Showing papers on "Catecholamine published in 2008"
TL;DR: It is observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens, which is consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation.
Abstract: Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction.
294 citations
TL;DR: Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 patients from the study by attending clinicians, and there was no difference in 28 and 90-day mortality.
Abstract: Objective
To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients.
278 citations
TL;DR: The present data suggest that NPY is released together with NA during strong, but probably not during mild, sympathetic activation under physiological conditions in man.
Abstract: Neuropeptide Y-like immunoreactivity (NPY-LI) and catecholamine concentrations in plasma were analysed during and after 60 min of physical exercise at a work load corresponding to 70% of individual maximal oxygen uptake in nine healthy men of average physical fitness. Systemic plasma NPY-LI increased progressively from 18 +/- 3 to 81 +/- 19 pmol X 1(-1) in parallel with a 10-fold increase in noradrenaline (NA) concentration. The increase in plasma NPY-LI during exercise and the decrease after completion of exercise were much slower than the corresponding changes in NA concentration. This difference is probably related to a slower diffusion of NPY into systemic circulation after release, as well as to a longer half-life of NPY than of NA in plasma. Reversed phase HPLC and sephadex G-50 gel-filtration chromatography revealed that the main component of NPY-LI in plasma during exercise eluted in a similar position as synthetic human NPY. During exercise plasma NPY-LI correlated well with the plasma concentration of NA (r = 0.80), but not with that of adrenaline (ADR), suggesting a neuronal origin of NPY. The self-ratings of perceived exertion (RPE) were well correlated with the plasma concentrations of both NPY-LI and NA. No clear-cut veno-arterial concentration difference was observed for NPY-LI. Isometric handgrip and orthostatic test doubled plasma NA concentrations but did not cause any increase in plasma NPY-LI. No change in plasma tachykinin-like immunoreactivity was detected during exercise. The present data suggest that NPY is released together with NA during strong, but probably not during mild, sympathetic activation under physiological conditions in man.
210 citations
TL;DR: It is shown that sympathetic nervous activity during mental arithmetic predicts future blood pressure, indicating a possible causal factor in the development of essential hypertension independent of the initial blood pressure.
Abstract: In the present study we hypothesized that arterial catecholamine concentrations during rest and 2 laboratory stress tests were independent predictors of blood pressure at an 18-year follow-up. At entry, blood pressure, heart rate, and arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age: 19.3+/-0.4 years, mean+/-SD) at rest, during a mental arithmetic test, and during a cold pressor test. After 18.0+/-0.9 years of follow-up, resting blood pressure was measured. The norepinephrine and epinephrine concentrations during the mental arithmetic explained 12.7% of the variation of future systolic blood pressure after adjusting for initial resting blood pressure, family history, body mass index, and systolic blood pressure during the stress test in a multiple regression analysis (adjusted R(2)=0.651; P<0.001). To conclude, the present study shows that sympathetic nervous activity during mental arithmetic predicts future blood pressure, indicating a possible causal factor in the development of essential hypertension independent of the initial blood pressure.
171 citations
TL;DR: Dopamine significantly enhances the efficacies of commonly used anticancer drugs and indicates that an inexpensive drug, which is being extensively used in the clinics, might have a role as an antiangiogenic agent for the treatment of breast and colon cancer.
Abstract: Purpose: Because neurotransmitter dopamine inhibits vascular permeability factor/vascular endothelial growth factor (VEGF)–induced angiogenesis and as anti-VEGF agents act synergistically with anticancer drugs, we therefore investigated whether dopamine can increase the efficacies of these drugs. Experimental Design: The effect of dopamine was investigated in human breast cancer–(MCF-7) and colon (HT29) cancer–bearing mice. Experimental groups received either dopamine or doxorubicin or dopamine plus doxorubicin in MCF-7 tumor-bearing mice, and either dopamine or 5-fluorouracil or dopamine plus 5-fluorouracil in HT29-bearing mice. Thereafter, tumor growth, angiogenesis, tumor cell apoptosis, life span, and the effect of dopamine on the growth and survival of tumor cells in vitro were determined. Finally, the effects of dopamine on tumor vascular permeability; on VEGF receptor-2, mitogen-activated protein kinase, and focal adhesion kinase phosphorylation; and also on the proliferation and migration of tumor endothelial cells were investigated. Results: Dopamine, in combination with anticancer drugs, significantly inhibited tumor growth and increased the life span when compared with treatment with dopamine or anticancer drugs alone. Dopamine had no direct effects on the growth and survival of tumor cells. The antiangiogenic action of dopamine was mediated by inhibiting proliferation and migration of tumor endothelial cells through suppression of VEGF receptor-2, mitogen-activated protein kinase, and focal adhesion kinase phosphorylation. Conclusion: Our study shows that dopamine significantly enhances the efficacies of commonly used anticancer drugs and also indicates that an inexpensive drug like dopamine, which is being extensively used in the clinics, might have a role as an antiangiogenic agent for the treatment of breast and colon cancer.
