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Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (D-βHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of D-βHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of D-βHB compared to active control glucose (N = 26). Effect of age and blood levels of D-βHB and glucose were used to further explore the effect of D-βHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of D-βHB. Importantly, the effect was specific to D-βHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of D-βHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.

Lipid metabolism is abnormal in Alzheimer's disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1-3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1-8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.

Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei - regions known to be important in mediating reinstatement of drug-taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal - striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Interest in brain-derived neurotrophic factor (BDNF) was greatly enhanced when it was recognized that its expression is reduced in neurodegenerative disorders, especially in Alzheimer's disease (AD). BDNF signaling through the TrkB receptor has a central role in promoting synaptic transmission, synaptogenesis, and facilitating synaptic plasticity making the BDNF-TrkB signaling pathway an attractive candidate for targeted therapies. Here we investigated the early effect of the small molecule TrkB agonist, 7,8 dihydroxyflavone (7,8-DHF), on AD-related pathology, dendritic arborization, synaptic density, and neurochemical changes in the 5xFAD mouse model of AD. We treated 5xFAD mice with 7,8-DHF for 2 months beginning at 1 month of age. We found that, in this model of AD, 7,8-DHF treatment decreased cortical Aβ plaque deposition and protected cortical neurons against reduced dendritic arbor complexity but had no significant impact on the density of dendritic spines. In addition 7,8-DHF treatment protected against hippocampal increase in the level of choline-containing compounds and glutamate loss, but had no significant impact on hippocampal neurogenesis., (Copyright © 2018. Published by Elsevier B.V.)

Gulf War Illness (GWI) is a chronic disease that affects the 1991 Gulf War (GW) veterans for which treatment is lacking. It has been hypothesized that drugs used to protect military personnel from chemical attacks and insects during the war: pyridostigmine bromide (PB),N, N-diethyl-m-toluamide (DEET), and permethrin (PER) together with stress may have contributed collectively and synergistically to generate GWI. There is a need to find markers of pathology to be used in pre-clinical trials. For this purpose we employed a previously validated mouse model of GWI evoked by daily exposure to PB (1.3 mg/kg), DEET (40 mg/kg), PER (0.13 mg/kg), and 5 min of restraint stress for 28 days to analyze behavior, brain pathology and neurochemical outcomes three months later. GWI-model mice were characterized by increased anxiety, decreased hippocampal levels of N-acetyl aspartate, GABA, the GABA-producing enzyme GAD-67 and microglial activation. We also observed that GWI model was sexually dimorphic on some measures: males had increased while females had decreased protein levels of the acetylcholine-synthesizing enzyme, choline acetyltransferase, in the septum and hippocampus and decreased levels of the receptor for brain-derived neurotrophic factor, TrkB140, in the hippocampus. Increased hippocampal levels of nerve growth factor were detected in males only. Together the data show behavioral and neuropathological abnormalities detected at 3 months post-exposure and that some of them are sexually dimorphic. Future preclinical studies for GWI may take advantage of this short latency model and should include both males and females as their response to treatment may differ., (Published by Elsevier B.V.)

Dysfunction in the resolution of inflammation may play a key role in Alzheimer's disease (AD). In this study, we found that the levels of specialized pro-resolving lipid mediators (SPMs) in the hippocampus of 5xFAD mice are significantly lower than in non-transgenic littermates. We, therefore, tested the hypothesis that treatment with resolvin E1 (RvE1) and lipoxin A4 (LXA4) alone or in combination will reverse the neuroinflammatory process and decrease Aβ pathology. 5xFAD mice were treated intraperitoneally starting at 1month of age with RvE1 or LXA4 alone or in combination at a dose of 1.5 μg/kg, 3 times a week until 3months of age. We found that treatment with RvE1 or LXA4 alone or in combination increased the concentration of RvE1, LXA4, and RvD2 in the hippocampus as measured by ELISA. Combination treatment of RvE1 and LXA4 had a more potent effect on the activation of microglia and astrocytes than either treatment alone, measured by immunohistochemistry with Iba1 and GFAP antibodies, respectively. The concentrations of Aβ40 and Aβ42 were measured by ELISA and the percentage of Aβ plaques were analyzed by immunohistochemistry. All treatments single and in combination, decreased the measures of Aβ pathology and restored the homeostasis reversing the inflammatory process for inflammatory cytokines and chemokines (GM-CSF, IFN-γ, IL-1β, IL-6, IL-10, TNF-α, MCP-1, MIP-1α, MIP-1β, and RANTES) as measured by multiplex immunoassay. Overall, the study showed that the levels of SPMs in the hippocampus of 5xFAD mice were significantly lower than in wild-type mice; that treatment with RvE1 and LXA4 restored the level of these compounds, reversed the inflammatory process, and decreased the neuroinflammation associated with Aβ pathology in 5xFAD mice., (Copyright © 2017. Published by Elsevier Inc.)

