Brain Norepinephrine Concentrations Research Articles

3 The impact of early-life cecal microbiota transplantation on injurious behaviors in egg-laying chickens

Abstract Injurious behaviors in laying hens are a critical issue facing the poultry egg industry. Recent studies have shown that the gut microbiota influences host brain function and behavioral characteristics in humans and various animals. In laying hens, it has been reported that injurious behaviors (such as aggression, feather pecking and cannibalism) are associated with dysregulation of the microbiota-gut-brain axis. To further interrogate the role of the microbiota-gut-brain axis on bird behavior, we used two inbred layer chicken lines, 63 and 72 (line 72 displays more aggressive behavior), and transferred pooled cecal contents from either line to day of hatch chicks. Cecal microbiota transplantation (CMT) from each line was conducted once daily, by gavage, from d 1 to 10, then boosted once weekly from wk 3 to 5. We hypothesized that the cecal microbiota composition and animal behavior in recipient birds would be similar to that of their donor animals because of the microbiota-gut-brain axis. Microbial communities were compared using 16S rRNA gene amplicon sequencing, behavior was recorded in home cages as well as in paired aggression tests, and physiological measurements were taken from brain tissue and blood to measure levels of neurotransmitters and immune function. When examining the differences in the donor birds, hypothalamic serotonin and tryptophan concentrations were greater for line 63 compared with line 72 birds (P < 0.05). Plasma corticosterone, heterophil/lymphocyte ratios, and central norepinephrine concentrations were less for line 63 birds (P < 0.05). Cecal microbial diversity was not statistically different between the lines, but many bacterial taxa were differentially abundant between the two lines. After cecal transplantation, 63-CMT (recipient) birds displayed less aggressive behavior with a greater hypothalamic serotonergic activity at wk 5, similar to donor birds. Correspondingly, two amplicon sequence variants (ASVs) belonging to Lachnospiraceae and one Ruminococcaceae UCG-005 ASV were positively correlated with the concentrations of brain tryptophan and serotonin, respectively. Along with greater aggression, 72-CMT birds seemed to have greater physical growth traits (increased body weight, ileal villus/crypt; P ≤ 0.05), but decreased concentrations of brain norepinephrine and dopamine, and the greatest ileal serotonin turnover in the ileum at wk 5 (P < 0.05). ASVs belonging to Mollicutes RF39 and GCA-900066225 in 72-CMT birds were negatively correlated with the brain 5-hydroxyindoleacetic acid (5-HIAA) at wk 5, and one Bacteroides ASV was negatively correlated with plasma serotonin at wk 16. Meanwhile, 63-CMT birds potentially had better gut health and immune function (greater concentrations of ileal mucosal secretory IgA, plasma IL-10; P < 0.05). These results suggest linkages among serotonergic activity, stress response, innate immunity, and gut microbiota populations and that CMT could be a novel strategy for reducing aggressive behavior through regulating signaling along the microbiota-gut-brain axis.

Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10mg/kg Al2 O3 NP (diameter: 24nm [transmission electron microscope], hydrodynamic diameter: 148nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

The effects of bupropion on hybrid striped bass brain chemistry and predatory behavior

Increased use of antidepressants has led to an increase in their detection in final treated wastewater effluents and receiving streams. Antidepressants are intended to modify human behavior by altering brain chemistry, and because of the high functional conservation of antidepressant target receptors in vertebrates, aquatic organisms may be at risk. The antidepressant bupropion is designed to alter brain norepinephrine and dopamine concentrations in humans. The objective of the present study was to understand if alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass (Morone saxatilis × Morone chrysops) brain by bupropion would alter this predator's ability to capture prey. The authors exposed hybrid striped bass to bupropion in a static system for 6 d, followed by a 6-d recovery period. During the present study's 12-d experiment, each hybrid striped bass was fed 4 unexposed fathead minnows every 3 d, and the time it took the hybrid striped bass to consume each of those 4 fathead minnows was quantified. After each feeding event, hybrid striped bass brains were harvested and analyzed for changes in several brain neurotransmitter concentrations, including serotonin, norepinephrine, dopamine, and many of their metabolites. Although bupropion altered the concentration of dopamine and many of the dopaminergic neurotransmitter metabolite concentrations in the brains on day 3 of the exposure, it did not alter the time to capture prey. This suggests that alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass brain does not alter a predator's ability to capture prey. Environ Toxicol Chem 2016;35:2058-2065. © 2016 SETAC.

