Lower Norepinephrine Research Articles

Effects of Lifelong Ethanol Consumption on Brain Monoamine Transmitters in Alcohol-Preferring Alko Alcohol (AA) Rats.

The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong ethanol consumption in alcohol-preferring AA (Alko Alcohol) line of rats, selected for high voluntary consumption of ethanol. Intake of ethanol on the level of 4.5–5 g/kg/day for about 20 months induced only limited changes in the neurotransmitter levels; the concentration of noradrenaline was significantly reduced in the frontal cortex. There was also a trend towards lower levels of dopamine and 5-hydroxytryptamine (5-HT) in the frontal cortex, and towards a lower noradrenaline level in the dorsal cortex. Aging was associated with a decreased concentration of dopamine in the dorsal cortex and with a declining trend in the striatum. The levels of 5-HT in the limbic forebrain were higher in the aged than in the young animals, and in the striatum, there was a trend towards higher levels in older animals. The data suggest that a continuous intake of moderate amounts of ethanol does not enhance the age-related alterations in brain monoamine neurotransmission, while the decline in the brain level of dopamine associated with aging may be a factor contributing to age-related neurological disorders.

Group III/IV muscle afferents impair limb blood flow during exercise in patients with heart failure

Patients with heart failure (HF) are characterized by altered muscle afferent feedback which might account for their hemodynamic and autonomic reflex abnormalities. We investigated the influence of group III/IV muscle afferents on the circulatory response to rhythmic exercise in HF. Nine patients (NYHA class II) performed single leg knee extensor exercise (25/50/80% peak workload) under both control conditions (Ctrl) and with lumbar intrathecal fentanyl impairing μ‐opioid receptor‐sensitive muscle afferents. Cardiac output (Q) and femoral blood flow (QL) were determined, and arterial/venous blood samples were collected at each workload. Fentanyl had no effect at rest. During exercise, Q was 8–13% lower with Fentanyl, secondary to a 13% reduction in stroke volume and a 2–5% reduction in heart rate. Lower norepinephrine spillover during Fentanyl exercise implicated a reduced sympathetic outflow and likely accounted for the 25% increase in leg vascular conductance. As a result of this attenuated sympathoexcitation, QL was, despite a 4% lower blood pressure, 10–14% higher during exercise with Fentanyl. Although leg O2 delivery was higher during exercise with Fentanyl, arteriovenous O2 difference remained unchanged resulting in 10–17% increase in leg O2 consumption (p<0.05). Thus, although group III/IV muscle afferents represent a key determinant of the central hemodynamic response in HF, our findings also reveal that these sensory neurons cause a sympathetically‐mediated impairment of QL during rhythmic exercise in this population.

Circulating Levels of Renalase, Norepinephrine, and Dopamine in Dialysis Patients

Background: hRenalase may degrade catecholamines and regulate sympathetic tone and blood pressure (BP). The aim of the study was to assess dopamine (DA), norepinephrine (NE), and renalase in 75 hemodialysis (HD) and 26 peritoneal dialysis (PD) patients and their correlations with heart rate (HR), BP, a type of hypotensive therapy, and residual renal function. Methods: Renalase, DA, NE were studied using commercially available assays. Results: Renalase and NE were higher and DA was lower in dialyzed groups comparing to healthy volunteers. Hemodialysis patients had lower NE and higher renalase level. Norepinephrine was higher in anuric patients in HD group. Renalase correlated with dialysis vintage and inversely with residual diuresis. Dopamine correlated with residual diuresis in the whole study cohort, with HR in PD patients, with renalase in HD patients. Norepinephrine correlated with aortic diameter in PD patients. Norepinephrine was significantly higher in patients with coronary artery disease (CAD) in HD group. Hemodialysis population with CAD had lower NE and higher DA and renalase level than their PD counterparts. In the follow up, 27% of HD group died. Cardiac death was diagnosed in 17% and there was higher renalase level than in noncardiac death. Conclusions: Elevated level of circulating renalase in dialysis patients is rather related to kidney function and the sympathetic nervous system hyperactivity found in this population. The real excess of renalase in the pathogenesis of cardiovascular disorders in patients with chronic kidney disease still remains to be proven. If confirmed, it may give a new way for pathophysiological therapy.