143 citations
TL;DR: Testing whether MC4-R mRNA is expressed in IBAT SNS outflow neurons using in situ hybridization for the former and injections of the transneuronal viral retrograde tract tracer, pseudorabies virus into IBAT adds significant support to the view that central melanocortins are important in controlling IBAT thermogenesis via the SNS innervation of this tissue.
Abstract: A precise understanding of neural circuits controlling lipid mobilization and thermogenesis remains to be determined. We have been studying the sympathetic nervous system (SNS) contributions to white adipose tissue (WAT) lipolysis largely in Siberian hamsters. Central melanocortins are implicated in the control of the sympathetic outflow to WAT, and, moreover, the melanocortin 4 receptors (MC4-R) appear to be principally involved. We previously found that acute third ventricular melanotan II (MTII; an MC3/4-R agonist) injections increase sympathetic drive (norepinephrine turnover) to interscapular brown adipose tissue (IBAT) and IBAT temperature. Here we tested whether MC4-R mRNA is expressed in IBAT SNS outflow neurons using in situ hybridization for the former and injections of the transneuronal viral retrograde tract tracer, pseudorabies virus (PRV) into IBAT, for the latter. Significant numbers of double-labeled cells for PRV and MC4-R mRNA were found across the neuroaxis (mean of all brain sites ∼60%), including the hypothalamic paraventricular nucleus (PVH; ∼80%). Acute parenchymal MTII microinjections into the PVH of awake, freely-moving hamsters, using doses below those able to increase IBAT temperature when injected into the third ventricle, increased IBAT temperature for as long as 4 h, as measured by temperature transponders implanted below the tissue. Collectively, these data add significant support to the view that central melanocortins are important in controlling IBAT thermogenesis via the SNS innervation of this tissue, likely through the MC4-Rs.
139 citations
TL;DR: It is interesting that the stress group showed a locomotor response to cocaine not different from control rats, thus suggesting a condition of sensitization to dopamine receptor stimulation.
Abstract: Chronic stress induces in rats a decreased reactivity toward noxious stimuli (escape deficit), which can be reverted by antidepressant treatments. The present study reports that this condition of behavioral deficit is accompanied by a decreased level of extracellular dopamine in the nucleus accumbens shell. To assess whether this finding was the result of a decreased release or of an enhanced removal of dopamine, we acutely administered cocaine, and 2 h later d-amphetamine, to stressed and control rats. The increases in dopamine output observed in stressed animals after cocaine administration were significantly lower than those observed in control rats; whereas the total amount of dopamine released after d-amphetamine administration was similar in both groups of rats. These data suggest a reduced activity of dopaminergic neurons as the possible mechanism underlying dopamine basal level reduction in stressed animals. It is interesting that the stress group showed a locomotor response to cocaine not different from control rats, thus suggesting a condition of sensitization to dopamine receptor stimulation. Imipramine administered daily concomitantly with stress exposure completely reverted the escape deficit condition of chronically stressed rats. Moreover, stressed rats treated with imipramine showed basal and cocaine stimulated levels of extraneuronal dopamine similar to those observed in control animals.
133 citations
TL;DR: 5‐HT2 receptors located in the striatum augment the release of dopamine produced by high doses of MDMA, and appear to be located on nondopaminergic elements of thestriatum.
Abstract: 5-Hydroxytryptamine2 (5-HT2) receptor antagonists have been shown to interfere with the stimulation of striatal dopamine synthesis and release produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). To localize the receptors responsible for the attenuation of MDMA-induced release, 5-HT2 receptor antagonists were infused via the microdialysis probe directly into the brains of awake, freely moving rats before the systemic administration of MDMA. Intrastriatal infusions of the selective 5-HT2 antagonist MDL 100, 907 produced a concentration-dependent inhibition of MDMA-induced dopamine release. Similar results were observed with intrastriatal infusions of the 5-HT2 antagonist amperozide. In contrast, infusion of MDL 100, 907 into the midbrain region near the dopaminergic cell bodies was with out effect on the MDMA-induced elevation of extracellular dopamine in the ipsilateral striatum. Neither antagonist attenuated basal transmitter efflux nor the MDMA-stimulated release of [3H]dopamine from striatal slices in vitro indicating that the in vivo effect of the antagonists was not due to inhibition of the dopamine uptake carrier. Intrastriatal infusion of tetrodotoxin reduced both basal and MDMA-stimulated dopamine efflux and eliminated the effect of intrastriatal MDL 100, 907. The results indicate that 5-HT2 receptors located in the striatum augment the release of dopamine produced by high doses of MDMA. Furthermore, these 5-HT2 receptors appear to be located on nondopaminergic elements of the striatum.