Activation of brain serotonergic system by repeated intracerebral administration of 5-hydroxytryptophan (5-HTP) decreases the expression and activity of liver cytochrome P450

Our recent studies suggest that brain serotonergic system may be involved in the neuroendocrine regulation of cytochrome P450 expression. Intracerebral injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine affected serum hormone concentration and increased the expression and activity of the hormone-dependent isoforms CYP1A1/2, CYP2C11 and CYP3A1. Therefore, the aim of the present study was to investigate the effect of stimulation of brain serotonergic system on cytochrome P450 expression in the liver. The serotonin precursor 5-hydroxytryptophan (5-HTP) was injected for 5 days to the lateral ventricles of rat brain. Afterwards, the brain concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid 5-HIAA, serum hormone levels and liver cytochrome P450 expression and activity were measured. 5-HTP potently increased the concentration of serotonin and its metabolite 5-HIAA in all the brain structures studied including the hypothalamus. The brain concentrations of noradrenaline or dopamine and its metabolites were not changed in that structure. At the same time, a significant decrease in the serum concentration of the growth hormone and an increase in that of thyroxine were observed. In the liver, the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A was diminished, which positively correlated with a decrease in the respective CYP protein levels and a reduction in the mRNA levels of CYP1A2, CYP2A2, CYP2C11, CYP3A1 and CYP3A2. The obtained results provide evidence to prove that brain serotonergic system negatively regulates liver cytochrome P450 expression via endocrine system and suggest mechanisms by which this enzyme may be regulated by drugs with a serotonergic profile such as antidepressants.

Neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines in the management of Alzheimer's disease

The present study was conducted to evaluate the neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines along with its antioxidant status. Scopolamine and natural aging were employed as an experimental amnesia inducing agents. The tested dose of Mangiferin (40, 20 and 10mg/kg) significantly improved the learning ability and retention of learned memory in Elevated plus Maze and Passive Shock Avoidance exteroceptive behavioural models. Pre-treatment with Mangiferin restored increased whole brain acetylcholinestrease, lipid peroxidation and reduced glutathione due to scopolamine and natural aging. Whole brain increased dopamine and nor-adrenaline content in brain in the inducing groups were reversed by tested doses of Mangiferin insignificantly. Moreover the cerebroprotective effect of Mangiferin was well supported by photomicrographs of Hippocampus of brain, where as severity of cell damage, number of pyknotic black neurons, formation of karyorrhexis, karyolysis and number of neuronal cell death were less comparative to scopolamine group. The observed effects of Mangiferin claim that it would be worthwhile to utilize in the treatment of Alzheimer's disease.

The case of the water polo player's shoulder—Clinical reasoning, assessment and management

of central neurotransmission in the heat might contribute to elucidate the mechanisms of fatigue. Studies from our lab showed that DA significantly enhanced performance, coinciding with the attainment of high core temperatures and heart rates, without any change in thermosensation and in the perception of effort. 2,3 In contrast, increased brain concentration of Noradrenaline (NA) strongly decreased performance in the heat and no effect of 5-HT could be detected. 4,5 Thermal regulation appears to be an important factor that will mainly be influenced by brain DA and NA in the PO/AH, although the exact role of other neurotransmitter systems is not clear so far. 6 It is very unlikely that one neurotransmitter system is responsible for the appearance of central fatigue. Most probably central fatigue is caused by a complex interplay between the different neurotransmitters systems, with the most important role for the catecholamines DA and NA. Although work to date has given us clear observations on external behavioural changes after pharmacological interventions, the exact role of the different brain areas linked to exercise capacity and thermoregulation have yet to be elucidated.

Delayed Increase of Brain Noradrenaline After Acute Footshock Stress in Rats

Several lines of evidence strongly suggest that accumulation of noradrenaline (NA) in the brain may underlie the hyperarousal symptoms experienced in post-traumatic stress disorder. In animal experiments, however, the effect of stress on NA content appears complex; acute stress reduces the level, while chronic stress tends to increase it. To explain this discrepancy, it is necessary to observe the long-term effects of acute stress on NA metabolism in the brain. In this study, rats were exposed to intermittent intense footshock stress for 1 h, and the brain NA content was measured for 7 days after the stress stimulus. Hypothalamic NA content was immediately reduced and recovered within 24 h. However, a significant NA increase was observed 7 days after the footshock. In the cerebral cortex and hippocampus, an increase in NA content was observed 1 day after the stress and lasted for at least 7 days. The fact that the content of 3-methoxy-4-hydroxyphenylglycol, a major NA metabolite, only transiently increased in all these regions possibly reflects NA release. These results indicate that increase in the brain NA content can be induced by acute stress, though its emergence is delayed. Importantly, this suggests that both acute and chronic stress may lead to NA accumulation under the same mechanism.

