Norepinephrine Output Research Articles

Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.

A 4-session written emotional disclosure intervention lowers 6-month sympathoadrenal urinary output in persons living with HIV

ObjectiveWe previously reported that a brief guided written emotional disclosure (WED) intervention resulted in significant reductions in post-traumatic stress disorder (PTSD) symptomology in women, but not men, living with HIV. Levels of 24-hour urinary output of epinephrine (E) and norepinephrine (NE) are shown to be elevated in persons diagnosed with PTSD. The current study tested whether there was an effect for the 4-week WED intervention on 6-month change in urinary E and NE output amongst persons living with HIV. MethodFourteen women and 11 men living with HIV randomized to four 30-min expressive writing sessions of either trauma writing or daily events writing in the parent trial were included based upon collection of urine specimens at baseline, 1-, and 6-months after the intervention. Total volume (µg) and concentration (µg/ml) of urinary E and NE were derived from the specimens as study outcomes. ResultsFour repeated measures analyses of covariance (ANCOVA) were performed to evaluate study outcomes using trauma- versus daily-writing as the between-subject factors and collection time point as the within-subject factor, controlling for age and sex. A group x time interaction was observed wherein the trauma writing treatment group showed a significantly greater decrease in total urinary output, F(2, 46) = 4.03, p = .03, and concentration, F(2, 46) = 4.74, p = .01 of epinepherine. Post-hoc analyses revealed the interaction effect for the total, F(2, 22) = 4.82, p = .03, and concentration, F(2, 22) = 7.57, p = .005, of urinary E output over 6-months was significant for women. Interactions were not observed in urinary NE output. ConclusionsSignificant reductions in the total output and concentration of urinary E were found up to 6-months following initiation of a 4-session guided written emotional disclosure intervention. Profiles of sympathoadrenal activity and response to expressive writing differ between men and women living with HIV. Futher research is need to characterize the putative pathways linking sympathoadrenal response to upstream neurobiological function and downstream inflammatory-immune status in women living with HIV and PTSD.

The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory.

Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.

Mercury in the human adrenal medulla could contribute to increased plasma noradrenaline in aging

Plasma noradrenaline levels increase with aging, and this could contribute to the sympathetic overactivity that is associated with essential hypertension and the metabolic syndrome. The underlying cause of this rise in noradrenaline is unknown, but a clue may be that mercury increases noradrenaline output from the adrenal medulla of experimental animals. We therefore determined the proportion of people from 2 to 104 years of age who had mercury in their adrenal medulla. Mercury was detected in paraffin sections of autopsied adrenal glands using two methods of elemental bioimaging, autometallography and laser ablation-inductively coupled plasma-mass spectrometry. Mercury first appeared in cells of the adrenal medulla in the 21–40 years group, where it was present in 52% of samples, and increased progressively in frequency in older age groups, until it was detected in 90% of samples from people aged over 80 years. In conclusion, the proportion of people having mercury in their adrenal medulla increases with aging. Mercury could alter the metabolism of catecholamines in the adrenal medulla that leads to the raised levels of plasma noradrenaline in aging. This retrospective autopsy study was not able to provide a definitive link between adrenal mercury, noradrenaline levels and hypertension, but future functional human and experimental studies could provide further evidence for these associations.

Overnight/first-morning urine free metanephrines and methoxytyramine for diagnosis of pheochromocytoma and paraganglioma: is this an option?

Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.

Nicotine, cocaine, amphetamine, morphine, and ethanol increase norepinephrine output in the bed nucleus of stria terminalis of freely moving rats.

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2-0.4 mg/kg), cocaine (2.5-5 mg/kg), amphetamine (0.25-0.5 mg/kg), and ethanol (0.5-1.0 g/kg), dose-dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress-induced drug seeking.