Pmch-Deficiency in Rats Is Associated with Normal Adipocyte Differentiation and Lower Sympathetic Adipose Drive

The orexigenic neuropeptide melanin-concentrating hormone (MCH), a product of Pmch, is an important mediator of energy homeostasis. Pmch-deficient rodents are lean and smaller, characterized by lower food intake, body-, and fat mass. Pmch is expressed in hypothalamic neurons that ultimately are components in the sympathetic nervous system (SNS) drive to white and interscapular brown adipose tissue (WAT, iBAT, respectively). MCH binds to MCH receptor 1 (MCH1R), which is present on adipocytes. Currently it is unknown if Pmch-ablation changes adipocyte differentiation or sympathetic adipose drive. Using Pmch-deficient and wild-type rats on a standard low-fat diet, we analyzed dorsal subcutaneous and perirenal WAT mass and adipocyte morphology (size and number) throughout development, and indices of sympathetic activation in WAT and iBAT during adulthood. Moreover, using an in vitro approach we investigated the ability of MCH to modulate 3T3-L1 adipocyte differentiation. Pmch-deficiency decreased dorsal subcutaneous and perirenal WAT mass by reducing adipocyte size, but not number. In line with this, in vitro 3T3-L1 adipocyte differentiation was unaffected by MCH. Finally, adult Pmch-deficient rats had lower norepinephrine turnover (an index of sympathetic adipose drive) in WAT and iBAT than wild-type rats. Collectively, our data indicate that MCH/MCH1R-pathway does not modify adipocyte differentiation, whereas Pmch-deficiency in laboratory rats lowers adiposity throughout development and sympathetic adipose drive during adulthood.

Effects of a TREM-Like Transcript 1–Derived Peptide During Hypodynamic Septic Shock in Pigs

The objective of this study was to determine the effects of a TREM (triggering receptor expressed on myeloid cells 1)-like transcript 1-derived peptide (LR12) administration during septic shock in pigs. Two hours after induction of a fecal peritonitis, anesthetized and mechanically ventilated adult male minipigs were randomized to receive LR12 (n = 6) or its vehicle alone (normal saline, n = 5). Two animals were operated and instrumented without the induction of peritonitis and served as controls (sham). Resuscitation was achieved using hydroxyethyl starch (up to 20 mL/kg) and norepinephrine infusion (up to 10 μg/kg per minute). Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokines concentrations were evaluated at regular intervals until 24 h after the onset of peritonitis when animals were killed under anesthesia. Peritonitis induced profound hypotension, myocardial dysfunction, lactic acidosis, coagulation abnormalities, and multiple organ failure. These disorders were largely attenuated by LR12. In particular, cardiovascular failure was dampened as attested by a better mean arterial pressure, cardiac index, cardiac power index, and S(v)O(2), despite lower norepinephrine requirements. LR12, a TREM-like transcript 1-derived peptide, exhibits salutary properties during septic shock in adult minipigs.

Cardiovascular responses to lower body negative pressure before and after 4 h of head-down bed rest and seated control in men and women