G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sphingosine 1-phosphate (SP1) receptors may be attractive targets for modulation of inflammatory processes in neurodegenerative diseases. Recently fingolimod, a functional S1P1 receptor antagonist, was introduced for treatment of multiple sclerosis. We postulated that anti-inflammatory mechanisms of fingolimod might also be protective in Alzheimer's disease (AD). Therefore, we treated a mouse model of AD, the 5xFAD model, with two doses of fingolimod (1 and 5 mg/kg/day) and measured the response of numerous markers of Aβ pathology as well as inflammatory markers and neurochemistry using biochemical, immunohistochemistry and high resolution magic angle spinning magnetic resonance spectroscopy (MRS). In mice at 3 months of age, we found that fingolimod decreased plaque density as well as soluble plus insoluble Aβ measured by ELISA. Fingolimod also decreased GFAP staining and the number of activated microglia. Taurine has been demonstrated to play a role as an endogenous anti-inflammatory molecule. Taurine levels, measured using MRS, showed a very strong inverse correlation with GFAP levels and ELISA measurements of Aβ, but not with plaque density or activated microglia levels. MRS also showed an effect of fingolimod on glutamate levels. Fingolimod at 1 mg/kg/day provided better neuroprotection than 5 mg/kg/day. Together, these data suggest a potential therapeutic role for fingolimod in AD.

Schnurri-2 (Shn-2) knockout (KO) mice have been proposed as a preclinical neuroinflammatory schizophrenia model. We used behavioral studies and imaging markers that can be readily translated to human populations to explore brain effects of inflammation. Shn-2 KO mice and their littermate control mice were imaged with two novel PET ligands; an inflammation marker [(11)C]PBR28 and the mGluR5 ligand [(18)F]FPEB. Locomotor activity was measured using open field exploration with saline, methamphetamine or amphetamine challenge. A significantly increased accumulation of [(11)C]PBR28 was found in the cortex, striatum, hippocampus and olfactory bulb of Shn-2 KO mice. Increased mGluR5 binding was also observed in the cortex and hippocampus of the Shn-2 KO mice. Open field locomotor testing revealed a large increase in novelty-induced hyperlocomotion in Shn-2 KO mice with abnormal (decreased) responses to either methamphetamine or amphetamine. These data provide additional support to demonstrate that the Shn-2 KO mouse model exhibits several behavioral and pathological markers resembling human schizophrenia making it an attractive translational model for the disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We investigated a triple transgene Alzheimer's disease (AD) mouse model that recapitulates many of the neurochemical, anatomic, pathologic and behavioral defects seen in human AD. We studied the mice as a function of age and brain region and investigated potential therapy with the non-steroidal anti-inflammatory drug ibuprofen. Magnetic resonance spectroscopy (MRS) showed alterations characteristic of AD (i.e. increased myo-inositol and decreased N-acetylaspartate (NAA)). Mice at 6 months of age showed an increase in myo-inositol in the hippocampus at a time when the Aβ is intracellular, but not in amygdala or cortex. Myo-inositol increased as a function of age in the amygdala, cortex and striatum while NAA decreased only in the hippocampus and cortex at 17-23 months of age. Ibuprofen protected the increase of myo-inositol at six months of age in the hippocampus, but had no effect at 17-23 months of age (a time when Aβ is extracellular). In vivo MRI and MRS showed that at 17-23 months of age there was a significant protective effect of ibuprofen on hippocampal volume and NAA loss. Together, these data show the following: the increase in myo-inositol occurs before the decrease in NAA in hippocampus but not cortex; the hippocampus shows earlier changes than does the amygdale or cortex consistent with earlier deposition of Aβ40-42 in the hippocampus and ibuprofen protects against multiple components of the AD pathology. These data also show a profound effect of housing on this particular mouse model., (Published by Elsevier B.V.)