The effects of age and ethnicity on the circadian variation of catecholamines and cortisol in employed women

BackgroundWomen employed outside the home in urban settings must adapt to changing circadian microenvironments. The pattern and extent of vasoactive hormone responses to these changes may depend upon age and ethnic background. The purpose of this study was to evaluate the effects of age and ethnicity on the circadian variation of urinary norepinephrine, epinephrine, and cortisol excretion across work, home and sleep microenvironments.MethodsThe subjects of the study were 95 women (38 European-American, age = 35.4 ± 7.4; 28 African-American, age = 33.4 ± 7.9; 12 Asian-American, age = 36.7 ± 9.3 and 17 Hispanic-American age = 31.6 ± 10.9) employed as secretaries, lab technicians or office supervisors in New York City. Variation in the hormones across the microenvironments was evaluated using repeated measures ANCOVA with age group (18–29.9; 30–39.9; 40–49.9) and ethnicity as fixed factors.ResultsThe results show that for norepinephrine and epinephrine, work excretion rates are substantially higher than sleep rates (p < .001), and for epinephrine home rates were higher than sleep rates (p < .001). Work and sleep cortisol excretion rates were also significantly higher than the rate at home, consistent with cortisol’s circadian rhythm. (p < .002). Women in their twenties had substantially lower norepinephrine excretion rates than women over 30 (p < .04). There were also ethnic differences in norepinephrine (p < .04) and epinephrine (p = .11) output with Asian-American women having the lowest and African-American women having the highest rates. This variation is likely related to the ethnic variation in weight. There was no significant variation in cortisol excretion with age or ethnicity.ConclusionThe circadian rates of norepinephrine excretion differ by age and that of both catecholamines differ by ethnicity among women working outside the home. It is speculated that the age variation in norepinephrine may contribute to the development of vasomotor symptoms.

Role of catalpol in ameliorating the pathogenesis of experimental autoimmune encephalomyelitis by increasing the level of noradrenaline in the locus coeruleus.

The endogenous neurotransmitter, noradrenaline, exerts anti-inflammatory and neuroprotective effects in vivo and in vitro. Reduced noradrenaline levels results in increased inflammation and neuronal damage. The primary source of noradrenaline in the central nervous system is tyrosine hydroxylase (TH)-positive neurons, located in the locus coeruleus (LC). TH is the rate-limiting enzyme for noradrenaline synthesis; therefore, regulation of TH protein expression and intrinsic enzyme activity represents the central means for controlling the synthesis of noradrenaline. Catalpol is an iridoid glycoside purified from Rehmannia glutinosa Libosch, which exerts a neuroprotective effect in multiple sclerosis (MS). The present study used an experimental mouse model of autoimmune encephalomyelitis to verify the neuroprotective effects of catalpol. Significant improvements in the clinical scores were observed in catalpol-treated mice. Furthermore, catalpol increased TH expression and increased noradrenaline levels in the spinal cord. In primary cultures, catalpol exerted a neuroprotective effect in rat LC neurons by increasing the noradrenaline output. These results suggested that drugs targeting LC survival and function, including catalpol, may be able to benefit patients with MS.

Morphology, Biochemistry, and Pathophysiology of MENX-Related Pheochromocytoma Recapitulate the Clinical Features.

Pheochromocytomas (PCCs) are tumors arising from neural crest-derived chromaffin cells. There are currently few animal models of PCC that recapitulate the key features of human tumors. Because such models may be useful for investigations of molecular pathomechanisms and development of novel therapeutic interventions, we characterized a spontaneous animal model (multiple endocrine neoplasia [MENX] rats) that develops endogenous PCCs with complete penetrance. Urine was longitudinally collected from wild-type (wt) and MENX-affected (mutant) rats and outputs of catecholamines and their O-methylated metabolites determined by mass spectrometry. Adrenal catecholamine contents, cellular ultrastructure, and expression of phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine, were also determined in wt and mutant rats. Blood pressure was longitudinally measured and end-organ pathology assessed. Compared with wt rats, mutant animals showed age-dependent increases in urinary outputs of norepinephrine (P = .0079) and normetanephrine (P = .0014) that correlated in time with development of tumor nodules, increases in blood pressure, and development of hypertension-related end-organ pathology. Development of tumor nodules, which lacked expression of N-methyltransferase, occurred on a background of adrenal medullary morphological and biochemical changes occurring as early as 1 month of age and involving increased adrenal medullary concentrations of dense cored vesicles, tissue contents of both norepinephrine and epinephrine, and urinary outputs of metanephrine, the metabolite of epinephrine. Taken together, MENX-affected rats share several biochemical and pathophysiological features with PCC patients. This model thus provides a suitable platform to study the pathogenesis of PCC for preclinical translational studies aimed at the development of novel therapies for aggressive forms of human tumors.

