Bacteria Invade the Brain Following Sterile Intracortical Microelectrode Implantation.

Brain-machine interface performance is largely affected by the neuroinflammatory responses resulting in large part from blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings strongly suggest that certain gut bacterial constituents penetrate the BBB and are resident in various brain regions of rodents and humans, both in health and disease. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could amplify dysregulation of the microbiome-gut-brain axis.

Small phenolic and indolic gut-dependent molecules in the primate central nervous system: levels vs. bioactivity.

Introduction: A rapidly growing body of data documents associations between disease of the brain and small molecules generated by gut-microbiota (GMB). While such metabolites can affect brain function through a variety of mechanisms, the most direct action would be on the central nervous system (CNS) itself.

Objective: Identify indolic and phenolic GMB-dependent small molecules that reach bioactive concentrations in primate CNS.

Changes in the Serum Metabolome of Patients Treated With Broad-Spectrum Antibiotics.

Background: The gut microbiome (GMB) generates numerous small chemicals that can be absorbed by the host and variously biotransformed, incorporated, or excreted. The resulting metabolome can provide information about the state of the GMB, of the host, and of their relationship. Exploiting this information in the service of biomarker development is contingent on knowing the GMB-sensitivity of the individual chemicals comprising the metabolome.

Urinary Metabolites of Green Tea as Potential Markers of Colonization Resistance to Pathogenic Gut Bacteria in Mice.

Background: The gut microbiome (GMB) generates numerous chemicals that are absorbed systemically and excreted in urine. Antibiotics can disrupt the GMB ecosystem and weaken its resistance to colonization by enteric pathogens such as . If the changes in GMB composition and metabolism are sufficiently large, they can be reflected in the urinary metabo-lome.

The phenolic interactome and gut microbiota: opportunities and challenges in developing applications for schizophrenia and autism.

Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges.

Quantification of phenolic acid metabolites in humans by LC-MS: a structural and targeted metabolomics approach.

Aim: Co-metabolism between a human host and the gastrointestinal microbiota generates many small phenolic molecules such as 3-hydroxy-3-(3-hydroxyphenyl)propanoic acid (3,3-HPHPA), which are reported to be elevated in schizophrenia and autism. Characterization of these chemicals, however, has been limited by analytic challenges.

Methodology/results: We applied HPLC to separate and quantify over 50 analytes, including multiple structural isomers of 3,3-HPHPA in human cerebrospinal fluid, serum and urine.

L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat.

We previously found that L-tyrosine (L-TYR) but not D-TYR administered by reverse dialysis elevated catecholamine synthesis in vivo in medial prefrontal cortex (MPFC) and striatum of the rat (Brodnik et al., 2012). We now report L-TYR effects on extracellular levels of catecholamines and their metabolites.

Large neutral amino acids levels in primate cerebrospinal fluid do not confirm competitive transport under baseline conditions.

In rodents, transport of large neutral amino acids (LNAAs) across the blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier is mediated by high affinity carriers. Net brain LNAA levels are thought to be determined mainly by this competitive transport from plasma. Since the affinity for LNAA transport at the BBB in primates is considerably higher than in rodents, brain influx and by extension LNAA brain levels, should be even more dependent on competitive transport.

Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

Objective: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting.

Method: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007.

A simplified method to quantify dysregulated tyrosine transport in schizophrenia.

Background: Schizophrenia is associated with altered tyrosine transport across plasma membranes. This is typically demonstrated by measuring the uptake of radiolabeled tyrosine in cultured human fibroblasts. Our primary goal was to determine whether tyrosine uptake could be characterized using unlabeled tyrosine.

Presynaptic regulation of extracellular dopamine levels in the medial prefrontal cortex and striatum during tyrosine depletion.

Rationale: Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe.

Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus.

In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus.

Increased tyrosine availability increases brain regional DOPA levels in vivo.

Tyrosine hydroxylation is considered to be the rate-limiting step in catecholamine synthesis. It is also assumed that under usual conditions, tyrosine 3-monooxygenase (EC 1.14.

Acute lithium administration selectively lowers tyrosine levels in serum and brain.

Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl(2)) 3.

Relationships between large neutral amino acid levels in plasma, cerebrospinal fluid, brain microdialysate and brain tissue in the rat.

Experimental limitations may preclude direct measurement of large neutral amino acid (LNAA) levels in brain tissue. Some data suggest that serum or cerebrospinal fluid (CSF) may provide an index of LNAA brain levels. We examined this in a series of experiments in rats, administering tyrosine, phenylalanine or valine IP 60min prior to harvesting of blood, CSF or brain tissue or during in vivo microdialysis of the brain.

Gamma-butyrolactone-induced dopamine accumulation in prefrontal cortex is affected by tyrosine availability.

Gamma-butyrolactone (GBL) elevates striatal and prefrontal cortex dopamine levels; only the striatal dopamine levels are elevated by increased dopamine synthesis. If increased dopamine synthesis is necessary in order for dopamine levels to be affected by tyrosine availability, then GBL-induced prefrontal cortex dopamine levels should be tyrosine insensitive. Rats received either vehicle, tyrosine (50 or 200 mg/kg i.

Tyrosine availability modulates potassium-induced striatal catecholamine efflux in vivo.

The relationship between tyrosine availability and high potassium (K+) induced dopamine (DA) and norepinephrine (NE) efflux was examined in striatum using in vivo microdialysis. High K+ (80 mM) was included in perfusate for two 30 min periods, 2.5 h apart.

Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels.

The relationship between limited tyrosine availability, DA (dopamine) synthesis and DA levels in the medial prefrontal cortex (MPFC) of the rat was examined by in vivo microdialysis. We administered a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA-) IP to lower brain tyrosine, and the norepinephrine transporter inhibitor desipramine (DMI) 10 mg/kg IP to raise MPFC DA levels without affecting DA synthesis. For examination of DOPA levels, NSD-1015 20 microM was included in perfusate.

Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine.

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015.

In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels.

We previously reported that depletion of brain tyrosine attenuated the acute clozapine (CLZ)-induced increase in medial prefrontal cortex (MPFC) dopamine (DA) levels. This effect was now examined after chronic CLZ treatment. Male rats received CLZ (10 mg kg(-1) day(-1)) in drinking water for 21 days.

Tyrosine administration does not affect desipramine-induced dopamine levels as measured in vivo in prefrontal cortex.

Using in vivo microdialysis, we examined whether tyrosine administration would potentiate the desipramine (DMI)-induced elevation of medial prefrontal cortex (MPFC) dopamine (DA) levels. DMI (10 or 20 mg/kg IP) increased MPFC DA levels but not DOPA accumulation. Tyrosine (12.