Cardiovascular deconditioning after a 4-h head-down bed rest (HDBR) might be a consequence of the time of day relative to pre-HDBR testing, or simply 4 h of confinement and inactivity rather than the posture change. Ten men and 11 women were studied during lower body negative pressure (LBNP) before and after 4-h HDBR and 4-h seated posture (SEAT) as a control for time of day and physical inactivity effects to test the hypotheses that cardiovascular deconditioning was a consequence of the HDBR posture, and that women would have a greater deconditioning response. Following HDBR, men and women had lower blood volume, higher heart rate with a greater increase during LBNP, a greater decrease of stroke volume during LBNP, lower central venous pressure, smaller inferior vena cava diameter, higher portal vein resistance index with a greater increase during LBNP, but lower forearm vascular resistance, lower norepinephrine, and lower renin. Women had lower vasopressin and men had higher vasopressin after HDBR, and women had lower pelvic impedance and men higher pelvic impedance. Following SEAT, brachial vascular resistance was reduced, thoracic impedance was elevated, the reduction of central venous pressure during LBNP was changed, women had higher angiotensin II whereas men had lower levels, and pelvic impedance increased in women and decreased in men. Cardiovascular deconditioning was greater after 4-h HDBR than after SEAT. Women and men had similar responses for most cardiovascular variables in the present study that tested the responses to LBNP after short-duration HDBR compared with a control condition.

Effects of a Homeopathic Combination Remedy on the Acute Stress Response, Well-Being, and Sleep: A Double-Blind, Randomized Clinical Trial

Stress impacts on health, causing stress-related illness. The aim of this study was to investigate stress dampening effects of the homeopathic combination remedy dysto-loges(®) S on physiological and psychological measures during acute stress. Additionally, effects of the substance on sleep and life quality were investigated. This randomized, double-blind, placebo-controlled single center study had a total duration of 15 days for each participant. The study was performed by Daacro, Trier, Germany. We included 40 women aged 30-50 years that regularly experienced impaired well-being when feeling stressed. Participants took three tablets daily for 14 days. On the final study day, participants took three pills in the morning and upon arrival at the study site. Thereafter, the Trier Social Stress Test (TSST) was performed. Primary endpoints were saliva cortisol responses to the stress test. Secondary biological endpoints were plasma cortisol, adrenocorticotrophic hormone, epinephrine, and norepinephrine (NE) and heart rates. Psychological secondary endpoints were well-being, anxiety, stress, and insecurity during the stress test as well as sleep and quality of life. Stress-induced cortisol levels did not differ between groups, but verum-treated participants were characterized by lower NE levels. Two weeks of treatment with the homeopathic substance resulted in a better sleep quality. Sleep improvement was associated with a higher hormonal response to the TSST in both groups. In addition, individuals with impaired sleep in the placebo group had higher unstimulated NE levels. This study provides preliminary evidence for beneficial effects of dysto-loges S on sleep quality. Improvement of sleep quality was positively associated with a normalized neuroendocrine stress response during acute stress, whereas an altered hormonal response was observed in participants with impaired sleep. We hypothesize that the test product may possibly reduce NE release.

391 BETA2-ADRENOCEPTOR POLYMORPHISMS (ARG16GLY) IS RELATED TO RESISTANCE TO WEIGHT LOSS INDUCED IMPROVEMENTS OF CARDIAC- AND RENAL COMPLICATIONS

Background: Obesity is an independent risk factor for cardiovascular and renal complications. We previously reported that the Arg16Gly, β2-adrenoceptor (ADRB2) polymorphism, accompanying high plasma norepinephrine (NE) could predict future weight gain, BP elevation and renal injury. The 1st line of treatment for obesity is weight loss (WL). In this study, we evaluated the relationships between ADRB2 polymorphisms (Arg16Gly), prevalence of LVH and renal function (creatinine clearance) over 2 years with WL program. Methods: Obese Japanese men (n = 154) were measured BMI, BP, plasma NE, leptin, creatinine, creatinine clearance (CCr), LVH determined by ECG and ADRB2 polymorphisms (Arg16Gly, Gln27Glu) before and after WL program (low caloric diet + exercise) over 2 years. Significant WL was defined >10% WL of entry BMI. Results: Significant WL was noted in 97 (63%) subjects and the frequencies of Gly16 were 39% for WL group vs. 54% for non-WL group (P < 0.05). At entry, subjects with Gly16 allele had higher levels of plasma NE, leptin, creatinine, higher prevalence of LVH, and lower CCr compared to those without Gly16 allele. WL group had lower fat-mass, NE, leptin and creatinine and LVH prevalence and higher CCr at entry compare dto non-WL group. WL group had greater changes in BMI, fat-mass, creatinine and CCr, and greater % reductions in NE and leptin over a 2-year period. Changes in fat-mass correlated with changes in creatinine, CCr, NE and BP over 2 years. Changes in plasma NE correlated with changes in CCr. In multiple regression analysis, plasma NE, fat-mass and BP levels were determinants for prevalence of LVH at entry and 2-year period. Conclusions: ADRB2 polymorphisms (Arg16Gly) accompanying high plasma NE is related to the prevalence of LVH and improving CCr with WL. Arg16Gly associated with high plasma NE may play an important role in cardio- and renal-complications in obesity.