Additive contributions of childhood adversity and recent stressors to inflammation at midlife: Findings from the MIDUS study.

We examined the joint contributions of self-reported adverse childhood experiences (ACEs) and recent life events (RLEs) to inflammation at midlife, by testing 3 competing theoretical models: stress generation, stress accumulation, and early life stress sensitization. We aimed to identify potential mediators between adversity and inflammation. Participants were 1,180 middle-aged and older adults from the Midlife in the United States (MIDUS) Biomarker Project (M age = 57.3 years, SD = 11.5; 56% female). A composite measure of inflammation was derived from 5 biomarkers: serum levels of C-reactive protein, interleukin-6, fibrinogen, E-selectin, and ICAM-1. Participants provided self-report data regarding ACEs, RLEs, current lifestyle indices (cigarette smoking, alcohol consumption, physical exercise, waist circumference), current depressive symptoms, and demographic/biomedical characteristics. We also used indices of hypothalamic-pituitary-adrenocortical outflow (12-hr urinary cortisol) and sympathetic nervous system output (12-hr urinary norepinephrine and epinephrine). Analyses indicated that ACEs and RLEs were independently associated with higher levels of inflammation, controlling for each other's effects. Their interaction was not significant. The results were consistent with the hypothesis that associations between ACEs and inflammation were mediated through higher urinary norepinephrine output, greater waist circumference, smoking, and lower levels of exercise, whereas higher waist circumference and more smoking partially mediated the association between RLEs and inflammation. In support of the stress accumulation model, ACEs and RLEs had unique and additive contributions to inflammation at midlife, with no evidence of synergistic effects. Results also suggested that norepinephrine output and lifestyle indices may help explain how prior stressors foster inflammation at midlife.

Vagus nerve stimulation in patients with Alzheimer ’s disease

Alzheimer’s disease (AD) is a devastating, progressive condition associated with memory and cognitive disturbances, mood swings and behavioral changes, and the quality of life reduction (1). AD is the most common cause of dementia in person older than 65 years, with 1 in 10 older than 65 years afflicted and half among those older than 85 years afflicted. More than 4.5 million persons are currently affected in the United States by AD, and is expected to nearly triple by the year 2050 in the absence of preventive treatments (2). AD is pathologically characterized by the accumulation of amyloid plaques and tau-associated neurofibrillary tangles (3). Patients with AD have increased cerebrospinal fluid (CSF) levels of tau protein and decreased CSF levels of β-amyloid. Although, patients with AD experience significant elevations in CSF tau levels, CSF tau levels have been shown to remain stable over extended periods of time (4). Several neurotransmitter systems are pathologically altered in AD. Cholinergic neurons in the nucleus basalis of Meynert degenerate early in the course of the disease. These neurons provide wide spread projections to the association cortices, and loss of acetlycholine is the mechanistic basis for cholinesterase inhibition in AD treatment. Glutamatergic function also is disregulated in AD, with inhibition of the pathological stimulation of the NMDA receptor providing the scientific rationale for the mechanism of the noncompetitive glutamate antagonist, memantine. In addition to the atrophy of the basal forebrain cholinergic system, marked neuronal loss occurs within the locus ceruleus and the raphe nucleus in AD (5). Significant reduction of norepinephrine in the temporal cortex occur in AD and correlates with the degree of cognitive impairment (6). Disturbances in serotonin metabolism also have been reported in AD (7). The U.S. Food and Drug Administration (FDA) had approved 5 drugs (tacrine, donepezil, rivastigmine, and galantamine) for the treatment of AD (8). None of these treatments have been shown to modify the disease process in patients with AD, but they provide benefit to the patient, family, and caregivers by slowing the patient’s progressive decline. Vagus nerve stimulation (VNS) has been shown to activate the locus ceruleus (9) and to increase norepinephrine (10) output into the basolateral amygdala and hippocampus in animal models. Activation of the raphe nucleus with VNS also has been recently demonstrated (11). Merill et al reported cognitive-enhancing effects of VNS during the first 6 months of treatment in a small pilot study of 10 patients with AD (12). Later, they published a follow-up report including additional 7 patients, with for at least 1 year for all 17 patients. Vagus nerve stimulation method promising new powerful alternative approaches in some neurological disorders especially in the treatment of refractory epilepsy (13). In this clinical research, 14 patients with Alzheimer’s disease who were treated with VNS were reviewed and the results were assed in the light of the literature. Only first and second phase of AD patients were included in the study. In total 14 AD patients (7 man and 7 women aged between 68 and 82 year old) participated in this study. Patients were followed up for one year. As soon as each implant was activated (two weeks after the implantation) attention of patients dramatically were improved, progressively going better On the other hand, 3 patients, who had difficulty in speaking along AD, improved by the VNS their talk within 3 months. According to our observed preliminary results, a new therapy potential is arising struggling against Alzheimer diseases