132 citations
TL;DR: The blunted plasma catecholamine responses after central AT1 receptor blockade indicate that endogenous Ang II in the brain is required for sympathoadrenal activation during immobilization stress.
Abstract: Angiotensin II (Ang II) type-1 (AT1) receptors are present in areas of the brain controlling autonomic nervous activity and the hypothalamic-pituitary-adrenal (HPA) axis, including CRH cells in the hypothalamic paraventricular nucleus (PVN). To determine whether brain AT1 receptors are involved in the activation of the HPA axis and sympathetic system during stress, we studied the effects of acute immobilization stress on plasma catecholamines, ACTH and corticosterone, and mRNA levels of CRH and CRH receptors (CRH-R) in the PVN in rats under central AT1 receptor blockade by the selective antagonist, Losartan. While basal levels of epinephrine, norepinephrine and dopamine in plasma were unaffected 30 min after i.c.v. injection of Losartan (10 microg), the increases after 5 and 20 min stress were blunted in Losartan treated rats (P < 0.05 for norepinephrine, and P < 0.01 for epinephrine and dopamine, vs controls). Basal or stress-stimulated plasma ACTH and corticosterone levels were unaffected by i.c.v. Losartan treatment. Using in situ hybridization studies, basal levels of CRH mRNA and CRH-R mRNA in the PVN were unchanged after i.c.v. Losartan. While Losartan had no effect on the increases in CRH-R mRNA levels 2 or 3 h after 1 h immobilization, it prevented the increases in CRH mRNA. The blunted plasma catecholamine responses after central AT1 receptor blockade indicate that endogenous Ang II in the brain is required for sympathoadrenal activation during immobilization stress. While Ang II appears not to be involved in the acute secretory response of the HPA axis, it may play a role in regulating CRH expression in the PVN.
128 citations
TL;DR: The augmented sympathetic activity in individuals with metabolic syndrome worsens prognosis of this high-risk population and the mechanisms linking metabolic syndrome with sympathetic activation are complex and not clearly understood.
Abstract: The metabolic syndrome is characterized by the clustering of various common metabolic abnormalities in an individual and it is associated with increased risk for the development of type 2 diabetes and cardiovascular diseases Its prevalence in the general population is approximately 25% Central fat accumulation and insulin resistance are considered as the common denominators of the abnormalities of the metabolic syndrome Subjects with metabolic syndrome have autonomic nervous system dysfunction characterized by predominance of the sympathetic nervous system in many organs, ie heart, kidneys, vasculature, adipose tissue, and muscles Sympathetic nervous system activation in metabolic syndrome is detected as increased heart rate and blood pressure, diminished heart rate variability, baroreceptor dysfunction, enhanced lipolysis in visceral fat, increased muscle sympathetic nerve activity, and high urine or plasma catecholamine concentrations as well as turnover rates The augmented sympathetic activity in individuals with metabolic syndrome worsens prognosis of this high-risk population The mechanisms linking metabolic syndrome with sympathetic activation are complex and not clearly understood Whether sympathetic overactivity is involved in the development of the metabolic syndrome or is a consequence of it remains to be elucidated since data from prospective studies are missing Intervention studies have demonstrated that the autonomic disturbances of the metabolic syndrome may be reversible
127 citations
TL;DR: Data show differential sympathetic drive to WAT and BAT for four different lipolytic stimuli, exemplifying the fat pad-specific pattern of WAT sympathetic drive across lipid-mobilizing conditions and emphasizing the need to analyze multiple adipose depots for measures of NETO and likely most measures.
Abstract: Surplus energy is principally stored in white adipose tissue (WAT) as triacylglycerol and mobilized via lipolysis through norepinephrine (NE) released from sympathetic nervous system terminals inne...