Noradrenergic ‘Tone’ Determines Dichotomous Control of Cortical Spike-Timing-Dependent Plasticity

Norepinephrine (NE) is widely distributed throughout the brain. It modulates intrinsic currents, as well as amplitude and frequency of synaptic transmission affecting the ‘signal-to-noise ratio’ of sensory responses. In the visual cortex, α1- and β-adrenergic receptors (AR) gate opposing effects on long-term plasticity of excitatory transmission. Whether and how NE recruits these plastic mechanisms is not clear. Here, we show that NE modulates glutamatergic inputs with different efficacies for α1- and β-AR. As a consequence, the priming of synapses with different NE concentrations produces dose-dependent competing effects that determine the temporal window of spike-timing dependent plasticity (STDP). While a low NE concentration leads to long-term depression (LTD) over broad positive and negative delays, a high NE concentration results in bidirectional STDP restricted to very narrow intervals. These results indicate that the local availability of NE, released during emotional arousal, determines the compound modulatory effect and the output of STDP.

The α2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The specific role of different isoforms of the Na,K-pump in the vascular wall is still under debate. We have previously suggested that the α(2) isoform of the Na,K-pump (α(2)), Na(+), Ca(2+)-exchange (NCX), and connexin43 form a regulatory microdomain in smooth muscle cells (SMCs), which controls intercellular communication and contractile properties of the vascular wall. We have tested this hypothesis by downregulating α(2) in cultured SMCs and in small arteries with siRNA in vivo. Intercellular communication was assessed by using membrane capacitance measurements. Arteries transfected in vivo were tested for isometric and isobaric force development in vitro; [Ca(2+)](i) was measured simultaneously. Cultured rat SMCs were well-coupled electrically, but 10 μM ouabain uncoupled them. Downregulation of α(2) reduced electrical coupling between SMCs and made them insensitive to ouabain. Downregulation of α(2) in small arteries was accompanied with significant reduction in NCX expression. Acetylcholine-induced relaxation was not different between the groups, but the endothelium-dependent hyperpolarizing factor-like component of the response was significantly diminished in α(2)-downregulated arteries. Micromolar ouabain reduced in a concentration-dependent manner the amplitude of norepinephrine (NE)-induced vasomotion. Sixty percent of the α(2)-downregulated arteries did not have vasomotion, and vasomotion in the remaining 40% was ouabain insensitive. Although ouabain increased the sensitivity to NE in the control arteries, it had no effect on α(2)-downregulated arteries. In the presence of a low NE concentration the α(2)-downregulated arteries had higher [Ca(2+)](i) and tone. However, the NE EC50 was reduced under isometric conditions, and maximal contraction was reduced under isometric and isobaric conditions. The latter was caused by a reduced Ca(2+)-sensitivity. The α(2)-downregulated arteries also had reduced contraction to vasopressin, whereas the contractile response to high K(+) was not affected. Our results demonstrate the importance of α(2) for intercellular coupling in the vascular wall and its involvement in the regulation of vascular tone.