High twin resemblance for sensitivity to hypoxia.

Physiological responses to hypoxia vary between individuals, and genetic factors are conceivably involved. Using a monozygotic twin design, we investigated the role of genetic factors in physiological responses to acute hypoxia. Thirteen pairs of monozygotic twin brothers participated in two experimental sessions in a normobaric hypoxic facility with a 2-wk interval. In one session, fraction of inspired O2 (FiO2) was gradually reduced to 10.7% (approximately 5300 m altitude) over 5 h. During the next 3 h at 10.7%, FiO2 subjects performed a 20-min submaximal exercise bout (EXSUB, 1.2 W·kg) and a maximal incremental exercise test (EXMAX). An identical control experiment was done in normoxia. Cardiorespiratory measurements were continuously performed, and 8-h urine output was collected. Compared with normoxia, hypoxia decreased (P < 0.05) arterial O2 saturation (%SpO2) at rest (-22%) and during exercise (-28%). Furthermore, V˙O2max (-39%), HRmax (HR, -8%), maximal pulmonary ventilation (V˙Emax, -11%), and urinary norepinephrine excretion (-31%) were reduced (P < 0.05) whereas HR at rest (25%) and during EXSUB (16%) and V˙E at rest (38%) and during EXSUB (70%) were increased (P < 0.05). However, hypoxia-induced changes (Δ) were not randomly distributed between subjects. Between-pair variance was substantially larger than within-pair variance (P < 0.05) for Δ%SpO2 at rest (approximately threefold) and during exercise (approximately fourfold), ΔV˙O2max (approximately fourfold), ΔHR during exercise (approximately seven- to eightfold), hypoxic ventilatory response (approximately sixfold), and Δ urinary norepinephrine output (approximately threefold). Incidence of acute mountain sickness (AMS) also yielded significant twin similarity (P < 0.05). AMS subjects showed approximately 50% greater drop in urinary norepinephrine and lower hypoxic ventilator response than AMS individuals. Our data suggest that genetic factors regulate cardiorespiratory responses, exercise tolerance, and pathogenesis of AMS symptoms in acute severe hypoxia. Hypoxia-induced sympathetic downregulation was associated with AMS.

In vivo fluorescence imaging and urinary monoamines as surrogate biomarkers of disease progression in a mouse model of pheochromocytoma.

Pheochromocytoma (PHEO) is a rare but potentially lethal neuroendocrine tumor arising from catecholamine-producing chromaffin cells. Especially for metastatic PHEO, the availability of animal models is essential for developing novel therapies. For evaluating therapeutic outcome in rodent PHEO models, reliable quantification of multiple organ lesions depends on dedicated small-animal in vivo imaging, which is still challenging and only available at specialized research facilities. Here, we investigated whether whole-body fluorescence imaging and monitoring of urinary free monoamines provide suitable parameters for measuring tumor progression in a murine allograft model of PHEO. We generated an mCherry-expressing mouse PHEO cell line by lentiviral gene transfer. These cells were injected subcutaneously into nude mice to perform whole-body fluorescence imaging of tumor development. Urinary free monoamines were measured by liquid chromatography with tandem mass spectrometry. Tumor fluorescence intensity and urinary outputs of monoamines showed tumor growth-dependent increases (P < .001) over the 30 days of monitoring post-tumor engraftment. Concomitantly, systolic blood pressure was increased significantly during tumor growth. Tumor volume correlated significantly (P < .001) and strongly with tumor fluorescence intensity (rs = 0.946), and urinary outputs of dopamine (rs = 0.952), methoxytyramine (rs = 0.947), norepinephrine (rs = 0.756), and normetanephrine (rs = 0.949). Dopamine and methoxytyramine outputs allowed for detection of lesions at diameters below 2.3 mm. Our results demonstrate that mouse pheochromocytoma (MPC)-mCherry cell tumors are functionally similar to human PHEO. Both tumor fluorescence intensity and urinary outputs of free monoamines provide precise parameters of tumor progression in this sc mouse model of PHEO. This animal model will allow for testing new treatment strategies for chromaffin cell tumors.

