level assessment based on the time of motionless in the illuminated compartment, time spent in light compartment, number of head dipping from dark to the illuminated compartment and number of returns from dark to the illuminated compartment registered in light/dark transitions test and brain monoamines (NA, DA, 5-HT) and their metabolites (MHPG, DOPAC, 5-HIAA) in the hypothalamus, midbrain, amygdala, hippocampus and pons were examined in 3, 12 and 24 months old Wistar rats. The lowest level of fear was registered in 12 months old rats, a slightly higher level in 3 months old rats and the highest in 24 months old rats. Locomotion activity showed a decreasing tendency within age according to a linear dependence in 3, 12 and 24 months old rats. Neurochemical data showed the decreased activity of NA system and increased activity of DA system in most structures already occurred in 12 months old rats. It remained at the same level in aged rats. The correlation analysis between the behavioral markers of fear level and distribution of monoamines in young, mature and aged rats showed diversified data, only some of them being consistent with the "serotonergic hypothesis" of fear/anxiety. Therefore, we cannot conclude what neurochemical background of fear is.     

Effect of pyridoxine deficiency on aromatic L-amino acid decarboxylase in adult rat brain

Summary We have investigated the effect of pyridoxine deficiency on aromatic L-amino acid decarboxylase (AADC) using both dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5HTP) as substrates in the rat brain. The activity ratios of DOPA decarboxylase/5HTP decarboxylase measured under optimal substrate and cofactor concentrations were different in the cerebellum, cerebral cortex, corpus striatum and hypothalamus of the normal rat. In pyridoxine deficiency, there were no parallel decreases in DOPA and 5HTP decarboxylase activities in various brain regions. Dialysis of brain homogenates, in the presence and absence of hydroxylamine, resulted in a total or near total loss of 5HTP decarboxylase activity compared to DOPA decarboxylase activity, indicating that pyridoxal phosphate may be more tightly bound to DOPA decarboxylase than to 5HTP decarboxylase. These results, indicating that pyridoxine deficiency has differential effects on the activity of AADC, are consistent with our earlier observation of non-parallel changes in dopamine and serotonin content in various brain regions of the pyridoxine-deficient rat.     

Influence of B vitamins on binding properties of serotonin receptors in the CNS of rats

Summary Treatment of normal adult rats with pyridoxine or a B-vitamin mixture resembling Neurobion^® 1 led to an increase in serotonin content of various brain areas and to a decrease in the number of serotonin S₂ receptors. The results indicate that the pyridoxal phosphate level in regions of the brain regulates the extent of decarboxylation of 5-hydroxytryptophan, the precursor of serotonin. The results also suggest a continuum from deficiency in pyridoxine to treatment of animals with a moderate excess of pyridoxine which is reflected in the synthesis and secretion into the synaptic cleft of the neurotransmitter serotonin.     

Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats

Anxiety is a symptom reflecting the dysregulation of monoaminergic neurotransmitters which may be modulated by estrogen. In our current study, we investigated the effects of chronic estrogen administration (10 microg/kg, s.c. for 4 weeks) on anxiety-like behavior using the elevated plus-maze with the corresponding changes of monoamines in the brain regions contributing to anxiety. The behavioral test revealed that estrogen-treated rats (Ovx+E(2)) spent more time in the open arm of the maze as well as a higher time/entry ratio in open arms than ovariectomized (Ovx) rats, indicating an anxiolytic property of estrogen. The increase in open arm time corresponded to an increase in uterine weight, indicated a correlation between the function of estrogen and its anxiolytic effect. Measurements of brain monoamines following estrogen treatment revealed decreases in norepinephrine, dopamine and serotonin in all of the brain regions studied, which also lead to an increase in turnover rates. The concentrations of norepinephrine in caudate putamen, of dopamine in nucleus accumbens, of serotonin in frontal cortex, hippocampus, caudate putamen, nucleus accumbens, and substantia nigra and of the serotonin metabolite, the 5-hydroxyindolacetic acid in substantia nigra of Ovx+E(2) rats were significantly lower than those of Ovx rats. Interestingly, the uterine weight was negatively correlated with the changes of dopamine and serotonin (with the exception of the hippocampus), suggesting a regulatory role of estrogen on these systems. From these data, we concluded that, in fact, there is a relationship between estrogen and monoamines (i.e. serotonin, dopamine) in modulating the anxiety-like behaviors in female rats.     