Effects of the α2-Adrenergic Agonist Clonidine on the Pharmacodynamics and Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in Healthy Volunteers

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.

Recurrent Postural Vasovagal Syncope

Background— The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (&gt;100 mm Hg) or low (70–100 mm Hg). We investigated neural circulatory control in these 2 phenotypes. Methods and Results— Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype ( P =0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups ( P =0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal, P =0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal, P =0.019), augmenting transmitter reuptake. Conclusions— Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.

Patients as a Scientific Resource: Comments on Receiving the Ahrens Award

Patients as a Scientific Resource: Comments on Receiving the Ahrens Award

Oligodendrocytes in Schizophrenia

Oligodendrocytes in Schizophrenia

Effects of Hyperosmotic Sodium Chloride Perfusion on Ischemia/Reperfusion Injury in Isolated Hearts of Normal and Stroke-Prone Spontaneously Hypertensive Rats

Background: Hyperosmotic solutions have been used successfully in different shock resuscitations with cardioprotection. This study was to examine the effects of hyperosmotic sodium chloride on isolated heart function and heart responses to ischemia/reperfusion in normotensive and hypertensive rats. The roles of hyperosmolarity-induced antioxidants including hyperosmolarity-relevant heat shock proteins as well as vasodilating endothelial nitric oxide synthase (eNOS) and vasoactive catecholamines were investigated.Methods: Hearts of normal rats and stroke-prone spontaneously hypertensive rats were isolated and perfused for 30 min with control Krebs-Henseleit buffer (osmolarity 300 mOsm/L) or hyperosmotic buffer of different sodium chloride concentrations (320, 350 and 400 mOsm/L) before subjected to 40-min global ischemia followed by 10-min hyperosmotic reperfusion and 30-min normal buffer reperfusion. Heart function, creatine phosphokinase leakage and myocardial antioxidants were examined. Myocardial antioxidants after hyperosmotic perfusion with different osmolytes were assayed with Western blotting.Results: Pre-ischemic hyperosmotic sodium chloride perfusion enhanced heart contractility and diastole function and reduced coronary vascular resistance in both normal and hypertensive hearts. Post-ischemic recoveries of heart function were improved in hyperosmotic perfused hearts, associated with lower creatine phosphokinase leakage, higher coronary flow, reduced coronary resistance and lower norepinephrine overflow. At the end of reperfusion, the myocardial activities of total superoxide dismutase and catalase, glutathione content as well as osmosis-relevant heat shock protein 32 and 90 were increased in hyperosmotic hearts. In addition to sodium chloride, in vitro hyperosmotic mannitol, glucose and raffinose also increased protein expressions of antioxidants including superoxide dismutase, catalase, heat shock protein 32 and 90 and vasodilating eNOS.Conclusion: Hyperosmotic perfusion enhanced heart function and preconditioned normal and hypertensive hearts against ischemia/reperfusion injury. The hyperosmolarity-induced up-regulations in myocardial antioxidants including heat shock proteins and eNOS may play an important role in the hyperosmolarity-induced cardioprotection.

Persistent sepsis-induced hypotension without hyperlactatemia: Is it really septic shock?

PurposeThe prognostic value of hyperlactatemia in septic shock is unquestionable. However, as current definitions do not include hyperlactatemia as a mandatory criterion, some hypotensive patients may be diagnosed as having septic shock despite exhibiting normolactatemia. The significance of persistent sepsis-induced hypotension without hyperlactatemia is unclear. Is it really septic shock? Our aim was to determine differences in outcome between patients diagnosed as having septic shock but exhibiting normal vs elevated lactate levels during evolution. We also explored the potential implications of including hyperlactatemia as an obligatory diagnostic criterion. MethodsWe performed retrospective analyses on a cohort of 302 septic shock patients. ResultsWhen we divided patients according to the presence of hyperlactatemia, 34% evolved without hyperlactatemia and exhibited a very low mortality risk (7.7% compared with 42.9% of those with hyperlactatemia). These patients also presented less severe organ dysfunctions and higher central venous O2 saturation values, and required lower norepinephrine doses. The potential inclusion of hyperlactatemia in septic shock definition would reduce incidence in 34% but increase absolute mortality risk in 11%. ConclusionsPersistent sepsis-induced hypotension without hyperlactatemia may not constitute a real septic shock. Our results support the need to review the current definition of septic shock. Hyperlactatemia could represent an objective parameter worth to be explored as a potential diagnostic criterion for septic shock.