Integrative Genetic Characterization and Phenotype Correlations in Pheochromocytoma and Paraganglioma Tumours

BackgroundAbout 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.AimThe purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.MethodsA total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.ResultsPathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases.ConclusionSomatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.

Antidepressants share the ability to increase catecholamine output in the bed nucleus of stria terminalis: a possible role in antidepressant therapy?

Antidepressants include a relatively wide spectrum of drugs that increase the synaptic concentration of monoamines, mostly through neurotransmitter reuptake blockade. The bed nucleus of stria teminalis (BNST) is considered a relay station in mediating the activation of stress response but also in the acquisition and expression of emotions. BNST is richly innervated by monoamines and sends back projections to the nucleus of origin. We previously showed that the administration of selective blockers of norepinephrine transporter (NET) increases the extracellular concentration (output) of dopamine, suggesting that dopamine could be captured by NET in the BNST. The aim of this study, carried out by means of in vivo microdialysis, was to ascertain the acute effects that antidepressants with varying mechanisms of action have on dopamine and norepinephrine output in the BNST. We observed that all the antidepressants tested (5-20mg/kgi.p.) increased the output of catecholamines, dose dependently. In particular, the maximum increases (as a percent of basal) for norepinephrine and dopamine respectively, were as follows: desipramine, 239 and 137; reboxetine, 185 and 128; imipramine, 512 and 359; citalopram, 95 and 122; fluoxetine, 122 and 68; bupropion, 255 and 164. These results suggest that catecholamine transmission in the BNST may be part of a common downstream pathway that is involved in the action mechanism of antidepressants. Consequently, it is hypothesized that a dysfunction of neuronal transmission in this brain area may have a role in the etiology of affective disorders.

Lactate levels remain significantly higher in non-survivors compared with survivors during therapeutic hypothermia after cardiac arrest

Purpose: Previous studies reported that lactate levels may be a reliable prognostic factor of outcome during the first hours after return of spontaneous circulation. However, implementation of a neuroprotective protocol with therapeutic hypothermia (TH) makes prognostication even more difficult. Furthermore, the prognostic value of lactate could be different in patients treated with hypothermia. In this study, we evaluated the effect of TH on lactate levels during the first 36 hours after CA. Methods: After IRB approval and with informed consent, data were collected from 43 consecutive patients admitted to the hospital after cardiac arrest. Cold saline (30 ml/kg) was administered at admission to emergency department. After PCI, therapeutic hypothermia (33°C) was induced by endovascular or surface cooling and maintained for 24 hours. All patients were sedated (propofol/remifentanil) for the duration of TH. Lactate was measured every hour. The threshold for hyperlactatemia was set for values exceeding 2 mmol/l. Data are presented as medians and interquartile ranges. Lactate was compared with the Mann Whitney U test. Results: Of 43 patients, 18 did not survived to hospital discharge due to post-ischemic brain damage. Temperature at CCU-admission was 34.7°C (34.1-35.4). Patients reached the target temperature of 33°C within 2 hours after TH induction. Median lactate levels at the start of TH were significantly different between survivors (2.22 mmol/l (1.7-3.3)) and non-survivors (4.65 mmol/l (3-6.7) p = 0.000). Lactate levels returned to normal values only after 24 hours of TH in survivors. In non-survivors, lactate levels remained higher than the threshold level throughout the maintenance of TH and re-warming. However, they were only significant different compared to survivors during the first 12 hours of TH. There was no difference in start values between survivors and non-survivors for pH, mean arterial pressure, cardiac output or dose of norepinephrine. Dose of norepinephrine increased during the first 5 hours in survivors and non-survivors and remained stable during the maintenance of TH. During re-warming, non-survivors had an increasing need of norepinephrine. There was no correlation between dose of norepinephrine and lactate levels. Conclusion: During therapeutic hypothermia after cardiac arrest, lactate levels are significant different between survivors and non-survivors during the first 12 hours. Lactate levels remain above the threshold for hyperlactatemia during TH and rewarming in non-survivors of cardiac arrest.