The novel nicotinic receptor antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [ 3H]norepinephrine overflow from rat hippocampal slices

Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC 50 = 2 nM) inhibits nicotine-evoked striatal [ 3H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [ 3H]NE release from rat hippocampal slices (EC 50 = 50 μM). bPiDDB inhibited (IC 50 = 430 nM; I max = 90%) [ 3H]NE release evoked by 30 μM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the α7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [ 3H]NE release (IC 50 = 31 and 275 nM, respectively; I max = 91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [ 3H]DA release from striatum than those mediating nicotine-evoked [ 3H]NE release from hippocampus.

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Noradrenaline modulates neuronal responses to GABA in vestibular nuclei

The effects of noradrenaline (NA) on the inhibitory responses to GABA were studied in vivo in neurons of the vestibular nuclei of the rat using extracellular recordings of single unit electrical activity and a microiontophoretic technique of drug application in loco. NA application influenced GABA-evoked inhibitions in 82% of tested neurons, depressing them in 42% and enhancing them in 40% of cases. The more frequent action of NA on GABA responses was depressive in lateral and superior vestibular nuclei (50% of neurons) and enhancing in the remaining nuclei (56% of neurons). The most intense effect of NA application was the enhancement of GABA responses induced in a population of lateral vestibular nucleus neurons, characterized by a background firing rate significantly higher than that of other units. The alpha2 noradrenergic receptor agonist clonidine mimicked the enhancing action of NA on GABA responses; this action was blocked by application of the specific alpha2 antagonist yohimbine. The beta adrenergic agonist isoproterenol induced either depressive or enhancing effects on GABA responses; the former more than the latter were totally or partially blocked by application of the beta antagonist timolol. It is concluded that NA enhances GABA responses by acting on noradrenergic alpha2 and to a lesser extent beta receptors, whereas depressive action involves beta receptors only.These results confirm the hypothesis that the noradrenergic system participates in the regulation of the vestibulospinal and the vestibulo-ocular reflexes and suggest that conspicuous changes of NA content in brain due to aging or stress could lead to a deterioration in the mechanisms of normal vestibular function.

The blood-brain barrier for catecholamines — Revisited

Although it is well-recognized that catecholamines are generally unable to penetrate the developed blood-brain barrier (BBB) to gain entry into brain, except at circumventricular sites where the BBB is absent or deficient, ontogenetic development of this barrier seems to have escaped systematic study. To explore BBB development, several approaches were used. In the first study rats were treated once on a specific day of postnatal ontogeny, as early as the day of birth, with the neurotoxin 6-hydroxydopamine (6-OHDA; 60 mg/kg), and then terminated in adulthood for regional analysis of endogenous norepinephrine (NE) content of brain. In another study, rats were treated once, on a specific day of postnatal ontogeny, with the BBB-permeable neurotoxin 6-hydroxydopa (6-OHDOPA; 60 mg/kg) following pretreatment with the BBB-impermeable amino acid decarboxylase inhibitor carbidopa (100 mg/kg IP), then terminated in adulthood for regional analysis of endogenous NE content of brain. In the third study rats were treated once, on a specific day of postnatal ontogeny, with the analog [3H]metaraminol, and terminated 1 hour later for determination of regional distribution of tritium in brain. On the basis of [3H]metaraminol distribution and NE depletions after neurotoxin treatments, it is evident that the BBB in neocortex, striatum, cerebellum and other brain regions forms in stages over a period of at least 2 weeks from birth. Moreover, because the BBB consists of several element (physical-, ion-restrictive-, and enzymatic-barrier), the method employed will derive data mainly applicable to the targeted aspect of the barrier, which may or may not necessarily coincide with elements of the barrier that have a different rate of ontogenetic development. Accordingly, it is evident that some aspects of physical- and ion-restrictive elements of the BBB form within approximately the first week after birth in rat neocortex and striatum, while enzymatic elements of the BBB form more than than 2 weeks later. Regardless, the BBB forms at earlier times in forebrain vs hindbrain regions.

Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain

Vagus nerve stimulation therapy, effective for treatment-resistant epilepsy, has recently been approved also for treatment-resistant depression; nevertheless, the molecular mechanism(s) underlying its therapeutic action remains unclear. Given that neurotrophic factors and monoamines could play a crucial role in the pathophysiology of depression, we tested whether vagus nerve stimulation increases the expression of brain-derived neurotrophic factor, fibroblast growth factor, and nerve growth factor as well as the concentration of norepinephrine in the rat brain. Rats were implanted with a vagus nerve stimulator device and the effects of acute stimulation were evaluated on the growth factors mRNA levels and norepinephrine concentration by ribonuclease protection assay and microdialysis, respectively. We found that acute vagus nerve stimulation increased the expression of brain-derived neurotrophic factor and fibroblast growth factor in the hippocampus and cerebral cortex, decreased the abundance of nerve growth factor mRNA in the hippocampus, and, similar to the antidepressant drug venlafaxine, increased the norepinephrine concentration in the prefrontal cortex. This study demonstrates that acute vagus nerve stimulation triggers neurochemical and molecular changes in the rat brain involving neurotransmitters and growth factors known to play a crucial role in neuronal trophism. These new findings contribute to the elucidation of the molecular mechanisms underlying the therapeutic actions of vagus nerve stimulation in both treatment-resistant depression and epilepsy.

The effect of sevoflurane and propofol on cerebral neurotransmitter concentrations during cerebral ischemia in rats.

Sevoflurane and propofol are neuroprotective possibly by attenuating central or peripheral catecholamines. We evaluated the effect of these anesthetics on circulating catecholamines and brain neurotransmitters during ischemia in rats. Forty male Sprague-Dawley rats were randomly assigned to one of the following treatment groups: fentanyl and N(2)O/O(2) (control), 2.0% sevoflurane, 0.8-1.2 mg x kg(-1) x min(-1) of propofol, and sham-operated rats with fentanyl and N(2)O/O(2). Ischemia (30 min) was produced by unilateral common carotid artery occlusion plus hemorrhagic hypotension to a mean arterial blood pressure of 32 +/- 2 mm Hg. Pericranial temperature, arterial blood gases, and pH value were maintained constant. Cerebral catecholamine and glutamate concentrations, sampled by microdialysis, and plasma catecholamine concentrations were analyzed using high-pressure liquid chromatography. During ischemia, circulating catecholamines were almost completely suppressed by propofol but only modestly decreased with sevoflurane. Sevoflurane and propofol suppressed brain norepinephrine concentration increases by 75% and 58%, respectively, compared with controls. Intra-ischemia cerebral glutamate concentration was decreased by 60% with both sevoflurane and propofol. These results question a role of circulating catecholamines as a common mechanism for cerebral protection during sevoflurane and propofol. A role of brain tissue catecholamines in mediating ischemic injury is consistent with our results. During incomplete cerebral ischemia, the neuroprotective anesthetics sevoflurane and propofol suppressed cerebral increases in norepinephrine and glutamate concentrations. In contrast, propofol, but not sevoflurane, suppressed the ischemia-induced increase in circulating catecholamines to baseline levels. The results question a role for plasma catecholamines in cerebral ischemic injury.

Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma

An imbalance between dopaminergic and noradrenergic systems is implicated in hyperactivity disorders such as attention deficit hyperactivity disorder (ADHD) and Tourette syndrome. We have identified the mouse mutant coloboma as an animal model for examining the neurological basis of hyperactivity. Coloboma mice exhibit spontaneous locomotor hyperactivity that is a result of a reduction in SNAP-25, a presynaptic protein that regulates exocytotic release. These mice exhibit an imbalance in catecholamine regulation whereby brain dopamine (DA) utilization is reduced while norepinephrine (NE) concentrations are significantly increased. Further, calcium-dependent NE release was also increased in these hyperactive mice, despite the reduction in SNAP-25. To determine the role of NE in the expression of hyperactivity, brain NE concentrations were reduced using the specific noradrenergic neurotoxin DSP-4 [ N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine hydrochloride]. DSP-4 treatment specifically decreased NE concentrations, but had no effect on brain DA or serotonin. Depletion of NE by DSP-4 through either systemic or central administration significantly reduced the locomotor activity in coloboma mice. These results suggest that NE regulation in the CNS plays an important role in the expression of hyperactivity in this mouse model, consistent with results of human studies and current models of ADHD.

