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Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2+/−) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2+/− mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2+/− mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2+/− mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2+/− mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions. © 2020 The Authors.

A device with four parallel channels was designed and manufactured by 3D printing in titanium. A simple experimental setup allowed splitting of the mobile phase in four parallel streams, such that a single sample could be analysed four times simultaneously. The four capillary channels were filled with a monolithic stationary phase, prepared using a zwitterionic functional monomer in combination with various dimethacrylate cross-linkers. The resulting stationary phases were applicable in both reversed-phase and hydrophilic-interaction retention mechanisms. The mobile-phase composition was optimized by means of a window diagram so as to obtain the highest possible resolution of dopamine precursors and metabolites on all columns. Miniaturized electrochemical detectors with carbon fibres as working electrodes and silver micro-wires as reference electrodes were integrated in the device at the end of each column. Experimental separations were successfully compared with those predicted by a three-parameter retention model. Finally, dopamine was determined in human urine to further confirm applicability of the developed device., Bylo navrženo a pomocí 3D tisku titanu vyrobeno zařízení se čtyřmi paralelními kanály. Jednoduché experimentální uspořádání umožnilo rozdělit mobilní fázi na čtyři paralelní proudy, tudíž bylo možné analyzovat najednou jeden vzorek čtyřikrát. Čtyři kapilární kanály byly naplněny monolitickou stacionární fází, připravenou ze zwitterionického funkčního monomeru v kombinaci s různých cross-linkery na bázi dimethakrylátu. Výsledné stacionární fáze byly použitelné jak pro retenci v systému obrácených fází, tak i pro HILIC. Složení mobilní fáze bylo optimalizováno okénkovým diagramem pro co největší rozlišení prekurzorů dopaminu a jeho metabolitů na všech kolonách. Miniaturizované elektrochemické detektory z uhlíkových mikroelektrod jako pracovní a stříbrných mikrodrátků jako referentní elektrody byly integrovány do konců každé kolony. Experimentální separace byly úspěšně porovnány s tříparametrickým retenčním modelem. Závěrem byl stanovován dopamin v lidské moči k potvrzení využitelnosti tohoto zařízení.

Background: Aberrant dopaminergic activity within fronto-striato-thalamic (FST) circuits is thought to contribute to psychosis onset. It remains unclear whether primary abnormality arises from bottom-up subcortical signaling or impaired top-down cortical regulation. We mapped causal interactions (effective connectivity) of dorsal and ventral FST circuits across the psychosis continuum and identified connections associated with striatal dopamine synthesis. Method(s): Spectral dynamic causal modelling (DCM) for resting-state functional magnetic resonance imaging (fMRI) modelled FST effective connectivity in: (1) 46 antipsychotic-naive first-episode psychosis (FEP) patients and 23 controls; (2) 36 established schizophrenia (SCZ) patients and 100 controls; and (3) 33 healthy individuals assessed for psychosis-like experiences (PLEs) with concurrent [18F]DOPA positron emission tomography. DCM estimated FST connectivity in patients and their respective controls, associations with symptom severity in all cohorts, and with striatal [18F]DOPA uptake in the PLE group. Result(s): Patients commonly showed midbrain disinhibition and reduced top-down influence of thalamus on nucleus accumbens. Cortical dysfunction was only apparent in the SCZ group. Positive symptoms were primarily associated with bottom-up connectivity in FEP and a mixture of bottom-up and top-down connectivity in SCZ and PLE groups, with disinhibition of ventromedial prefrontal cortex and extrinsic connectivity of the midbrain implicated across all cohorts. Thalamic and midbrain connectivity were associated with striatal [18F]DOPA uptake. Conclusion(s): We identified a primary role for subcortical dysconnectivity in psychosis, with cortical dysfunction emerging in established illness. Effective connectivity of the midbrain and thalamus are robustly linked to positive symptom severity and striatal dopamine synthesis capacity, suggesting a central role in the emergence of psychotic symptoms. Supported By: Nationa