Although functional MRI traditionally has been applied mainly to study changes in task-induced brain function, evolving acquisition methodologies and improved knowledge of signal mechanisms have increased the utility of this method for studying responses to pharmacological stimuli, a technique often dubbed "phMRI". The proliferation of higher magnetic field strengths and the use of exogenous contrast agent have boosted detection power, a critical factor for successful phMRI due to the restricted ability to average multiple stimuli within subjects. Receptor-based models of neurovascular coupling, including explicit pharmacological models incorporating receptor densities and affinities and data-driven models that incorporate weak biophysical constraints, have demonstrated compelling descriptions of phMRI signal induced by dopaminergic stimuli. This report describes phMRI acquisition and analysis methodologies, with an emphasis on data-driven analyses. As an example application, statistically efficient data-driven regressors were used to describe the biphasic response to the mu-opioid agonist remifentanil, and antagonism using dopaminergic and GABAergic ligands revealed modulation of the mesolimbic pathway. Results illustrate the power of phMRI as well as our incomplete understanding of mechanisms underlying the signal. Future directions are discussed for phMRI acquisitions in human studies, for evolving analysis methodologies, and for interpretative studies using the new generation of simultaneous PET/MRI scanners. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small molecule tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1(G93A)). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1(G93A) mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases., (Published by Elsevier Ireland Ltd.)

We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function., (© 2013 Published by Elsevier B.V.)

The pathological accumulation of the β-amyloid protein (Aβ) has been closely associated with synaptic loss and neurotoxicity contributing to cognitive dysfunction in Alzheimer's disease (AD). Oligomers of Aβ42 appear to be the most neurotoxic form. Two of the most promising attempts to reduce Aβ accumulation have been with scyllo-inositol, an inositol steroisomer, that stabilizes Aβ42 peptide and prevents it from progressing to oligomers and fibrils and R-flurbiprofen, a purified enantiomer of the classical racemic non-steroidal anti-inflammatory drugs (NSAID), flurbiprofen, that retains the ability to specifically lower Aβ42. In the present study we evaluated the effects of scyllo-inositol and the combination treatment of scyllo-inositol+R-flurbiprofen on amyloid pathology and hippocampal-dependent memory function in 5XFAD mice, a model of Aβ pathology characterized by an enormous production of Aβ42. Our expectations were that the combination treatment of scyllo-inositol+R-flurbiprofen would have an additive effect in preventing Aβ accumulation and that cognition would be improved. Mice treated with scyllo-inositol exhibit 41 and 35% reduction in the deposition of the amyloid plaques stained by antibody against Aβ42 and Aβ40 respectively. Scyllo-inositol was not more effective when combined with R-flurbiprofen for the measures tested. Scyllo-inositol treated mice performed significantly better at the radial arm water maze (RAWM) task than untreated and scyllo-inositol+R-flurbiprofen treated mice., (© 2013.)

This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET (11)C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The technique of functional magnetic resonance (fMRI), using various cognitive, motor and sensory stimuli has led to a revolution in the ability to map brain function. Drugs can also be used as stimuli to elicit an hemodynamic change. Stimulation with a pharmaceutical has a number of very different consequences compared to user controllable stimuli, most importantly in the time course of stimulus and response that is not, in general, controllable by the experimenter. Therefore, this type of experiment has been termed pharmacologic MRI (phMRI). The use of a drug stimulus leads to a number of interesting possibilities compared to conventional fMRI. Using receptor specific ligands one can characterize brain circuitry specific to neurotransmitter systems. The possibility exists to measure parameters reflecting neurotransmitter release and binding associated with the pharmacokinetics and/or the pharmacodynamics of drugs. There is also the ability to measure up- and down-regulation of receptors in specific disease states. phMRI can be characterized as a molecular imaging technique using the natural hemodynamic transduction related to neuro-receptor stimulus. This provides a coupling mechanism with very high sensitivity that can rival positron emission tomography (PET) in some circumstances. The large numbers of molecules available, that do not require a radio-label, means that phMRI becomes a very useful tool for performing drug discovery. Data and arguments will be presented to show that phMRI can provide information on neuro-receptor signaling and function that complements the static picture generated by PET studies of receptor numbers and occupancies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Chronic use of cocaine is associated with lasting alterations in brain metabolism, circuitry, and receptor properties. We used neuroimaging with pharmacological magnetic resonance imaging to assess alterations in response to cocaine (0.5 mg/kg) in animals trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement, as well as saline-yoked controls, after 28 days of cocaine abstinence. We fitted the cerebral blood volume (CBV) curves for full-width half-maximum (FWHM) as well as peak CBV response. There were significant increases in the FWHM of the response curves in the cocaine self-administering (SA) animals as compared with saline-yoked controls in the medial prefrontal cortex (mPFC) and the caudate/putamen (CPu), and increases in peak CBV in the M1 motor cortex, CPu, and pedunculopontine tegmental nucleus. Functional connectivity analysis showed increased correlations in the cocaine SA rats upon acute cocaine challenge, especially in the S1, mPFC, and thalamus. As D3 receptor expression is postulated to increase following chronic cocaine administration, we also examined the response to 0.2 mg/kg of the D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT). Cocaine SA animals showed a decreased overall CBV response to this drug, except in the globus pallidus. The hypothalamus showed a negative CBV change in response to cocaine challenge, similar to that noted with the D3 agonist, and showed a smaller response in the cocaine SA animals than in the controls. Given the good coupling of cerebral hemodynamics with dopamine dynamics previously observed with pharmacological magnetic resonance imaging, these data suggest that increased persistence of dopamine in the prefrontal cortex may be responsible for some of the behavioral alterations observed subsequent to chronic cocaine use., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion.