Sex-dependent changes in anxiety, memory, and monoamines following one week of stress

Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.     

Serotonergic receptor upregulation in cerebral cortex and down regulation in brainstem of streptozotocin induced diabetic rats: Antagonism by pyridoxine and insulin

Insulin secretion and glucose homeostasis is implicated through serotonergic function. Pyridoxine is involved in decarboxylation step in synthesis of serotonin. The present study was carried out to find the role of insulin in combination with pyridoxine on the concentrations of 5-HT and 5-HIAA, 5-HT receptor binding, 5-HTT gene expression and immunohistochemistry studies in the cerebral cortex and brainstem of streptozotocin induced diabetic rats. 5-HT content showed a significant decrease with a significant increase in 5-HIAA in cerebral cortex (p < 0.01) and brain stem (p < 0.001) in diabetic rats. 5-HT receptor binding parameters, B_max and K_d, showed a significant decrease (p < 0.001) in diabetic rats in cerebral cortex whereas in brainstem it showed a significant increase (p < 0.001) compared to control. Gene expression studies of 5-HTT in cerebral cortex showed a significant down regulation (p < 0.001) and in brainstem an upregulation (p < 0.001) in diabetic rats compared to control. Insulin and pyridoxine treatment to diabetic rats reversed the 5-HT content, B_max, K_d and gene expression of 5-HTT confirmed by immunohistochemistry studies in cerebral cortex and brainstem to near control. Thus our results suggest that pyridoxine along with insulin has a role in the regulation of insulin synthesis and release through serotonergic function which has clinical significance in the management of diabetes.     

Monoamine levels and monoamine oxidase activity in different regions of rat brain as a function of age

The levels of norepinephrine, dopamine, 5-hydroxytryptamine and the activity of monoamine oxidase were estimated in cerebral cortex, cerebellum, medulla oblongata, hypothalamus, striatum and midbrain of 21-day-old, 3-, 6-, 12- and 24-month-old male albino rats of Wistar strain. No significant change with age was found in the levels of all the three amines in cerebral cortex and cerebellum, while medulla oblongata showed a significant decrease of all the amines by 24 months of age. Hypothalamic norepinephrine, dopamine and striatal dopamine showed a highly significant decrease by 24 months of age, whereas 5-hydroxytryptamine in hypothalamus, norepinephrine and 5-hydroxytryptamine in striatum and dopamine in midbrain did not show any appreciable change with age. Monoamine oxidase activity in all the regions except cerebellum showed a significant increase by 24 months of age compared to 3- and 6-month-old rats.     

On the appearance of monoamines in the sympathetic systems and the chromaffin tissue in the mouse embryo

Summary The early development of the sympathetic chain with adjacent ganglia and chromaffin tissue and the appearance of monoamines in these organs was mapped with the Falck-Hillarp fluorescence technique. In the 11 days embryo a few fluorescent cells are found lateral to the aorta in the thoracal region. During the following days the sympathetic chain with segmentally arranged ganglia develops. The cells have a weak to medium fluorescence intensity. A migration of fluorrescent cells ventral to the sympathetic chain can be seen in embryos 12 days old. These migrating cells will later form the prevertebral ganglia and the chromaffin tissue. At the 14 days old stage the adrenal medulla and the paraganglia can be distinguished, while the prevertebral plexa are differentiated in the 15 days old embryo.The chromaffin tissue has a brilliant fluorescence but in the neonatal stages parts of the paraganglia show a weaker fluorescence and though they have their largest extension around the 10th day of postnatal life a brilliant fluorescence can be seen only in a smaller part of the ganglia at that time. The paraganglia are reduced in adult stages.     