Background: Aberrant dopaminergic activity within fronto-striato-thalamic (FST) circuits is thought to contribute to psychosis onset. It remains unclear whether primary abnormality arises from bottom-up subcortical signaling or impaired top-down cortical regulation. We mapped causal interactions (effective connectivity) of dorsal and ventral FST circuits across the psychosis continuum and identified connections associated with striatal dopamine synthesis. Method(s): Spectral dynamic causal modelling (DCM) for resting-state functional magnetic resonance imaging (fMRI) modelled FST effective connectivity in: (1) 46 antipsychotic-naive first-episode psychosis (FEP) patients and 23 controls; (2) 36 established schizophrenia (SCZ) patients and 100 controls; and (3) 33 healthy individuals assessed for psychosis-like experiences (PLEs) with concurrent [18F]DOPA positron emission tomography. DCM estimated FST connectivity in patients and their respective controls, associations with symptom severity in all cohorts, and with striatal [18F]DOPA uptake in the PLE group. Result(s): Patients commonly showed midbrain disinhibition and reduced top-down influence of thalamus on nucleus accumbens. Cortical dysfunction was only apparent in the SCZ group. Positive symptoms were primarily associated with bottom-up connectivity in FEP and a mixture of bottom-up and top-down connectivity in SCZ and PLE groups, with disinhibition of ventromedial prefrontal cortex and extrinsic connectivity of the midbrain implicated across all cohorts. Thalamic and midbrain connectivity were associated with striatal [18F]DOPA uptake. Conclusion(s): We identified a primary role for subcortical dysconnectivity in psychosis, with cortical dysfunction emerging in established illness. Effective connectivity of the midbrain and thalamus are robustly linked to positive symptom severity and striatal dopamine synthesis capacity, suggesting a central role in the emergence of psychotic symptoms. Supported By: Nationa

Background: Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and ant-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive. Methods: We compared various behavioral and biochemical parameters between Nur77 knockout −/− and wild-type +/+ mice in basal and haloperidol-challenged conditions. Results: We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are associated with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression. Conclusion: Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.

Background: Animal studies have demonstrated an interaction within the striatum between the angiotensin and dopaminergic systems. In rats, the angiotensin converting enzyme (ACE) inhibitor, perindopril, crosses the blood brain barrier and increases striatal dopamine synthesis and release. In humans, angiotensin type 1 receptors have been found on dopaminergic neurons in the substantia nigra and striatum. In Parkinson's disease, there is a marked reduction of these receptors associated with the nigrostriatal dopaminergic neuron loss. Aim(s): We performed a double blind placebo controlled crossover pilot study in seven patients to investigate the effect of the ACE inhibitor, perindopril on the clinical features of moderately severe Parkinson's disease. Result(s): After a four week treatment period with perindopril, patients had a faster onset in their motor response to L-dopa and a reduction in 'on phase' peak dyskinesia, p=0.021 and p=0.014 respectively. Patients also reported more 'on' periods during their waking day in their movement diary, p=0.007. Perindopril was well tolerated without any significant postural hypotension or renal dysfunction. Conclusion(s): These results suggest that ACE inhibitors such as perindopril may have a place in the management of motor fluctuations and dyskinesia in Parkinson's disease and justify further study.

Striatal injury increases dopamine metabolism in the nigrostriatal system but it is unclear whether this response is due to increased synthesis and activation of tyrosine hydroxylase within existing dopamine terminals and/or branching and sprouting of new terminals. While monitoring the density of tyrosine hydroxylase immunoreactive fibers suggests that sprouting occurs, this technique alone cannot adequately answer this question since the intensity of staining and thus the visibility of individual fibers are intimately linked to dopaminergic activity. However, by examining axons and their branches using markers that are independent of dopamine metabolism it is possible to determine whether dopaminergic sprouting does in fact take place. One month after using a Scouten wire knife to create a small lesion in the left striatum of normal C57/bl-6 mice, silver staining revealed an increase in the total number of neuronal fibers throughout the injured striatum. This was accompanied by intense staining of tyrosine hydroxylase- positive fibers around the wound and an increased density of striatal fibers labeled with dextran-biotin after injection of this neuronal tracer into the substantia nigra 1 month after striatal surgery and 5 days prior to sacrifice. The increase in tyrosine hydroxylase immunoreactivity confirms previous observations of increased dopaminergic activity after striatal injury. The increases in silver staining and dextran-biotin transport provide independent evidence that this increase in dopaminergic activity occurs because of sprouting of new fibers originating in the substantia nigra.