TL;DR: Brain slices from transgenic mice that synthesize placental alkaline phosphatase (PLAP) are labeled on neurons containing tyrosine hydroxylase with antibody–fluorochrome conjugate, PLAP‐Cy5 to support heterologous uptake of catecholamines and volume transmission in the PFC of mice.
Abstract: Monitoring the release and uptake of catecholamines from terminals in weakly innervated brain regions is an important step in understanding their importance in normal brain function To that end, we have labeled brain slices from transgenic mice that synthesize placental alkaline phosphatase (PLAP) on neurons containing tyrosine hydroxylase with antibody-fluorochrome conjugate, PLAP-Cy5 Excitation of the fluorochrome enables catecholamine neurons to be visualized in living tissue Immunohistochemical fluorescence with antibodies to tyrosine hydroxylase and dopamine beta-hydroxylase revealed that the PLAP labeling was specific to catecholamine neurons In the prefrontal cortex (PFC), immunohistochemical fluorescence of the PLAP along with staining for dopamine transporter (DAT) and norepinephrine transporter (NET) revealed that all three exhibit remarkable spatial overlap Fluorescence from the PLAP antibody was used to position carbon-fiber microelectrodes adjacent to catecholamine neurons in the PFC Following incubation with L-DOPA, catecholamine release and subsequent uptake was measured and the effect of uptake inhibitors examined Release and uptake in NET and DAT knockout mice were also monitored Uptake rates in the cingulate and prelimbic cortex are so slow that catecholamines can exist in the extracellular fluid for sufficient time to travel approximately 100 microm The results support heterologous uptake of catecholamines and volume transmission in the PFC of mice
TL;DR: Results suggest that NM is a more complex pigment than synthetic dopaminemelanin formed via dopamine autoxidation alone, and suggests a peptide component in NMstructure.
Abstract: Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.
TL;DR: It is demonstrated that the fetal lethality of Insm1 mutant mice is caused by catecholamine deficiency, which highlights the importance of InSm1 in the development of the sympatho-adrenal lineage.
Abstract: Insm1 (IA-1) encodes a Zn-finger factor that is expressed in the developing nervous system. We demonstrate here that the development of the sympatho-adrenal lineage is severely impaired in Insm1 mutant mice. Differentiation of sympatho-adrenal precursors, as assessed by the expression of neuronal subtype-specific genes such as Th and Dbh, is delayed in a pronounced manner, which is accompanied by a reduced proliferation. Sympathetic neurons eventually overcome the differentiation blockade and mature correctly, but sympathetic ganglia remain small. By contrast, terminal differentiation of adrenal chromaffin cells does not occur. The transcription factors Mash1 (Ascl1), Phox2a, Gata3 and Hand2 (previously dHand) control the differentiation of sympatho-adrenal precursor cells, and their deregulated expression in Insm1 mutant mice demonstrates that Insm1 acts in the transcriptional network that controls differentiation of this lineage. Pronounced similarities between Mash1 and Insm1 phenotypes are apparent, which suggests that Insm1 might mediate aspects of Mash1 function in the subtype-specific differentiation of sympatho-adrenal precursors. Noradrenaline is the major catecholamine produced by developing sympatho-adrenal cells and is required for fetal survival. We demonstrate that the fetal lethality of Insm1 mutant mice is caused by catecholamine deficiency, which highlights the importance of Insm1 in the development of the sympatho-adrenal lineage.
TL;DR: Combined inhibition of dopamine (DA)/norepinephrine (NE) reuptake improves exercise performance and increases core temperature in the heat as discussed by the authors, and this effect may primaril...
Abstract: Combined inhibition of dopamine (DA)/norepinephrine (NE) reuptake improves exercise performance and increases core temperature in the heat. A recent study demonstrated that this effect may primaril...
TL;DR: An essential role for activity-evoked cytoskeletal rearrangement and the action of myosin II in the regulation of catecholamine and neuropeptide exocytosis is demonstrated and represents an essential element of the sympathetic stress response.