Effect of the α2-Agonist Dexmedetomidine on Cerebral Neurotransmitter Concentrations during Cerebral Ischemia in Rats

This study investigates whether neuroprotection seen with dexmedetomidine is associated with suppression of peripheral or central sympathetic tone. Thirty fasted male Sprague-Dawley rats were intubated and ventilated with isoflurane and N2O/O2 (fraction of inspired oxygen = 0.33). Catheters were inserted into the right femoral artery and vein and into the right jugular vein. Cerebral blood flow was measured using laser Doppler flowmetry. Bilateral microdialysis probes were placed into the cortex and the dorsal hippocampus. At the end of preparation, the administration of isoflurane was replaced by fentanyl (bolus: 10 microg/kg; infusion: 25 microg x kg(-1) x h(-1)). Animals were randomly assigned to one of the following groups: group 1 (n = 10): control animals; group 2 (n = 10): 100 microg/kg dexmedetomidine administered intraperitoneally 30 min before ischemia; group 3 (n = 10): sham-operated rats. Ischemia (30 min) was produced by unilateral carotid artery occlusion plus hemorrhagic hypotension to a mean arterial blood pressure of 30-35 mmHg to reduce ipsilateral cerebral blood flow by 70%. Pericranial temperature, arterial blood gases, and pH were maintained constant. Cerebral catecholamine and glutamate concentrations and plasma catecholamine concentrations were analyzed using high-performance liquid chromatography. During ischemia, dexmedetomidine suppressed circulating norepinephrine concentrations by 95% compared with control animals. In contrast, brain norepinephrine and glutamate concentrations were increased irrespective of dexmedetomidine infusion before ischemia. The current data show that the increase of circulating catecholamine concentrations during cerebral ischemia was suppressed with dexmedetomidine. In contrast, dexmedetomidine does not suppress elevation in brain norepinephrine and glutamate concentration associated with cerebral ischemia. This suggests that the neuroprotective effects of dexmedetomidine are not related to inhibition of presynaptic norepinephrine or glutamate release in the brain.

Effect of atenolol on cadmium-induced testicular toxicity in male rats

Cadmium-induced stress adversely affects testicular activity and causes sympathetic stimulation. To investigate the effect of atenolol, a β-adrenergic receptor blocker, on testicular androgen synthesis after cadmium treatment, adult Sprague-Dawley strain male rats were given a single sc dose of cadmium chloride 0.45 mg/kg BW. Animals were killed on day 3 after treatment. Adrenal weight, adrenal Δ 5-3β-hydroxysteroid dehydrogenase (Δ 5-3β-HSD) activity, serum corticosterone, and brain noradrenaline were increased significantly while testicular Δ 5-3β-HSD and 17β-HSD activities, serum testosterone, and accessory sex organs weight were decreased. Oral coadministration of atenolol at a dose of 2.0 mg/kg body weight for 3 days resulted in complete protection of adrenal Δ 5-3β-HSD, testicular Δ 5-3β-HSD, and 17β-HSD activities, adrenal weight, serum corticosterone, and serum testosterone when compared with cadmium-only group and there were no significant differences in these parameters from the vehicle control values. Simultaneous administration of cadmium and atenolol also protected brain noradrenaline content and reduced the rise of testicular cadmium concentration. All the parameters were similar to control levels in rats treated with atenolol alone. We conclude that atenolol may protect testicular androgen synthesis by inhibiting the action of noradrenaline on testicular Leydig cells and adrenocortical hyperactivity in cadmium-treated rats.

Brain alterations in depression.

This article describes a number of studies by our research group to find brain structures that may be involved in the symptoms of idiopathic depression, depression in Alzheimer's disease and depression in Parkinson's disease. Until recently, idiopathic depression has generally been related to deficiencies of aminergic systems. In Alzheimer patients we found a strong decrease in the number of neurons in the locus coeruleus and brain noradrenaline concentrations, but in depressed Alzheimer patients we did not find an extra de crease. This is in agreement with the finding that there is no cell loss in the locus coeruleus in idiopathic depression. We did find, however, that the number of corticotropin-releasing hormone-, vasopressin- and oxytocin expressing neurons, the number of corticotropin-releasing hormone neurons co-expressing vasopressin and the amount of corticotropin-releasing hormone -mRNA in idiopathic depression were strongly increased in the paraventricular nucleus of the hypothalamus. This result supports the hypothesis on the pathogenetic involvement of the hypothalamo-pituitary-adrenal axis in depression and is of clinical relevance, since it may provide a theoretical rationale for antidepressive therapy with CRH antagonists.