Comparison of effects of monoamines on transmission in spinal pathways from group I and II muscle afferents in the cat

Summary The actions of noradrenaline (NA) and 5-hydroxytryptamine (5-HT; serotonin) were compared with those of L-3,4-dihydroxyphenylalanine methyl ester (Methyl-L-DOPA) on transmission to spinal interneurones in mid-lumbar (L4 and L5) segments of the cat spinal cord. The drugs were applied ionophoretically and their effects were tested on monosynaptic field potentials evoked by nerve impulses in hindlimb group I and group II muscle afferent fibres and on responses of interneurones with synaptic input from these fibres. Of field potentials recorded at various locations, both NA and 5-HT depressed those evoked from group II fibres in the intermediate and ventral horn regions of the spinal cord but not, or only occasionally, in the dorsal horn. Field potentials of group I origin were not depressed. The tested interneurones were located where group II field potentials were affected. NA, 5-HT and Methyl-L-DOPA depressed responses to electrical stimulation of group II fibres but not responses evoked by group I fibres. The depression consisted of an increase in the latency and a decrease in the number of action potentials evoked by the stimuli. All three drugs were also found to decrease the amplitude of intracellularly recorded monosynaptic EPSPs of group II origin but not of monosynaptic EPSPs evoked in the same neurones by group I fibres. Interneuronal firing induced by DL-homocysteic acid was depressed as effectively as responses to electrical stimulation of peripheral nerves. The possibility of presynaptic and/or postsynaptic mechanisms of the selective depression of synaptic actions of group II origin are discussed.     

Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is characterized by monoaminergic and hypothalamic-pituitary-adrenal (HPA)-axis abnormalities. Understanding monoamine-HPA-axis responses following stress and restress may provide a greater understanding of the neurobiology of PTSD and of its treatment. Hippocampal and frontal cortex serotonin, noradrenaline and dopamine, plasma corticosterone and aversive behavior were studied in rats on day 1 and day 7 post acute stress (AS = sequential restraint stress, swim stress and halothane exposure), and on day 1 and day 7 post restress (RS = swim stress). After AS, there was an early increase in both avoidant behavior and corticosterone (1 h after stress), with subsequent normalisation (day 7), suggesting an adequate adaptive response to the stressor. However, restress (RS) evoked a significant early HPA-axis hyporesponsiveness (1 h after RS) and a later significant increase in avoidant behavior on day 7 post RS. Hippocampal serotonin, noradrenaline and dopamine concentrations were unchanged 1 h post AS, but were significantly raised on day 7 post AS. Restress, however, reduced serotonin and noradrenaline levels 1 h after and on day 7 post RS, respectively, while dopamine was unchanged. In the frontal cortex only dopamine levels were altered, being significantly elevated 1 h after AS, and reduced on day 7 post RS. AS and RS thus differently effect the HPA-axis, evoking regional-specific brain monoamine changes that underlie maladaptive behavior and other post stress-related sequelae.     

Ontogeny of brain monoamines in lean and obese female Zucker rats

Differences in monoamine and metabolite levels were previously observed between lean and obese 16 week-old female Zucker rats. In order to test whether these variations exist initially in young animals, catecholamines (CA), serotonin (5-HT) and some of their metabolites were assayed in brain areas of Zucker rats between 5 and 16 weeks of age. The levels of most compounds in all areas studied increased with age in both groups. At 5 weeks of age, there was no difference between lean and obese rats. At 8 weeks, a reduction of dopamine (DA) metabolites appeared in the striatum and cortex of obese rats and persisted up to 16 weeks. A reduction of the 5-HT metabolite, 5-hydroxyindolacetic acid (5-HIAA), occurred at 8 weeks only. At 16 weeks, increases of DA and 5-HT in the hypothalamus and decreases of norepinephrine (NE), 5-HT and 5-HIAA in the hippocampus appeared. These data suggest that the development of obesity occurs before any monoamine alterations.     

Effects of carotid sinus nerve transection on changes in neuropeptide Y and indolamines induced by long-term hypoxia in rats

 Long-term hypoxia induces changes in neuropeptide-Y-like immunoreactivity (NPY-LI) and/or in the content of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) at the central level. To determine whether these alterations depend on the integrity of carotid body (CB) chemoreceptors, intact rats or those whose carotid sinus nerve was transected (CSNT) were exposed to hypoxia (10% O₂) or to normoxia for 14 days. Thereafter, NPY-LI, 5-HT and 5-HIAA levels in discrete brain regions were determined. The increase in NPY-LI in the ventrolateral medulla oblongata (VLM) of intact hypoxic rats was mostly abolished after CSNT and therefore is mainly mediated by CB chemoreceptors. In contrast, other hypoxia-induced changes were similar or even enhanced in CSNT as compared to intact rats and therefore do not depend on the integrity of CB chemoreceptors. This was the case for the increase of NPY-LI in the striatum and the caudal dorsomedian medulla oblongata (DMM), as well as for all the changes in 5-HT and 5-HIAA in the DMM, the VLM, the raphe nuclei, the striatum and the frontal cortex. We propose that long-term hypoxia alters brain NPY-LI and indolamine content through the stimulation of CB chemoreceptors or ancillary chemoreceptors, as well as through local biochemical or morphological mechanisms. Received: 5 May 1998 / Received after revision: 27 July 1998 / Accepted: 3 September 1998     