Abstract: Chromaffin cells of the adrenal medulla are innervated by the sympathetic nervous system. Stimulation causes chromaffin cells to fire action potentials, leading to the exocytosis of various classes of transmitters into the circulation. Low-frequency electrical stimulation (action potentials delivered at 0.5 Hz) causes adrenal chromaffin cells to selectively release catecholamines through a kiss-and-run fusion event. Elevated electrical stimulation (action potentials at 15 Hz) evokes fusion pore dilation, full granule collapse, and additional release of the neuropeptide-containing proteinaceous granule core. Here we apply single-cell electrophysiological, electrochemical, and fluorescence measurements to investigate the cellular mechanism for this shift in exocytic behavior. We show that at low-frequency stimulation, a filamentous-actin cell cortex plays a key role in stabilizing the kiss-and-run fusion event. Increased stimulation disrupts the actin cortex, driving full granule collapse. We show that pharmacological perturbation of the actin cortex supersedes stimulus frequency in controlling exocytic mode. Finally, we show that nonmuscle myosin II activation contributes to the cytoskeleton-dependent control of the fusion event. Inhibition of myosin II or myosin light chain kinase under elevated stimulation frequencies inhibits fusion pore dilation and maintains the granule in a kiss-and-run mode of exocytosis. These results demonstrate an essential role for activity-evoked cytoskeletal rearrangement and the action of myosin II in the regulation of catecholamine and neuropeptide exocytosis and represent an essential element of the sympathetic stress response.
TL;DR: Elevated dopamine‐β‐hydroxylase activity in ID provides a tentative explanation for the increased NE response to l‐DOPA, providing new evidence that ID results in altered synthesis and functioning of DAT and perhaps suggests some compensatory changes in NE metabolism.
Abstract: Iron deficiency (ID) disrupts brain dopamine (DA) and norepinephrine (NE) metabolism including functioning of monoamine transporters and receptors. We employed caudate microdialysis and no net flux (NNF) in post-weaning rats to determine if ID decreased the extraction fraction (Ed). Five micromolar quinpirole, a dopamine D2 receptor agonist, resulted in 80% decrease in extracellular DA and 45% higher Ed in control animals. The D2 agonist had no effect on Ed in ID animals despite a reduction in basal DA. DAT mRNA levels were reduced by 58% with ID, while DAT protein in ventral midbrain and caudate and membrane associated DAT were also reduced by ID. Carbidopa/l-DOPA was administered to determine if elevated extracellular DA in ID was due to increased release. The DA response to l-DOPA in ID rats was 50% smaller and delayed, whereas the NE response was threefold higher. The caudate concentration of NE was also elevated in ID. Elevated dopamine-β-hydroxylase activity in ID provides a tentative explanation for the increased NE response to l-DOPA. These experiments provide new evidence that ID results in altered synthesis and functioning of DAT and perhaps suggests some compensatory changes in NE metabolism.
TL;DR: The dopamine transporter requires an intact catechol with a primary ethylamine side chain for optimal activity relative to shorter side chain derivatives (side chains longer than two carbons were not tested), the 3‐hydroxylgroup of dopamine is the more critical hydroxyl group, and the β rotamer of the extended conformation of dopamine are transported preferentially.
Abstract: The apparent second-order association rate constant of dopamine binding to the striatal transporter (approximately 1 x 10(6) M-1 s-1) as well as the transporter turnover number (approximately 1.5 s-1) was estimated using rotating disk electrode voltammetry to monitor apparent zero trans entry of dopamine into striatal suspensions. The substrate specificity of the transporter was also assessed using catechol derivatives. Dopamine and norepinephrine were transported, whereas epinephrine and the acidic metabolites of dopamine were not transported. The metabolite, 3-methoxytyramine, was transported with a Km seven times greater than and a Vmax close to that for dopamine. 4-Methoxytyramine was transported more facilely than the 3-methoxy derivative. N-Alkylation of the amine side chain of dopamine reduced transport dramatically. 4-Ethylcatechol and 3,4-dihydroxybenzylamine were transported with velocities 79 and 91% less than that for dopamine, respectively. The rigid analogue 6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene was transported with a greater velocity than the 5,7-dihydroxy derivative. Finally, the apparent Km values for 4-ethylcatechol, 1-amino-2-phenylethane, tyramine, and m-tyramine as cosubstrates with dopamine were 1.1, 11, 17, and 2.6 microM, respectively. Pretreatments of striatal suspensions with chloroethylnorapomorphine, N-ethylmaleimide, Hg2+, 4,5-dihydroxy-4,5-dioxo-1H-pyrrolo[2,3-f] quinoline-2,7,9-tricarboxylic acid (a redox modulator of receptors in neuronal as well as other tissues), and neuraminidase reduced the velocity of transport of dopamine, whereas N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline had no effect. Thus, the dopamine transporter requires an intact catechol with a primary ethylamine side chain for optimal activity relative to shorter side chain derivatives (side chains longer than two carbons were not tested), the 3-hydroxyl group of dopamine is the more critical hydroxyl group, and the beta rotamer of the extended conformation of dopamine is transported preferentially. The catechol appears to mediate the recognition of the substrate, whereas the amine side chain apparently facilitates the conformational change of the transporter that results in movement of dopamine into or across the membrane.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: It is demonstrated for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD, as steady state levels of 24‐OHC and 27‐OHCs are tightly regulated in the brain, and disturbances in these levels may contribute to the pathogenic of PD.