Rationale: Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry., Objectives: We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry., Methods: We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography., Results: D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques., Conclusions: MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum.

There is evidence that inositol isomers may help protect against formation of toxic fibrils of Abeta fragments in Alzheimer's disease mouse models. Scyllo-inositol is one of the more promising inositol isomers for the potential treatment of Alzheimer's disease (AD) and can be detected using MRS in human subjects. In this manuscript we demonstrate using MRS, in two different mouse models of AD (APP x PS1 and APP x PS1 x tau), that we could detect increased scyllo-inositol in the hippocampus and frontal cortex in mice fed water supplemented with 16.5 mg/L of scyllo-inositol equivalent to about 3.3 mg/kg/day. We used both brain extracts using solution MRS as well as intact brain tissue using high resolution magic angle spinning (HRMAS) to ensure that any membrane-associated scyllo-inositol would be detected. By brain extracts we detected a 3.0 fold increase in scyllo-inositol in the scyllo-fed AD mice compared to normal diet (p < 0.001). Using HRMAS we detected a 2.2-2.4-fold increase in scyllo-inositol (p < 0.001). Scyllo-inositol treatment was associated with an increase in glutamine in hippocampus. The concentrations of scyllo-inositol were higher in the hippocampus than in the frontal cortex. Mice have a smaller concentration of scyllo-inositol than humans (ca. 100 microM vs. 500 microM in humans). Given the ease with which scyllo-inositol can be measured in human MRS data with high signal to noise ratios, these data suggest that MRS will prove useful for evaluation of inositol treatment trials in AD subjects., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age., (Copyright 2010 S. Karger AG, Basel.)

Prior studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may lower the incidence of Alzheimer's disease (AD) and delay onset or slow progression of symptoms in mouse models of AD. We examined the effects of chronic NSAID treatment in order to determine which elements of the pathological features might be ameliorated. We compared the effects of the NSAIDs ibuprofen and celecoxib on immunohistological and neurochemical markers at two different ages in APPxPS1 mice using measurements of amyloid plaque deposition, Abeta peptide levels, and neurochemical profiles using magnetic resonance spectroscopy (MRS). At 6 months of age, few neurochemical changes were observed between PSAPP mice and WT mice using MRS. Ibuprofen, but not celecoxib, treatment significantly decreased the Abeta(42/40) ratio in frontal cortex at 6 months, but overall amyloid plaque burden was unchanged. Consistent with prior findings in mouse models, at 17 months of age, there was a decrease in the neuronal markers NAA and glutamate and an increase in the astrocytic markers glutamine and myo-inositol in AD mice compared to WT. Ibuprofen provided significant protection against NAA and glutamate loss. Neither of the drugs significantly affected myo-inositol or glutamine levels. Both ibuprofen and celecoxib lowered plaque burden without a significant effect on Abeta(1-42) levels. NAA levels significantly correlated with plaque burden. These results suggest that selective NSAIDs (ibuprofen and possibly celecoxib) treatment can protect against the neuronal pathology., (Published by Elsevier Inc.)

Amyotrophic lateral sclerosis (ALS) presents challenges for diagnosis and objective monitoring of disease progression. We show, using pharmacologic MRI, that alterations in motor circuitry can be characterized using a passive stimulus in a rat model of familial ALS as a function of symptom progression. Presymptomatic familial ALS rats had a pattern of activation to amphetamine that was statistically indistinguishable from the wild-type controls. In contrast, symptomatic rats showed significantly decreased response in sensorimotor cortex and increased response in M2 motor cortex, caudate/putamen, and thalamus. These results are similar to findings in humans of altered response to motor tasks in ALS. It may be plausible to use a passive amphetamine challenge as a biomarker to assess progression of the disease and efficacy of potential treatments.