Behavioral lateralization in the T-maze and monoaminergic brain asymmetries

Recently we have reported a marked rat lateralization in the T-maze choice. The present study examines the relationship between the ascending monoaminergic systems and the T-maze behavioral asymmetry. There were no significant differences for serotonin or norepinephrine between the T-maze preferred and non-preferred brain sides in the s. nigra, ventral tegmental area, striatum, acumbens, frontal lobe or hippocampus. Only in the hippocampus was dopamine concentration significantly greater for the brain site ipsilateral to the T-maze choice side. Previously, we reported that both apomorphine, a dopamine receptor agonist, and 6-hydroxydopamine lesion in the medial forebrain bundle of the catecholaminergic neurons affect the T-maze asymmetry; we therefore suggested that the T-maze choice could be related with the ascending dopaminergic systems. The present data strongly support this hypothesis and suggest that the DA cells involved in the spatial asymmetry in the T-maze are included in the dopaminergic mesohippocampal system.     

Inhalative formaldehyde exposure enhances aggressive behavior and disturbs monoamines in frontal cortex synaptosome of male rats

Formaldehyde (FA) exposure is known to be toxic to central nervous system of mammals. In this paper, we evaluated the aggressive behavior after repetitive inhalative FA exposure to male SD rats, and explored the potential mechanism. The rats, ranging from 160 to 180 g, were randomly designated into the orchiectomized (ORX) group, the control and the inhalative FA treatment groups. Eight rats underwent orchiectomy surgery. Three days after the orchiectomy surgery, the inhalative FA (monitored to be 13.5 ± 1.5 ppm) treatment began. We found that the male SD rats, those were exposed to FA showed more aggressive behavior compared to the control. And the ORX rats exhibited less aggressive behavior than the control. Furthermore, the dopamine increased and 5-HT decreased significantly in frontal cortex synaptosome after inhalative FA treatment. It is the first to evaluate aggressive behavior and identified monoamines disturbances in the frontal cortex synaptosome after the repetitive inhalative FA exposure to rodents.     

Both long and brief maternal separation produces persistent changes in tissue levels of brain monoamines in middle-aged female rats

Adverse experiences early in life are associated with an increased incidence of later psychopathology including depression. Based on evidence that dysfunction of central monoaminergic systems is involved in the pathophysiology of depression, we hypothesize that early adversity could negatively affect these systems. To test this we have investigated the effects of maternal separation, which has been suggested to model early-life stress and the development of a depression-like syndrome in the rat, on brain monoaminergic systems. Since depression is more common in women and the risk of developing this disorder appears to increase with age, we have studied such effects in middle-aged female rats. Rat pups were separated for 180 min (long maternal separation; LMS) or 15 min (brief maternal separation; BMS, often referred to as neonatal handling) twice daily for 2 weeks postpartum. An animal facility-reared (AFR) group was also included. At 15 months of age tissue levels of monoamines and their metabolites in several different brain regions were analyzed. In the LMS females tissue levels of both 5-HT and 5-hydroxyindole acetic acid (5-HIAA) were significantly increased in the dorsal raphe nucleus, and 5-HIAA and homovanillic acid levels were also elevated in the nucleus accumbens as compared with AFR and BMS rats. In the cingulate cortex both LMS and BMS decreased noradrenaline (NA) levels, although this effect was more pronounced in the LMS rats. On the other hand, BMS decreased 5-HT, 5-HIAA, dopamine (DA) as well as NA levels in the amygdala and produced an increase in DA levels in response to acute stress in the hypothalamus, an effect not seen in AFR rats. Our results demonstrate that LMS produced persistent alterations in both serotonergic, noradrenergic and dopaminergic systems in brain regions that have been suggested to be implicated in the pathophysiology of depression. In addition, BMS affected brain monoaminergic levels mainly in the amygdala.