Abstract: Evidence suggests that environmental and dietary factors may contribute to the pathogenesis of Parkinson's disease (PD). High dietary intake of cholesterol is such a factor that has been shown to increase or decrease the risk of PD. However, because circulating cholesterol does not cross the blood-brain barrier, the mechanisms linking dietary cholesterol to the pathogenesis of PD remain to be understood. In contrast to cholesterol, the oxidized cholesterol metabolites (oxysterols), 24S-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), can cross the blood-brain barrier and may place the brain at risk of degeneration. In this study, we incubated the human neuroblastoma SH-SY5Y cells for 24 h with 24-OHC, 27-OHC, or a mixture of 24-OHC plus 27-OHC, and have determined effects on tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis) levels, alpha-synuclein levels, and apoptosis. We demonstrate that while 24-OHC increases the levels of tyrosine hydroxylase, 27-OHC increases levels of alpha-synuclein, and induces apoptosis. Our findings show for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD. As steady state levels of 24-OHC and 27-OHC are tightly regulated in the brain, disturbances in these levels may contribute to the pathogenesis of PD.
TL;DR: It is estimated that DA constitutes 2%-4% of the catecholamine released by exocytosis from sympathetic nerves and that 50%-90% of plasma DA has a sympathoneural source.
Abstract: Background: Determinants of plasma norepinephrine (NE) and epinephrine concentrations are well known; those of the third endogenous catecholamine, dopamine (DA), remain poorly understood. We tested in humans whether DA enters the plasma after corelease with NE during exocytosis from sympathetic noradrenergic nerves.
Methods: We reviewed plasma catecholamine data from patients referred for autonomic testing and control subjects under the following experimental conditions: during supine rest and in response to orthostasis; intravenous yohimbine (YOH), isoproterenol (ISO), or glucagon (GLU), which augment exocytotic release of NE from sympathetic nerves; intravenous trimethaphan (TRI) or pentolinium (PEN), which decrease exocytotic NE release; or intravenous tyramine (TYR), which releases NE by nonexocytotic means. We included groups of patients with pure autonomic failure (PAF), bilateral thoracic sympathectomies (SNS-x), or multiple system atrophy (MSA), since PAF and SNS-x are associated with noradrenergic denervation and MSA is not.
Results: Orthostasis, YOH, ISO, and TYR increased and TRI/PEN decreased plasma DA concentrations. Individual values for changes in plasma DA concentrations correlated positively with changes in NE in response to orthostasis ( r = 0.72, P < 0.0001), YOH ( r = 0.75, P < 0.0001), ISO ( r = 0.71, P < 0.0001), GLU ( r = 0.47, P = 0.01), and TYR ( r = 0.67, P < 0.0001). PAF and SNS-x patients had low plasma DA concentrations. We estimated that DA constitutes 2%–4% of the catecholamine released by exocytosis from sympathetic nerves and that 50%–90% of plasma DA has a sympathoneural source.
Conclusions: Plasma DA is derived substantially from sympathetic noradrenergic nerves.
TL;DR: Results not only indicate that in vivo adrenal gene transfer is an effective way of manipulating adrenal gland signalling, but also identify GRK2 as a critically important molecule involved in CA secretion.
TL;DR: Diminished levels of 22:6n‐3 docosahexaenoic acid, the most ubiquitous metabolite generated by LNA is proposed to reduce the anti‐oxidant arsenal in the developing brain and cause microglia activation and enhanced oxidative stress to increase the risk of certain DA‐associated neurological disorders.