The relationship between exercise and amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by motor neuron loss, rapidly progressive weakness and early death has been controversial. We studied the effect of a high (HEX) and moderate-level exercise (MEX) on body weight, motor performance and motor neuron counts in the ventral horn of spinal cords in a transgenic mouse model of ALS (G93A-SOD1) that overexpresses a mutated form of the human SOD1 gene that is a cause of familial ALS. These transgenic mice show several similarities to the human disease, including rapid progressive motor weakness from 100 days of age and premature death at around 135 days of age. Mice were exposed to high or mid-level exercise of left sedentary (SED). At 70, 95 and 120 days of age, spinal cords were processed following euthanasia. Motor neurons larger than 15 mum in diameter were counted with a design-based stereological protocol using an optical fractionator probe in the ventral horn of different regions of the cord and compared to wild-type littermates. Moderate exercise delayed the onset of motor deficit by over a week. High exercise slightly but significantly hastened the onset of motor performance deficits. Motor neuron density in the lumbar cord was significantly higher in MEX group compared to SED at 95 days of age. These results show the beneficial effects of moderate exercise on the preservation of motor performance that correlates with higher motor neuron density in the ventral horn of the lumbar spinal cord in G93A mice., (Published by Elsevier B.V.)

As current radiological approaches cannot accurately localize prostate cancer in vivo, biopsies are conducted at random within prostates for patients at risk for prostate cancer, leading to high false-negative rates. Metabolomic imaging can map cancer-specific biomolecular profile values onto anatomical structures to direct biopsy. In this preliminary study, we evaluated five whole prostates removed during prostatectomy from biopsy-proven cancer patients on a 7-tesla human whole-body magnetic resonance scanner. Localized, multi-cross-sectional, multivoxel magnetic resonance spectra were used to construct a malignancy index based on prostate cancer metabolomic profiles obtained from previous intact tissue analyses with a 14-tesla spectrometer. This calculated malignancy index is linearly correlated with lesion size and demonstrates a 93 to 97% overall accuracy for detecting the presence of prostate cancer lesions, suggesting the potential clinical utility of this approach.

We investigated the effects of disease progression on brain regional neurochemistry in a mutant mouse model of familial amyotrophic lateral sclerosis (FALS; the G93A model) using in vivo and in vitro magnetic resonance spectroscopy (MRS). There were numerous changes in the brain spectra that were brain region dependent. At early time points starting around 80 days of age there were increases in brain glutamate. At later time points there were more extensive changes including decreased N-acetyl aspartate and glutamate and increased glutamine, taurine and myo-inositol. The effects of the disease were most severe in spinal cord followed by medulla and then sensorimotor cortex. There were no changes noted in cerebellum as a control region. The effects of creatine supplementation in the diet (2%) were measured in wild-type and FALS animals in medulla, cerebellum and cortex. The increase in brain creatine was largest in cerebellum (25%) followed by medulla (11%) and then cortex (4%), reflecting the ordering of creatine kinase activity. There was a protective effect of creatine on N-acetyl aspartate loss in the medulla at late stages. Creatine supplementation had a positive effect on weight retention, leading to a 13% increase in weight between 120 and 130 days. MRS shows promise in monitoring multiple facets of neuroprotective strategies in ALS and ALS models.

It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates exhibiting L-dopa-induced dyskinesia. Magnetic resonance imaging (MRI) performed before and after injection of Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) revealed an intact BBB in the basal ganglia showing that l-dopa-induced dyskinesia is not associated with a disrupted BBB in this model.

Unlabelled: We studied the metabolic responses to different DA concentrations elicited by four doses of D-amphetamine (AMPH, 0, 0.25, 0.5, 1.0, or 3.0 mg/kg). We compared the degree of DA release (via microdialysis) with striatal cAMP activity and whole brain maps of cerebral blood volume (rCBV) changes (via pharmacological MRI, phMRI)., Results: AMPH increased DA release in the caudate/putamen (CPu) and cAMP activity in the CPu, nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) in a linear dose-dependent manner (P < 0.0001). The cAMP data suggest that, postsynaptically, signal transduction induced by D1 receptor is stronger than that of D2 receptor at the higher doses (1-3 mg/kg). phMRI showed that, while higher doses of AMPH (3 mg/kg (n = 7) and 1 mg/kg (n = 6)) induced significant rCBV increases in the CPu and NAc, the degree of rCBV increase was much smaller with AMPH of 0.5 mg/kg (n = 6). In contrast, AMPH of 0.25 mg/kg (n = 8) induced significant rCBV decreases in the anteromedial CPu and NAc. The sign switch of rCBV in response to AMPH from low to high doses likely reflects the switching in the balance of D2/D3 stimulation vs. D1/D5 stimulation. In conclusion, degree of postsynaptic signal transduction is linearly correlated to the extracellular DA concentration. However, the presynaptic binding may dominate the overall DA innervation at the lower range of DA concentration., (2009 Wiley-Liss, Inc.)