Personality and illness: Genetic connections?

Illness is strongly influenced by genetics. Personality traits are influenced by genetics and have linkages with, at least, affective illness. Because genetics influences both personality and illness, we studied by literature review the genes that illness and personality traits share and, by office assessment, our patient population's illnesses and personality traits. This led to the following hypothesis: illness is related to more Submissive than Dominant personality trait and thus to lower norepinephrine activity. Patient affect and personality are often noted to be subdued in chronic illness, but whether from cause or effect is difficult to determine. After reviewing the literature on wellness, personality and genes, we endeavored to explore and better delineate our impressions of illness and personality relationships and to set the stage for a genetic hypothesis by using an online personality test in an ob-gyn practice to determine which traits could be used as proxies for personality trait genes. We thus confirmed our clinical impression that women with psychiatric and/or medical illness have more Submissive personality. The medical literature on gene markers shared by Submissive personality and illness in our population suggests the hypothesis that this relationship could be mediated by genetically lower neurotransmitter activity. Both norepinephrine activity and monoamine oxidase A, the enzyme controlling its catabolism, are in concert to blunt neuronal activity in such diverse states as depression, asthma, obesity, autoimmune illness, and in smokers. Conversely, norepinephrine activity is enhanced in breastfeeders and in other settings known to be related to good health. A point for possible divergence from the hypothesis is that African-Americans have enhanced norepinephrine activity yet poorer health outcomes although the effect of environmental risk factors in African-Americans is considered prominent by researchers. The possible importance of this hypothesis is that it changes emphasis slightly from one of splitting diagnoses to one of grouping them to achieve fresh insight. If we assess what is found in common in diverse illnesses of mind and body, we have yet another tool to assess causation. Although this hypothesis is offered somewhat in a boldness of spirit to take a new look at our many perplexing clinical problems, it is also offered with humility in light of the complexity with which we deal in patient care.

Impact of 2 Doses of Clorgyline on the Rat Preimplantation Embryo Development and the Monoamine Levels in Urine

We have evaluated the impact of chronic administration of clorgyline, a potent monoamine oxidase A inhibitor and a former antidepressant, on the preimplantation embryo development in Wistar rats. Females were injected intraperitoneally daily for 30 days with saline (control animals), or with a low-dose clorgyline (LDC, 0.1 mg/kg per d) or with a high-dose clorgyline (HDC, 1 mg/kg per d). Embryos were isolated on day 5 of pregnancy and urine was collected by puncture of the urinary bladder. The number of embryos per female did not differ between experimental groups and control, but we have recorded a decreased number of embryos in HDC group compared to LDC (P < .05). We have found that LDC significantly reduced the presence of healthy embryos and increased the presence of the degenerated embryos (P < .001). The administration of the LDC resulted in the lowest cell number in blastocysts. We have observed significantly increased serotonin levels in HDC group compared to both control (P < .05) and LDC animals (P < .01). Norepinephrine (NE) levels in both experimental groups were significantly elevated compared to controls. Dopamine levels did not differ between groups (P > .05). We speculate that lesser negative effect of HDC compared to LDC on the preimplantation embryo development could be the consequence of the lower NE levels and/or elevated serotonin levels. Potential mechanisms mediating clorgyline-induced impaired preimplantation embryo development are proposed.