Abstract: The consequences of maternal linolenic acid (LNA, 18:3n-3) dietary deficiency on key dopamine (DA)-associated regulatory proteins in mesolimbic and mesocortical structures of the postnatal rat brain have been investigated. A marked (4.5-fold) decrease of the DA-synthesizing enzyme tyrosine hydroxylase accompanied by a down-regulation (approx 7.5-fold) of the vesicular monoamine transporter (VMAT-2) and a depletion of VMAT-associated vesicles in the hippocampus were observed in deficient offspring compared with adequately fed controls. The DA transporter (DAT) was not affected by the LNA deficiency indicative of a DAT/VMAT-2 ratio increase that may enhance the risk of damage of the dopaminergic (DAergic) terminal. A robust increase in DA receptor (DAR1 and DAR2) levels was noticed in the cortex and striatum structures possibly to compensate for the low levels of DA in synaptic clefts. Microglia activation characterized by enhanced levels of ED1 antibody and nuclear internalization of p65 NFκB was noticed following LNA deficiency. Diminished levels of 22:6n-3 docosahexaenoic acid (Schiefermeier and Yavin 2002), the most ubiquitous metabolite generated by LNA is proposed to reduce the anti-oxidant arsenal in the developing brain and cause microglia activation and enhanced oxidative stress to increase the risk of certain DA-associated neurological disorders.
TL;DR: Blunted increases in norepinephrine following stress with increasing OC potentially mirroring blunted stress reactivity of the sympathetic nervous system are suggested.
TL;DR: Accumulating evidence documents the endogenous peptide catestatin as a novel regulator of cardiac function and blood pressure.
Abstract: Catestatin is a 21-amino acid residue, cationic and hydrophobic peptide that is formed endogenously by proteolytic cleavage of its precursor chromogranin A, a major protein co-stored and co-released with catecholamines from the storage vesicles in adrenal chromaffin cells and adrenergic neurons. This peptide exhibits potent catecholamine release-inhibitory activity by acting on the neuronal nicotinic acetylcholine receptor. It also stimulates histamine release from mast cells via heterotrimeric G-proteins in a receptor-independent manner. Plasma levels of catestatin are diminished not only in hypertensive patients but also in their still-normotensive offspring, indicating its role in the pathogenesis of hypertension. Consistently, exogenous catestatin rescues hypertension in chromogranin A knockout mice and diminishes blood pressure responses to activation of sympathetic outflow in rats. These hypotensive actions of catestatin may be caused directly by autocrine inhibition of catecholamine release from the sympathoadrenal system and indirectly by paracrine stimulation of the potent vasodilator histamine release from mast cells. Recently, three human variants of catestatin displaying differential potencies for inhibition of catecholamine secretion have been identified. One of these variants (Gly364Ser) causes increased baroreceptor sensitivity, increased cardiac parasympathetic activity, and decreased cardiac sympathetic activity, and it seems to alter the risk for hypertension. These cardiovascular effects may have resulted by action of this peptide in the baroreceptor centre of the nucleus tractus solitarius. Thus, accumulating evidence documents the endogenous peptide catestatin as a novel regulator of cardiac function and blood pressure.
TL;DR: Citalopram and talopram are structurally closely related, but they have very distinct pharmacological profiles as selective inhibitors of the serotonin and norepinephrine transporters, respectively.
Abstract: Citalopram and talopram are structurally closely related, but they have very distinct pharmacological profiles as selective inhibitors of the serotonin and norepinephrine transporters, respectively. A systematic structure−activity relationship study was performed, in which each of the four positions distinguishing the two compounds were varied. The inhibitory potencies of the resulting 16 compounds were tested at both serotonin and norepinephrine transporters. This showed that particularly two of the four positions are determinants for the biological activity.
TL;DR: The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe.
Abstract: Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. ...
TL;DR: The results show that PNS may produce a complex change in accumbal dopamine and noradrenaline transmission, and the possibility that these changes might be correlated with the development of psychiatric disorders or with an increased vulnerability to drug addiction.
Abstract: Gestational stress [prenatal stress (PNS)] has been associated with low birth weight, preterm delivery, and higher vulnerability to psychiatric disorders such as schizophrenia, depression or attention deficit with hyperactivity disorder. The alteration of catecholamine transmission has been attributed a major role in the etiology of psychiatric disturbances. We investigated the effect of PNS on basal and stimulated dopamine and noradrenaline output in the nucleus accumbens of freely moving adolescent and young adult rats (30-35 and 60-70 postnatal days respectively) because of the importance of this area in drug dependence and possibly in psychiatric disorders that are treated with drugs that act on dopamine and noradrenaline transmission. Stimulation was obtained with intraperitoneal amphetamine (0.25 mg/kg) or subcutaneous nicotine (0.4 mg/kg). The results showed the following: (i) basal and amphetamine-stimulated dopamine output in adolescent and adult PNS rats is higher than in controls; (ii) nicotine-stimulated dopamine output is lower than in controls in adolescent but not in adult PNS rats; (iii) basal noradrenaline output is lower than in controls in adolescent but not in adult PNS rats; (iv) amphetamine-stimulated noradrenaline output is higher than in controls in adult but not in adolescent PNS rats; (v) nicotine-stimulated noradrenaline output in PNS rats is higher than in controls, although only in adults. These results show that PNS may produce a complex change in accumbal dopamine and noradrenaline transmission. We discuss the possibility that these changes might be correlated with the development of psychiatric disorders or with an increased vulnerability to drug addiction.