Parkinson's disease (PD) is a common and often devastating neurodegenerative disease affecting up to one million individuals in the United States alone. Multiple lines of evidence support mitochondrial dysfunction as a primary or secondary event in PD pathogenesis; a better understanding, therefore, of how mitochondrial function is altered in vivo in brain tissue in PD is a critical step toward developing potential PD biomarkers. In vivo study of mitochondrial metabolism in human subjects has previously been technically challenging. However, proton and phosphorus magnetic resonance spectroscopy ((1)H and (31)P MRS) are powerful noninvasive techniques that allow evaluation in vivo of lactate, a marker of anaerobic glycolysis, and high energy phosphates, such as adenosine triphosphate and phosphocreatine, directly reflecting mitochondrial function. This article reviews previous (1)H and (31)P MRS studies in PD, which demonstrate metabolic abnormalities consistent with mitochondrial dysfunction, and then presents recent (1)H MRS data revealing abnormally elevated lactate levels in PD subjects.

Altered gene activities are underlying causes of many neurological disorders. The ability to detect, image, and report endogenous gene transcription using magnetic resonance (MR) holds great potential for providing significant clinical benefits. In this review, we present the development of conjugates consisting of gene-targeting short nucleic acids (oligodeoxynucleotides, or sODN) and superparamagnetic iron oxide nanoparticles (SPION, an MR susceptibility T(2) agent) for reporting gene activity using transcription MRI (tMRI). We will discuss 1) the target specificity of sODN, 2) selection of contrast agents for tMRI, 3) the distribution and uptake, 4) sequence specificity, 5) histology of SPION and sODN, 6) data acquisition and quantitative analysis for tMRI, and 7) application of gene transcript-targeting nanoparticles in biology and medicine. We will also discuss methods of validating the correlation between results from conventional assays (in situ hybridization, PCR, histology Prussian blue stain and immunohistochemistry) in postmortem samples and retention of SPION-sODN using tMRI. The application of our novel contrast probe to report and target gene transcripts in the mesolimbic pathways of living mouse brains after amphetamine exposure will be discussed. Because of the targeting ability in the nucleic acid sequence, the concept of tMRI probes with complementary nucleic acid (antisense DNA or short interfering RNA) allows not only tracking, targeting, binding to intracellular mRNA, and manipulating gene action but also tracing cells with specific gene action in living brains. Transcription MRI will lend itself to myriad applications in living organs.

We examined the effects of ibuprofen on cognitive deficits, Abeta and tau accumulation in young triple transgenic (3xTg-AD) mice. 3xTg-AD mice were fed ibuprofen-supplemented chow between 1 and 6 months. Untreated 3xTg-AD mice showed significant impairment in the ability to learn the Morris water maze (MWM) task compared to age-matched wild-type (WT) mice. The performance of 3xTg-AD mice was significantly improved with ibuprofen treatment compared to untreated 3xTg-AD mice. Ibuprofen-treated transgenic mice showed a significant decrease in intraneuronal oligomeric Abeta and hyperphosphorylated tau (AT8) immunoreactivity in the hippocampus. Confocal microscopy demonstrated co-localization of conformationally altered (MC1) and early phosphorylated tau (CP-13) with oligomeric Abeta, and less co-localization of oligomeric Abeta and later forms of phosphorylated tau (AT8 and PHF-1) in untreated 3xTg-AD mice. Our findings show that prophylactic treatment of young 3xTg-AD mice with ibuprofen reduces intraneuronal oligomeric Abeta, reduces cognitive deficits, and prevents hyperphosphorylated tau immunoreactivity. These findings provide further support for intraneuronal Abeta as a cause of cognitive impairment, and suggest that pathological alterations of tau are associated with intraneuronal oligomeric Abeta accumulation.