Effect of intracerebral norepinephrine depletion on outcome from severe forebrain ischemia in the rat

Manipulations of plasma catecholamine concentrations influence outcome from ischemic brain insults. It has been suggested that these effects are mediated by influences on brain catecholamine concentrations. This study examined whether major changes in brain norepinephrine concentrations can alter outcome from severe forebrain ischemia. Sprague–Dawley rats were administered 50 mg/kg i.p. N-(chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4) or were left untreated (control). One week later, these rats were subjected to either 7 or 8 min of normothermic forebrain ischemia (bilateral carotid occlusion and MABP=30 mmHg) and allowed to recover for 4 days. Histologic damage was then evaluated. In other control and DSP-4-treated animals, hippocampal microdialysate norepinephrine concentrations were measured before, during and after 8 min of forebrain ischemia. Norepinephrine concentrations were also determined in brain homogenates from non-ischemic DSP-treated and control rats. A 95% depletion of norepinephrine was observed in brain homogenates from non-ischemic DSP-4-treated rats compared with control. During ischemia, microdialysate norepinephrine concentrations increased in control but not in DSP-4-treated rats ( P=0.002). For plasma, intra-ischemic epinephrine concentrations increased 8–10-fold and returned to baseline values post-ischemia with no differences between groups. Plasma norepinephrine values remained unchanged in both groups. Histologic damage resulting from either 7 or 8 min of ischemia in hippocampal structures, caudoputamen, and neocortex was similar between DSP-4-treated and control groups. This study could not identify any effect of major changes in brain norepinephrine concentrations on ischemic brain damage. These data indicate that peripheral catecholamine effects on near-complete forebrain ischemic outcome are unlikely to be mediated by effects on central catecholamine concentrations.

Pre-ischemic depletion of brain norepinephrine decreases infarct size in normothermic rats exposed to transient focal cerebral ischemia

This study examined the importance of brain norepinephrine concentration on outcome from a focal ischemic insult. Fasted temperature-controlled male Wistar rats pretreated with DSP-4, ( N-(chloroethyl)- N-ethyl-2-bromobenzylamine), to selectively deplete brain norepinephrine, were subjected to reversible filament occlusion of the middle cerebral artery for 75 min in the awake state. After 3 days recovery, total infarct volume in DSP-4 treated rats (185±107 mm 3) was reduced vs. untreated control animals (242±71 mm 3, P=0.04). Subcortical infarct volume was also smaller in the DSP-4 group (93±44 vs. 121±28 mm 3, P=0.02). Cortical infarct volume was not statistically different between groups. Neurologic function correlated with infarct-size. These findings suggest that brain norepinephrine affects stroke development either by direct neuronal toxicity and/or through influences on the penumbral circulation. Dampening of the central stress response induced by the onset of stroke may thus be advantageous.

Effects of chronic mild stress (CMS) and imipramine administration, on spleen mononuclear cell proliferative response, serum corticosterone level and brain norepinephrine content in male mice.

There is increasing evidence that stress and emotional reactions produce changes in various immune processes. These changes may be due to alterations of the stress responses endocrine and for autonomic mediating mechanisms. In order to study such effects, the impact of chronic mild stress (CMS) application, and of subsequent imipramine administration were studied on the spleen mononuclear cell proliferative response period. OFI strain male mice were subjected to 4 or 7 weeks of CMS. The effects of these treatments on serum corticosterone levels and hypothalamic and hippocampal norepinephrine (NE) contents were also assessed. Subjects submitted to CMS had a higher spleen mononuclear cell proliferative response after either treatment duration. Imipramine treatment diminished this response enhancement in CMS exposed animals, but did not alter the proliferative responses of control subjects. Serum corticosterone levels, as well as hypothalamic and hippocampal nonrepinephrine contents did not significantly vary between groups. Taken together, these results suggest that CMSs effects on immune reactivity are not related to serum glucocorticoids or NE changes in these locations associated with the hypothalamic-pituitary- adrenocortical (HPA) axis.