Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

Introduction: Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Methods: Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Results: Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. Conclusions: This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release

NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression

This is the publisher's version, also available electronically from http://www.jneurosci.org/content/32/25/8574Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality

Subclinical atherosclerosis is linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms

Aim To assess the rate of matrix Gla-protein carboxylation in patients with small intestinal bacterial overgrowth (SIBO) and to decipher its association with subclinical atherosclerosis. METHODS Patients with suspected SIBO who presented with a low risk for cardiovascular disease and showed no evidence of atherosclerotic plaques were included in the study. A glucose breath test was performed in order to confirm the diagnosis of SIBO and vascular assessment was carried out by ultrasound examination. Plasma levels of the inactive form of MGP (dephosphorylateduncarboxylated matrix Gla-protein) were quantified by ELISA and vitamin K2 intake was estimated using a food frequency questionnaire. RESULTS Thirty-nine patients were included in the study. SIBO was confirmed in 12/39 (30.8%) patients who also presented with a higher concentration of dephosphorylated-uncarboxylated matrix Gla-protein (9.5 \u3bc g/L vs 4.2 \u3bc g/L; P = 0.004). Arterial stiffness was elevated in the SIBO group (pulse-wave velocity 10.25 m/s vs 7.68 m/s; P = 0.002) and this phenomenon was observed to correlate linearly with the levels of dephosphorylated-uncarboxylated matrix Gla-protein ( f = 0.220, R 2 = 0.366, P = 0.03). Carotid intima-media thickness and arterial calcifications were not observed to be significantly elevated as compared to controls. CONCLUSION SIBO is associated with reduced matrix Gla-protein activation as well as arterial stiffening. Both these observations are regarded as important indicators of subclinical atherosclerosis. Hence, screening for SIBO, intestinal decontamination and supplementation with vitamin K2 has the potential to be incorporated into clinical practice as additional preventive measures

Radial Artery as a Coronary Artery Bypass Conduit:20-Year Results

BACKGROUND: There is a lack of evidence for the choice of the second conduit in coronary surgery. The radial artery (RA) is a possible option, but few data on very-long-term outcomes exist. OBJECTIVES: This study describes 20-year results of RA grafts used for coronary artery bypass grafting and the effects of RA removal on forearm circulation. METHODS: We report the results of the prospective 20-year follow-up of the first 100 consecutive patients who received the RA as a coronary bypass conduit at our institution. RESULTS: Follow-up was 100% complete. There were 64 deaths, 23 (35.9%) from cardiovascular causes. Kaplan-Meier 20-year survival was 31%. Of the 36 survivors, 33 (91.6%) underwent RA graft control at a mean of 19.0 \ub1 2.5 years after surgery. The RA was found to be patent in 24 cases (84.8% patency). In the overall population, probability of graft failure at 20 years was 19.0 \ub1 0.2% for the left internal thoracic artery (ITA), 25.0 \ub1 0.2% for the RA, and 55.0 \ub1 0.2% for the saphenous vein (p = 0.002 for RA vs. saphenous vein, 0.11 for RA vs. ITA, and p 90%, but not location of distal anastomosis, significantly influenced long-term RA graft patency. No patients reported hand or forearm symptoms. The ulnar artery diameter was increased in the operated arm (2.44 \ub1 0.43 mm vs. 2.01 \ub1 0.47 mm; p < 0.05) and correlated with the peak systolic velocity of the second palmar digital artery (Pearson coefficient: 0.621; p < 0.05). CONCLUSIONS: The 20-year patency rate of RA grafts is good, and not inferior to the ITA, especially when the conduit is used to graft a vessel with >90% stenosis. RA harvesting does not lead to hand or forearm symptoms, even at a very-long-term follow-up

Computing the effective action with the functional renormalization group

The \u201cexact\u201d or \u201cfunctional\u201d renormalization group equation describes the renormalization group flow of the effective average action \u393 k. The ordinary effective action \u393 0 can be obtained by integrating the flow equation from an ultraviolet scale k= \u39b down to k= 0. We give several examples of such calculations at one-loop, both in renormalizable and in effective field theories. We reproduce the four-point scattering amplitude in the case of a real scalar field theory with quartic potential and in the case of the pion chiral Lagrangian. In the case of gauge theories, we reproduce the vacuum polarization of QED and of Yang\u2013Mills theory. We also compute the two-point functions for scalars and gravitons in the effective field theory of scalar fields minimally coupled to gravity. \ua9 2016, The Author(s)