The subcortical response to peripheral somatosensory stimulation is not well studied. Prior literature suggests that somatosensory stimulation can affect dopaminergic tone. We studied the effects of electrical stimulation near the median nerve on the response to an amphetamine-induced increase in synaptic dopamine. We applied the electrical stimulation close to the median nerve 20 min after administration of 3mg/kg amphetamine. We used fMRI and microdialysis to measure markers of dopamine (DA) release, together with the release of associated neurotransmitters of striatal glutamate (Glu) and gamma-aminobutyric acid (GABA). Changes in cerebral blood volume (CBV), a marker used in fMRI, indicate that electrical stimulation significantly attenuated increased DA release (due to AMPH) in the striatum, thalamus, medial prefrontal and cingulate cortices. Microdialysis showed that electrical stimulation increased Glu and GABA release and attenuated the AMPH-enhanced DA release. The striatal DA dynamics correlated with the CBV response. These results demonstrate that electrical stimulation near the median nerve activates Glu/GABA release, which subsequently attenuate excess striatal DA release. These data provide evidence for physiologic modulation caused by electroacupuncture at points near the median nerve.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD. In addition, transcriptional suppression of trophic factors occurs in human and transgenic mouse models of HD, suggesting that a loss of trophic support might contribute to degeneration. Since anti-glutamate approaches have been effective in improving disease phenotype in HD mice, we examined whether deafferentation of the corticostriatal and nigrostriatal pathways may mitigate striatal stress and neurodegeneration. Both surgical and chemical lesions of the corticostriatal and nigrostriatal pathways, respectively, improved the behavioral, neuropathological, and biochemical phenotype in R6/2 transgenic mice and extended survival. Decortication ameliorated hindlimb clasping, striatal neuron atrophy, and huntingtin-positive aggregates, improved N-acetyl aspartate/creatine levels, reduced oxidative stress, and significantly lowered striatal glutamate levels. In addition, 6-hydroxydopamine lesioned mice showed extended survival along with a significant reduction in striatal glutamate. These results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient. Thus, modulation of synaptic influences continues to have therapeutic potential in HD.

Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphenylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at the human dopamine D3 (hD3) receptor (Ki = 1-5 nM) as measured in competition binding assays. Several analogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors, several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile.

A growing body of evidence indicates a role for D(3) receptors in l-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D(3)-preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and l-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naïve and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated l-DOPA treatment. Such increase in rCBV is consistent with D(1) receptor-like signaling occurring in response to D(3) stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of l-DOPA-induced dyskinesia in patients.

The functional anatomical role of the basal ganglia in bimanual coordination is unknown. Utilizing functional MRI (fMRI) at 3 T, we analyzed brain activity during three different typing tasks. The first task consisted of typing with parallel finger movements (moving left to right with four fingers on both hands). The second task was mirror movements (moving little finger to index finger on both hands), and the third task compared a resting condition with right-handed unimanual typing (moving little finger to index finger). Task dependent BOLD activity in the supplementary motor area (SMA) and dorsolateral premotor areas was observed. In addition, activation patterns were present in the cerebellar vermis during bimanual coordination tasks, with greater activation in the parallel than in the mirror condition. Finally, we also identified activity in the putamen during the tasks described above. Interestingly, putaminal activity was greatest during the period of motor task initiation, and activity during this period was greatest in the parallel condition. Our results suggest a critical role of the basal ganglia in the neural control of bimanual coordination.

The rapid development of transgenic mouse models of neurodegenerative diseases, in parallel with the rapidly expanding growth of MR techniques for assessing in vivo, non-invasive, neurochemistry, offers the potential to develop novel markers of disease progression and therapy. In this review we discuss the interpretation and utility of MRS for the study of these transgenic mouse and rodent models of neurodegenerative diseases such as Alzheimer's (AD), Huntington's (HD) and Parkinson's disease (PD). MRS studies can provide a wealth of information on various facets of in vivo neurochemistry, including neuronal health, gliosis, osmoregulation, energy metabolism, neuronal-glial cycling, and molecular synthesis rates. These data provide information on the etiology, natural history and therapy of these diseases. Mouse models enable longitudinal studies with useful time frames for evaluation of neuroprotection and therapeutic interventions using many of the potential MRS markers. In addition, the ability to manipulate the genome in these models allows better mechanistic understanding of the roles of the observable neurochemicals, such as N-acetylaspartate, in the brain. The argument is made that use of MRS, combined with correlative histology and other MRI techniques, will enable objective markers with which potential therapies can be followed in a quantitative fashion., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Nicotine is one of the most addictive substances known. To better understand the mechanisms of action, we mapped the regional brain response to nicotine administration using pharmacologic magnetic resonance imaging (phMRI) in rats. We measured the regional response of relative cerebral blood volume (rCBV) in rats to a challenge of 0.07 mg/kg (0.43 micromol/kg) of nicotine. The areas of the brain with significant and reproducible changes in the rCBV response were (in descending order of magnitude) infralimbic cortex, hippocampus (subiculum), agranular insular/pyriform cortex, visual cortex, interpeduncular area, nucleus accumbens, cingulate cortex, thalamus, and septum. This pattern of response is consistent with stimulation of both cholinergic and dopaminergic neuronal pathways and is consistent with the known behavioral properties of nicotine. The peak CBV response to nicotine occurred between 9 and 13 min depending upon brain region, and the average full width half-maximum of the rCBV response was 27 min. The high spatial and temporal resolution of the phMRI technique lends itself well to further, more detailed, studies of nicotine dynamics.