Differential activation of amygdala Arc expression by positive and negatively valenced emotional learning conditions.

Norepinephrine is released in the amygdala following negatively arousing learning conditions. This event initiates a cascade of changes including the transcription of activity-regulated cytoskeleton-associated protein (Arc) expression, an early-immediate gene associated with memory encoding. Recent evidence suggests that the valence of emotionally laden encounters may generate lateralized, as opposed to symmetric release of this transmitter in the right or left amygdala. It is currently not clear if valence-induced patterns of selective norepinephrine output across hemispheres are also reproduced in downstream pathways of cellular signaling necessary for memory formation. This question was addressed by determining if Arc expression is differentially distributed across the right and left amygdala following exposure to positively or negatively valenced learning conditions respectively. Male Sprague Dawley rats were randomly assigned to groups exposed to the Homecage only, five auditory tones only, or five auditory tones paired with footshock (0.35 mA) during Pavlovian fear conditioning. Western blot analysis revealed that Arc expression in the right amygdala was elevated significantly above that observed in the left amygdala 60 and 90 min following fear conditioning. Similarly, subjects exposed to a negatively valenced outcome consisting of an unexpected reduction in food rewards showed a greater level of Arc expression in only the right, but not left basolateral amygdala. Presenting a positively valenced event involving an unexpected increase in food reward magnitude following bar pressing, resulted in significantly greater Arc expression in the left, but not right basolateral amygdala (p < 0.01). These findings indicate that the valence of emotionally arousing learning conditions is reflected at later stages of synaptic plasticity involving the transcription of immediate early genes such as Arc.

Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat

A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E(2) (PGE(2)) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE(2)-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD.

The influence of angiotensin on the uptake of noradrenaline by the isolated heart of the rabbit.

Abstract The influence of angiotensin on the removal of noradrenaline (10 ng/ml) from the perfusion medium and on the net-uptake of noradrenaline (5 and 20 μg/ml) was examined in the rabbit isolated heart. Concentrations of angiotensin, known to augment the output of noradrenaline from rabbit heart during sympathetic nerve stimulation, did not inhibit the removal of infused noradrenaline from the perfusion fluid. Only very high concentrations of angiotensin (13 μg/ml) significantly diminished the loss of noradrenaline. The positive inotropic effect of noradrenaline was not potentiated by angiotensin. On the other hand, cocaine, in doses which enhance the output of noradrenaline during sympathetic stimulation greatly reduced the loss of noradrenaline from the perfusion fluid. Neither angiotensin (130 ng/ml) nor metanephrine (5 and 20 μg/ml) significantly influenced the net-uptake of noradrenaline from high concentrations. The observations made support the assumption that an increase of transmitter liberation rather than inhibition of transmitter inactivation is responsible for the increase caused by angiotensin in the output of noradrenaline during stimulation of sympathetic nerves.

Role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo

In vitro evidence indicates that norepinephrine release in the mammalian hippocampus is modulated by glutamate receptors. With the use of microdialysis, we have now evaluated the role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo. Stimulation of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors by local administration of NMDA (1–100 μM) resulted in a concentration-dependent decrease in the extracellular concentration of norepinephrine in the hippocampus of freely moving rats, whereas the blockade of these receptors with MK801 (1–100 μM) induced a concentration-dependent increase in norepinephrine output. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptors with AMPA (1–100 μM) resulted in a biphasic effect on the extracellular norepinephrine concentration, with a decrease in this parameter apparent at 10 μM and an increase at 100 μM. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect on norepinephrine output. The GABA A receptor antagonist bicuculline (10 μM) prevented the decrease in hippocampal norepinephrine output induced by either NMDA or 10 μM AMPA. Our results thus implicate ionotropic glutamate receptors as key regulators of norepinephrine release in the hippocampus and may therefore provide a basis for the development of new drugs for stress-related disorders.