Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists.
ABSTRACT 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.
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.
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.
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.
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.
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ABSTRACT: 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.Neuropharmacology 03/2014; · 4.82 Impact Factor
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ABSTRACT: The primary degradation products identified in aqueous 7 molal (m) methyldiethanolamine (MDEA) loaded to 0.1 mol CO2/mol alkalinity and degraded in the Integrated Solvent Degradation Apparatus (ISDA) were diethanolamine (DEA), bicine and formate. DEA and bicine represented 43 and 9 % of the carbon loss, respectively, after the solvent was cycled for 167 hours. An MDEA loss of 8.8 mM/hr and a formate production of 0.6 mM/hr were measured when 7 m MDEA cycled from 55 to 120 °C in the ISDA in its initial design, which allowed bubble entrainment. When bubble entrainment was minimized through coalescence and removal, the MDEA loss and formate production were cut in half (4.6 mM/hr and 0.31 mM/hr). When dissolved oxygen was stripped from cycled MDEA with N2 gas at 2 L/min, the MDEA loss was negligible, and the formate production was reduced to 0.05 mM/hr. Designers of CO2 scrubbing systems for post-combustion capture should minimize dissolved and entrained oxygen carryover into the stripper. Stripping of entrained and dissolved oxygen before the stripper is recommended to avoid high temperature oxidation. An oxygen solubility limit exists at a thermal reactor temperature of 120 °C which can be expressed as an apparent upper limit of dissolved O2 available to degrade ∼1.3 mM MDEA/pass. The oxidative degradation model compensates for the complete consumption of dissolved oxygen in the thermal reactor at higher temperatures (>100 °C). The model assumes that all oxidative degradation is occurring in the thermal reactor under plug-flow reactor (PFR) behavior, and compensates for complete oxygen consumption with a stoichiometric factor (S). The regressed values of S, Ea, and ko for formate were 0.1, 107 kJ/mol, and 2.4 1/hr, respectively. The predicted rates of formate production approximately match the measured rates over the entire measured temperature range of 55 to 120 °C. Oxidation Inhibitor A is ineffective over the temperature range of 90 to 120 °C in cycled solventsEnergy Procedia 01/2011; 4:23-28.
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ABSTRACT: This paper aims to better understand the physiological meaning of negative correlations in resting state functional connectivity MRI (r-fcMRI). The correlations between anatomy-based brain regions of 18 healthy humans were calculated and analyzed with and without a correction for global signal and with and without spatial smoothing. In addition, correlations between anatomy-based brain regions of 18 naïve anesthetized rats were calculated and compared to the human data. T-statistics were used to differentiate between positive and negative connections. The application of spatial smoothing and global signal correction increased the number of significant positive connections but their effect on negative connections was complex. Positive connections were mainly observed between cortical structures while most negative connections were observed between cortical and non-cortical structures with almost no negative connections between non-cortical structures. In both human and rats, negative connections were never observed between bilateral homologous regions. The main difference between positive and negative connections in both the human and rat data was that positive connections became less significant with time-lags, while negative connections became more significant with time-lag. This effect was evident in all four types of analyses (with and without global signal correction and spatial smoothing) but was most significant in the analysis with no correction for the global signal. We hypothesize that the valence of r-fcMRI connectivity reflects the relative contributions of cerebral blood volume (CBV) and flow (CBF) to the BOLD signal and that these relative contributions are location-specific. If cerebral circulation is primarily regulated by CBF in one region and by CBV in another, a functional connection between these regions can manifest as an r-fcMRI negative and time-delayed correlation. Similarly, negative correlations could result from spatially inhomogeneous responses of rCBV or rCBF alone. Consequently, neuronal regulation of brain circulation may be deduced from the valence of r-fcMRI connectivity.PLoS ONE 11/2014; 9(11):e111554. · 3.53 Impact Factor