Activation of α1 and α2 noradrenergic receptors exert opposing effects on excitability of main olfactory bulb granule cells

The mammalian main olfactory bulb (MOB) receives a dense noradrenergic innervation from the pontine nucleus locus coeruleus that is important for neonatal odor preference learning and odor processing in mature animals. Modulation of GABAergic granule cells (GCs) is thought to play a key role in the net functional impact of norepinephrine (NE) release in the MOB, yet there are few direct studies of the influence of NE on these cells. In the present study we investigated noradrenergic modulation of GC excitability using electrophysiological approaches in rat MOB slices. A moderate concentration of NE (10 μM) and the α1 receptor agonist phenylephrine (10 μM) depolarized and increased spontaneous or current injection-evoked spiking in GCs. By contrast, low NE concentrations (0.1–1.0 μM) or the α2 receptor agonist clonidine (Clon, 10 μM) hyperpolarized and decreased the discharge of GCs. The effects of NE (10 μM) were blocked by antagonism of α1 and α2 receptors. Inhibitory effects of low NE concentrations were blocked or converted to excitatory responses by α2 receptor blockade, whereas excitatory effects of the moderate NE concentration were converted to inhibitory responses after α1 receptor blockade. NE (10 μM) and phenylephrine elicited inward currents that reversed near the potassium equilibrium potential. The effects of NE and phenylephrine were associated with increased membrane input resistance. Clonidine elicited an outward current associated with decreased membrane input resistance that reversed near the potassium equilibrium potential. These results indicate that α1 and α2 receptor activation exert opposing effects on GC excitability. Low concentrations of NE acting via α2 receptors suppress GC excitability, while higher concentrations of NE acting at α1 receptors increase GC excitability. These findings are consistent with recent findings that α1 and α2 receptor activation increase and decrease, respectively, GABAergic inhibition of mitral cells. The differential affinities of α1 and α2 noradrenergic receptor subtypes may allow for differential modulation of GABA release and olfactory processing as a function of the level of NE release, which in turn, is regulated by behavioral state.

Association of anosmia with autonomic failure in Parkinson disease

Olfactory dysfunction and autonomic failure are gaining recognition as nonmotor manifestations of Parkinson disease (PD). This observational study assessed whether in PD anosmia and autonomic failure are related to each other or to neuroimaging evidence of striatal dopamine deficiency. Olfactory function was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) in 23 patients with sporadic PD. Baroreflex-cardiovagal gain was quantified from the relationship between cardiac interbeat interval and systolic pressure during the Valsalva maneuver and baroreflex-sympathoneural function by responses of systolic pressure to the Valsalva maneuver and of hemodynamics and plasma norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels to orthostasis. 6-[(18)F]Fluorodopamine PET and plasma and skeletal muscle microdialysate NE and DHPG were used to indicate cardiac and extracardiac noradrenergic innervation and brain 6-[(18)F]fluorodopa PET to indicate striatal dopaminergic innervation. Parkinsonism was assessed by UPDRS scores. Compared to patients with PD and normal to moderately decreased sense of smell, patients with anosmic PD had lower mean baroreflex-cardiovagal gain (p = 0.04), larger falls in systolic pressure during the Valsalva maneuver and orthostasis (p = 0.04, p = 0.02), smaller orthostatic increments in plasma NE and DHPG (p = 0.003, p = 0.03), lower cardiac septal:hepatic and renal cortical:hepatic ratios of 6-[(18)F]fluorodopamine-derived radioactivity (p = 0.01, p = 0.06), and lower microdialysate NE and DHPG (p = 0.01; p = 0.006). Neither clinical severity of parkinsonism nor the putamen:occipital cortex ratio of 6-[(18)F]fluorodopa-derived radioactivity was related to the UPSIT category. In Parkinson disease, anosmia is associated with baroreflex failure and cardiac and organ-selective extracardiac noradrenergic denervation, independently of parkinsonism or striatal dopaminergic denervation.