The coupling between neurotransmitter-induced changes in neuronal activity and the resultant hemodynamic response is central to the interpretation of neuroimaging techniques. In the present study, MRI experiments showed that dopamine transporter blockers such as cocaine and dopamine releasers such as amphetamine and D1 receptor agonists induced large positive increases in relative cerebral blood volume (rCBV) that were not sensitive to nitric oxide synthase inhibition. However, D1/D5 receptor antagonism with SCH-23390 prevented or blocked the hemodynamic response without any concomitant effect on dopamine release. Dopamine D2/D3 receptor agonists, in contrast, induced negative changes in rCBV in brain regions corresponding largely to those endowed with these receptors. D1 and D5 receptor mRNAs were expressed in microvessels of responsive brain areas, while D2 and D3 receptors were not consistently associated with the microvascular bed. D3 receptors had an astroglial localization. Together, these experiments show that direct effects of dopamine upon the vasculature cannot be ignored in measuring the hemodynamic coupling associated with dopaminergic drugs. These results further suggest that this coupling is partially mediated through D1/D5 receptors on the microvasculature leading to increased rCBV and through astroglial D3 receptors leading to decreased rCBV. These data provide additional support for the role of local post-synaptic events in neurovascular coupling and emphasize that the interpretation of fMRI signals exclusively in terms of neuronal activity may be incomplete.

Objective: An audit of opioid prescribing in a large teaching hospital across all specialties was conducted to identify areas for improvement., Methods: Opioid medications prescribed for the entire patient admission were recorded and assessed using quality statements., Results and Discussion: Of 334 patients reviewed 209 (62.6%) were prescribed an opioid. Poly-prescribing of 'when required' (p.r.n.) opioids was frequent with 107 (51.2%) patients having more than one 'p.r.n.' opioid. Dosing intervals were too long for 146 (69.8%) patients leaving them at risk of breakthrough pain. The intramuscular route was prescribed for 100 (47.8%) patients, and 49 (23.4%) of prescriptions had an inappropriate variety of administration routes., Conclusion: Although the criteria for assessing opioid prescribing were stringent the prescribing was sub-optimal. This survey will form the basis for future quality initiatives.

Huntington's disease is a neurodegenerative illness caused by expansion of CAG repeats at the N-terminal end of the protein huntingtin. We examined longitudinal changes in brain metabolite levels using in vivo magnetic resonance spectroscopy in five different mouse models. There was a large (>50%) exponential decrease in N-acetyl aspartate (NAA) with time in both striatum and cortex in mice with 150 CAG repeats (R6/2 strain). There was a linear decrease restricted to striatum in N171-82Q mice with 82 CAG repeats. Both the exponential and linear decreases of NAA were paralleled in time by decreases in neuronal area measured histologically. Yeast artificial chromosome transgenic mice with 72 CAG repeats, but low expression levels, had less striatal NAA loss than the N171-82Q mice (15% vs. 43%). We evaluated the effect of gene context in mice with an approximate 146 CAG repeat on the hypoxanthine phosphoribosyltransferase gene (HPRT). HPRT mice developed an obese phenotype in contrast to weight loss in the R6/2 and N171-82Q mice. These mice showed a small striatal NAA loss (21%), and a possible increase in brain lipids detectable by magnetic resonance (MR) spectroscopy and decreased brain water T1. Our results indicate profound metabolic defects that are strongly affected by CAG repeat length, as well as gene expression levels and protein context.

Loss of dopamine in the nigrostriatal system causes a severe impairment in motor function in patients with Parkinson's disease and in experimental neurotoxic models of the disease. We have used non-invasive imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (MRI) to investigate in vivo the changes in the dopamine system in neurotoxic models of Parkinson's disease. In addition to classic neurotransmitter studies, in these models, it is also possible to characterize associated and perhaps pathogenic factors, such as the contribution of microglia activation and inflammatory responses to neuronal damage. Functional imaging techniques are instrumental to our understanding and modeling of disease mechanisms, which should in turn lead to development of new therapies for Parkinson's disease and other neurodegenerative disorders.