Background: Animal studies have demonstrated an interaction within the striatum between the angiotensin and dopaminergic systems. In rats, the angiotensin converting enzyme (ACE) inhibitor, perindopril, crosses the blood brain barrier and increases striatal dopamine synthesis and release. In humans, angiotensin type 1 receptors have been found on dopaminergic neurons in the substantia nigra and striatum. In Parkinson's disease, there is a marked reduction of these receptors associated with the nigrostriatal dopaminergic neuron loss. Aim(s): We performed a double blind placebo controlled crossover pilot study in seven patients to investigate the effect of the ACE inhibitor, perindopril on the clinical features of moderately severe Parkinson's disease. Result(s): After a four week treatment period with perindopril, patients had a faster onset in their motor response to L-dopa and a reduction in 'on phase' peak dyskinesia, p=0.021 and p=0.014 respectively. Patients also reported more 'on' periods during their waking day in their movement diary, p=0.007. Perindopril was well tolerated without any significant postural hypotension or renal dysfunction. Conclusion(s): These results suggest that ACE inhibitors such as perindopril may have a place in the management of motor fluctuations and dyskinesia in Parkinson's disease and justify further study.

Striatal injury increases dopamine metabolism in the nigrostriatal system but it is unclear whether this response is due to increased synthesis and activation of tyrosine hydroxylase within existing dopamine terminals and/or branching and sprouting of new terminals. While monitoring the density of tyrosine hydroxylase immunoreactive fibers suggests that sprouting occurs, this technique alone cannot adequately answer this question since the intensity of staining and thus the visibility of individual fibers are intimately linked to dopaminergic activity. However, by examining axons and their branches using markers that are independent of dopamine metabolism it is possible to determine whether dopaminergic sprouting does in fact take place. One month after using a Scouten wire knife to create a small lesion in the left striatum of normal C57/bl-6 mice, silver staining revealed an increase in the total number of neuronal fibers throughout the injured striatum. This was accompanied by intense staining of tyrosine hydroxylase- positive fibers around the wound and an increased density of striatal fibers labeled with dextran-biotin after injection of this neuronal tracer into the substantia nigra 1 month after striatal surgery and 5 days prior to sacrifice. The increase in tyrosine hydroxylase immunoreactivity confirms previous observations of increased dopaminergic activity after striatal injury. The increases in silver staining and dextran-biotin transport provide independent evidence that this increase in dopaminergic activity occurs because of sprouting of new fibers originating in the substantia nigra.

Background: Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and ant-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive. Methods: We compared various behavioral and biochemical parameters between Nur77 knockout −/− and wild-type +/+ mice in basal and haloperidol-challenged conditions. Results: We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are associated with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression. Conclusion: Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.

There is evidence that the dopaminergic system is sensitive to altered pO2 in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of fifteen newborn piglets (2 - 5 days old). Two PET scans were performed in each piglet. Eleven animals underwent a period of normoxia and moderate hypoxia/hypercapnia (H/H). The remaining four animals were used as an untreated control group. Simultaneously, the brain tissue pO2 was recorded, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rate of oxygen (CMRO2) was determined. In addition, in four untreated and six H/H treated piglets the relative amounts of fluorodopamine and the respective metabolites were determined in brain tissue samples using HPLC analysis. H/H conditions were induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding CO2 to the inspired gas resulting in an arterial pO2 between 74 and 79 mmHg. H/H elicited a more than 3-fold increase of the CBF(P < 0.05) so that CMRO2 remained unchanged throughout the H/H period. Despite this, the brain tissue pO2 was reduced from 19 ± 4 to 6 ± 3 mmHg /P < 0.05). The permeability-surface area product of FDOPA (PSFDOPA) was unchanged. However, the transfer rate of FDOPA (k3FDOPA of the nigrostriatal dopaminergic system and the relative amounts of fluorodopamine and the respective metabolites were significantly increased (P < 0.05). It is suggested that H/H induces an increase of AADC activity. However, an H/H-induced CBF increase m

Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to asphyxia. However, the respective enzyme activities have not yet been measured in the living neonatal brain. In this study, we hav used F18-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron-emission tomography l(PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine (DA), in the brain of newborn piglets. Simultaneously, the cerebral blood flow (CBF) was measured with colored microspheres. Asphyxia elicited an up to threefold increase of the CBF. Despite this, the blood-brdain transfer of FDOPA as well as the clearance rate constants from brain were unchanged. However, the synthesis rate of FDA from FDOPA was significantly increased in frontal cortex, striatum, and midbrain. The increase of the AADC activity and the decrease of monoamine oxidase activity may contribute to the increase of extracellular DA during asphyxia which is expected to be involved in severe disturbances of neuronal metabolism, e.g., by generating free radicals.