TL;DR: The ability of a CB1 antagonist applied locally in the frontal cortex of adult male Sprague-Dawley rats, to block the actions of systemic WIN 55,212-2 was examined, suggesting activation of cortical cannabinoid receptors contributes to alterations in norepinephrine levels in this brain region.
TL;DR: In conclusion, during HS intake, the increased dopamine production via Na/K-ATPase inhibition prevents an increase in BP in the presence of oxidative stress, which results from a defective renal D1R function leading to the failure of dopamine to inhibit Na-K- ATPase and promote sodium excretion.
Abstract: Renal dopamine plays an important role in maintaining sodium homeostasis and blood pressure (BP) during increased sodium intake. The present study was carried out to determine whether renal dopamine D1 receptor (D1R) dysfunction contributes to increase in salt sensitivity during oxidative stress. Male Sprague-Dawley rats, divided into various groups, received tap water (vehicle); 1% NaCl (high salt [HS]); L-buthionine sulfoximine (BSO), an oxidant; and HS plus BSO with or without Tempol, an antioxidant, for 12 days. Compared with vehicle, HS intake increased urinary dopamine production and decreased basal renal Na/K-ATPase activity but did not affect BP. BSO-treated rats exhibited oxidative stress and a mild increase in BP. In these rats, D1R expression and G protein coupling were reduced, and SKF38393, a D1R agonist, failed to inhibit Na/K-ATPase activity and promote sodium excretion. Concomitant administration of BSO and HS caused oxidative stress, D1R dysfunction, and a marked increase in BP. Although renal dopamine production was increased, it failed to reduce the basal Na/K-ATPase activity in these animals. Treatment of BSO plus HS rats with Tempol decreased oxidative stress and restored endogenous, as well as exogenous, D1R agonist-mediated Na/K-ATPase inhibition and normalized BP. In conclusion, during HS intake, the increased dopamine production via Na/K-ATPase inhibition prevents an increase in BP. During oxidative stress, D1R function is defective, and there is mild hypertension. However, in the presence of oxidative stress, HS intake causes marked elevation in BP, which results from a defective renal D1R function leading to the failure of dopamine to inhibit Na/K-ATPase and promote sodium excretion.
TL;DR: It is suggested that NO is capable of attenuating cutaneous vasoconstrictor responsiveness to norepinephrine via postsynaptic mechanisms, as well as an orthostatic stress in the heat-stressed human.
Abstract: Previously, we found that nitric oxide (NO) inhibits cutaneous vasoconstrictor responsiveness evoked by whole body cooling, as well as an orthostatic stress in the heat-stressed human (Shibasaki M, Durand S, Davis SL, Cui J, Low DA, Keller DM, Crandall CG J Physiol 585: 627–634, 2007) However, it remains unknown whether this response occurs via NO acting through presynaptic or postsynaptic mechanisms The aim of this study was to test the hypothesis that NO is capable of impairing cutaneous vasoconstriction via postsynaptic mechanisms Skin blood flow was monitored over two forearm sites where intradermal microdialysis membranes were previously placed Skin blood flow was elevated four- to fivefold through perfusion of the NO donor sodium nitroprusside at one site and through perfusion of adenosine (primarily non-NO mechanisms) at a second site Once a plateau in vasodilation was evident, increasing concentrations of norepinephrine (1 × 10−8 to 1 × 10−2 M) were administrated through both microdialysis probes, while the aforementioned vasodilator agents continued to be perfused Cutaneous vascular conductance was calculated by dividing skin blood flow by mean arterial blood pressure The administration of norepinephrine decreased cutaneous vascular conductance at both sites However, the dose of norepinephrine at the onset of vasoconstriction (−59 ± 13 vs −72 ± 07 log M norepinephrine, P = 0021) and the concentration of norepinephrine resulting in 50% of the maximal vasoconstrictor response (−49 ± 12 vs −61 ± 02 log M norepinephrine dose; P = 0012) occurred at significantly higher norepinephrine concentrations for the sodium nitroprusside site relative to the adenosine site, respectively These results suggested that NO is capable of attenuating cutaneous vasoconstrictor responsiveness to norepinephrine via postsynaptic mechanisms