Magnetic resonance imaging and histological evidence for the blockade of cuprizone-induced demyelination in C57BL/6 mice.

Several neuroimaging studies have revealed that the brains of schizophrenic patients exhibit abnormalities in white matter pathways. Using magnetic resonance imaging (MRI) methods, such as T2-weighted imaging and diffusion tensor imaging (DTI), it is possible to objectively quantify white matter structural properties in patients as well as the pharmacological effect on white matter. In the preclinical domain, these strategies, however, have been hindered by a lack of in vivo imaging assays. One preclinical approach that has been used to pharmacologically challenge the integrity of the white matter is the chronic administration of the copper chelator, cuprizone. In the present study, C57BL/6 mice were given 0.2% cuprizone in their diet for five weeks with or without the antipsychotic drug, quetiapine (10 mg/kg). In accordance with previous studies, myelin breakdown in cuprizone-exposed mice was measured by using T2-weighted MRI and DTI. Here, we demonstrate that cuprizone-induced white matter changes were attenuated by quetiapine treatment. These MRI-based results and trends were confirmed by histological and immunohistochemistry measures. This study suggests that the cuprizone-exposed C57BL/6 mouse is a potential animal model to investigate the impact of treatments on white matter abnormalities in schizophrenia.

Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI.

BACKGROUND AND PURPOSE: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. EXPERIMENTAL APPROACH: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. KEY RESULTS: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. CONCLUSION AND IMPLICATIONS: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.

Mapping brain activity following administration of a nicotinic acetylcholine receptor agonist, ABT-594, using functional magnetic resonance imaging in awake rats.

Administration of ABT-594, a potent agonist for nicotinic acetylcholine receptors with selectivity for the alpha4beta2 receptor subtype, is known to modulate a diverse array of behaviors including those associated with nociception, anxiety and motor function. In this study, we sought to gain insight into the neural actions of ABT-594, in vivo, by conducting functional magnetic resonance imaging in awake and anesthetized rats. Using T(2)*-weighted gradient echo imaging and an ultrasmall superparamagnetic iron oxide contrast agent, functional imaging was conducted on a 4.7 T magnet to measure changes in relative cerebral blood volume. In awake, restrained, male Sprague-Dawley rats that were acclimated to the imaging environment, injection of ABT-594 (0.03-0.3 micromol/kg, i.v.) evoked changes to relative cerebral blood volume in several neural regions including the cingulate, somatosensory, motor, auditory, and pre-frontal cortices as well as the thalamus and the periaqueductal gray/dorsal raphe. These effects were typically bimodal with significant decreases in relative cerebral blood volume at the 0.03 micromol/kg dose and increases at the higher doses (0.1 and 0.3 micromol/kg). The decreases and increases in relative cerebral blood volume were often observed within the same region, but triggered by different doses. Both increases and decreases in relative cerebral blood volume were blocked by pretreatment with the noncompetitive nicotinic acetylcholine receptor antagonist, mecamylamine (5 micromol/kg, i.p.) in awake rats. Administration of ABT-594 (0.1 micromol/kg, i.v.) to alpha-chloralose-anesthetized rats did not significantly alter relative cerebral blood volume in any brain region suggesting an anesthetic-related interference with the effects of ABT-594. The neural regions affected by administration of ABT-594 corresponded well to the known pre-clinical behavioral profile for this compound, and demonstrate the utility of using functional magnetic resonance imaging in awake animals to study pharmacological action.

A method to create an optimum current distribution and homogeneous B1 field for elliptical birdcage coils.

For a birdcage coil with elliptical cross-section, a sinusoidal current pattern does not provide a homogeneous B1 field. A simple theory was developed to create an optimized current distribution for elliptical birdcage coils. This optimized current pattern can create a perfectly homogeneous B1 field inside any elliptical shape. To verify the theory, a 16-element high-pass elliptical birdcage coil was built inside a circular RF shield. The current was optimized by using the inductance characteristics of the coil components to calculate the end-ring capacitances. The B1 field was theoretically calculated and experimentally mapped for the optimized elliptical bird-cage coil and a nonoptimized coil. The results demonstrate that by optimizing the current distribution, a very homogeneous B1 field is produced. This method can be directly applied in design and construction of elliptical birdcage coils for imaging of the naturally occurring elliptical cross-sectional geometries in the human body.

Exogenous methemoglobin as a cyanide antidote in rats.

The effects of the administration of methemoglobin (MetHb) prepared in vitro were evaluated in Sprague-Dawley rats given increasing doses of potassium cyanide (KCN). Median lethal dose (LD50) studies were conducted by giving intraperitoneal injections of KCN (in 0.3- to 0.5-ml volumes), then 2 min later administering intravenous (iv) doses of 1000, 1500, or 2500 mg/kg of MetHb through the tail vein. Control rats received an equivalent volume of saline. The resulting LD50 values for KCN were 7.4 +/- 1.1, 11.7 +/- 1.1, 13.9 +/- 1.0, and 14.2 +/- 1.0 mg/kg (mean +/- SD) for the control (no MetHb) and 1000-, 1500-, and 2500-mg/kg dose groups, respectively. Additional groups of rats were given 1000, 1500, or 2500 mg/kg MetHb and submitted for necropsy. The gross finding of darkened kidneys was present in both dose groups, but became consistent and more prominent in the 2500-mg/kg dose group. Evidence of pathologic changes was not present in other organs. Single-dose pharmacokinetic studies were conducted using iv doses of 1600 and 2500 mg/kg MetHb. The elimination half-life was similar in both doses (62.6 min), but the volume of distribution (95.3 +/- 7.2 and 126.3 +/- 5.2 ml/kg, mean +/- SE) and clearance (1.1 +/- 0.1 and 1.5 +/- 0.1 ml/min/kg) were significantly different (P less than 0.05) for the 1600- and 2500-mg/kg dose groups, respectively. From these data we conclude that although MetHb is cleared from the vascular system rapidly, it may be an effective and nontoxic antidote for doses of cyanide up to twice that of the control LD50.

Nonlinear reflection properties of germanium associated with thermal effects.

Thermal excitations on a germanium surface under simultaneous irradiation by two monochromatic optical beams, one strong and one weak, are predicted as functions of the angular separation and frequency difference between the beams, their relative polarization, their intensities, and pulse durations. Nonlinear optical reflection for Q-switched ruby laser pulses is then described. Weak reflected and diffracted beam intensities show tendencies in which the former is preferentially enhanced for a downshifted weak beam frequency, while the latter depends only on the shift magnitude. Both are suppressed for large shifts or large angular separations between input beams.