The effect of an acute intraperitoneal (i.p.) injection of acetaldehyde, 20 mg/kg or 100 mg/kg, on the microdialysate content of both amino acids and monoamines was studied in the nucleus accumbens (NA) by a microdialysis technique. Acetaldehyde, AGH, which was detectable at levels of 50-130 mu Lmol/g brain tissue 10 min after injection, evoked a significant decrease in the extracellular microdialysis dopamine content, which was sustained for the period of the study, i.e. 120 min. Homovanillic acid, HVA, decreased significantly when the lower dose of ACH was administered while dihydrophenylacetic acid, DOPAC, showed no significant change with either dose of ACH during the period of the study. Serotonin levels decreased significantly after both doses of acetaldehyde, with significant increases of its major metabolite, hydroxyindolacetic acid, 5-HIAA, with the higher acetaldehyde dose. Taurine increased significantly, only during the first twenty minutes, after both doses of acetaldehyde, although neither of the excitatory amino acids assayed, glutamate and aspartate, nor the inhibitory amino acid, GABA, showed any significant changes. Acetaldehyde clearly evokes significant perturbation ill the monoamine content of the NA, such changes being the converse to those reported for monoamines after ethanol administration, which might indicate a negative reinforcement effect. (C) 1997 Published by Elsevier Science Ltd.

Congestive heart failure (CHF) is a complex clinical syndrome in which the kidney has a central pathophysiological role. An imbalance between vasoconstrictor-antinatriuretic and vasodilator-natriuretic forces is a key feature of the pathophysiology of CHF. This review summarizes current understanding of disturbances in vasodilator-natriuretic systems in CHF. The key vasodilator systems involved are: the natriuretic peptide family atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), urodilatin, dopamine (DA), endothelium-derived relaxing factors and prostaglandins. Renal responses to ANP are blunted in CHF, under the influence of haemodynamic, neuro-humoral, receptor and post-receptor events. BNP, secreted in response to left ventricular load, may circulate in high concentrations in CHF, with similar effects to ANP. Urodilatin is a newly discovered peptide of renal origin whose physiological role is under investigation. Neural endopeptidase inhibitors have shown some promise in the treatment of human CHF, particularly when combined with ACE inhibition or angiotensin II receptor blockade. The renal DA system is influenced by sodium intake and DA metabolism is altered in CHF. The place of orally active DA prodrugs and DA agonist in the management of patients with CHF is still undecided. In CHF, basal release of nitric oxide may be preserved or even enhanced. However, stimulated release of nitric oxide may be reduced. Renal effects of nitric oxide or arginine in CHF have yet to be defined. Renal prostaglandins play an important role in offsetting renal and systemic vasoconstriction and fluid retention in CHF. The recent availability of specific receptor antagonist should lead to clearer definition of the relative roles of renal angiotensin II inhibition and bradykinin potentiation in the benefical responses to angiotensin converting enzyme (ACE-I) in CHF. Prostaglandin-E1 (PG-E1) and prostaglandin-E2 (PG-E2) infusion may have some benefit for the treatment

Congestive heart failure (CHF) is a complex clinical syndrome in which the kidney has a central pathophysiological role. An imbalance between vasoconstrictor-antinatriuretic and vasodilator-natriuretic forces is a key feature of the pathophysiology of CHF. This review summarizes current understanding of disturbances in vasodilator-natriuretic systems in CHF. The key vasodilator systems involved are: the natriuretic peptide family atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), urodilatin, dopamine (DA), endothelium-derived relaxing factors and prostaglandins. Renal responses to ANP are blunted in CHF, under the influence of haemodynamic, neuro-humoral, receptor and post-receptor events. BNP, secreted in response to left ventricular load, may circulate in high concentrations in CHF, with similar effects to ANP. Urodilatin is a newly discovered peptide of renal origin whose physiological role is under investigation. Neural endopeptidase inhibitors have shown some promise in the treatment of human CHF, particularly when combined with ACE inhibition or angiotensin II receptor blockade. The renal DA system is influenced by sodium intake and DA metabolism is altered in CHF. The place of orally active DA prodrugs and DA agonist in the management of patients with CHF is still undecided. In CHF, basal release of nitric oxide may be preserved or even enhanced. However, stimulated release of nitric oxide may be reduced. Renal effects of nitric oxide or arginine in CHF have yet to be defined. Renal prostaglandins play an important role in offsetting renal and systemic vasoconstriction and fluid retention in CHF. The recent availability of specific receptor antagonist should lead to clearer definition of the relative roles of renal angiotensin II inhibition and bradykinin potentiation in the benefical responses to angiotensin converting enzyme (ACE-I) in CHF. Prostaglandin-E1 (PG-E1) and prostaglandin-E2 (PG-E2) infusion may have some benefit for the treatment