Excitability properties of medial forebrain bundle axons of A9 and A10 dopamine cells

A9 and A10 units identified as dopaminergic were recorded with extracellular micropipettes. The units were antidromically activated by electrical stimulation at the level of the preoptic area. The absolute refractory periods ranged from 1.2 to 2.5 ms. During the 2–8 ms of the relative refractory period, conduction was slower than normal by up to 1.5 ms. The time constant, C, of the strength-duration curve ranged from 0.4 to 0.6 ms. The current (I)-distance (D) relationship, tested by moving the stimulating electrode past the axon, was approximately parabolic (I = K D exp 2), with the constant of the equation, K, ranging from 900 to 2000 μA/mm exp 2, for 0.5 ms pulses. This relationship allows calculation of the radius of the field of dopamine axon excitation at any current. These high K values show that axons of dopamine cells cannot be activated unless high current densities are derivered, even when electrodes are placed near the axons. These data allow determination of the extent to which dopamine axons can be the directly activated substrates for behaviors, such as self-stimulation and circling, which are evoked by electrical stimulation of the medial forebrain bundle or internal capsule.     

Total sleep deprivation increases extracellular serotonin in the rat hippocampus

Sleep deprivation exerts antidepressant effects after only one night of deprivation, demonstrating that a rapid antidepressant response is possible. In this report we tested the hypothesis that total sleep deprivation induces an increase in extracellular serotonin (5-HT) levels in the hippocampus, a structure that has been proposed repeatedly to play a role in the pathophysiology of depression. Sleep deprivation was performed using the disk-over-water method. Extracellular levels of 5-HT were determined in 3 h periods with microdialysis and measured by high performance liquid chromatography coupled with electrochemical detection. Sleep deprivation induced an increase in 5-HT levels during the sleep deprivation day. During an additional sleep recovery day, 5-HT remained elevated even though rats displayed normal amounts of sleep. Stimulus control rats, which had been allowed to sleep, did not experience a significant increased in 5-HT levels, though they were exposed to a stressful situation similar to slee-deprived rats. These results are consistent with a role of 5-HT in the antidepressant effects of sleep deprivation.     

Validation of MTF measurement for digital mammography quality control

The modulation transfer function (MTF) describes the spatial resolution properties of imaging systems. In this work, the accuracy of our implementation of the edge method for calculating the presampled MTF was examined. Synthetic edge images with known MTF were used as gold standards for determining the robustness of the edge method. These images simulated realistic data from clinical digital mammography systems, and contained intrinsic system factors that could affect the MTF accuracy, such as noise, scatter, and flat-field nonuniformities. Our algorithm is not influenced by detector dose variations for MTF accuracy up to 1/2 the sampling frequency. We investigated several methods for noise reduction, including truncating the supersampled line spread function (LSF), windowing the LSF, applying a local exponential fit to the LSF, and applying a monotonic constraint to the supersampled edge spread function. Only the monotonic constraint did not introduce a systematic error; the other methods could result in MTF underestimation. Overall, our edge method consistently computed MTFs which were in good agreement with the true MTF. The edge method was then applied to images from a commercial storage-phosphor based digital mammography system. The calculated MTF was affected by the size (sides of 2.5, 5, or 10 cm) and the composition (lead or tungsten) of the edge device. However, the effects on the MTF were observed only with regard to the low frequency drop (LFD). Scatter nonuniformity was dependent on edge size, and could lead to slight underestimation of LFD. Nevertheless, this negative effect could be minimized by using an edge of 5 cm or larger. An edge composed of lead is susceptible to L-fluorescence, which causes overestimation of the LFD. The results of this work are intended to underline the need for clear guidelines if the MTF is to be given a more crucial role in acceptance tests and routine assessment of digital mammography systems: the MTF algorithm and edge object test tool need to be publicly validated.     

Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine

Functional brain imaging studies of subjects with Major Depressive Disorder (MDD) have suggested that decreased dorsolateral (DLPFC) and increased ventrolateral (VLPFC) prefrontal cortical activity mediate the depressed state. Pre- to post-treatment studies indicate that these abnormalities normalize with successful treatment. We performed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans on 16 outpatients with MDD before and after treatment with paroxetine (target dose = 40 mg/day). Regions of interest (ROIs) for this analysis were drawn by a rater blind to subject identity on the magnetic resonance image of each subject and transferred onto their coregistered PET scans. We hypothesized that DLPFC metabolism would increase, while ventral frontal metabolism [in the VLPFC, the orbitofrontal cortex (OFC), and the inferior frontal gyrus (IFG)] would decrease with successful treatment. Treatment response was defined as a decrease in the Hamilton Depression Rating Scale of > 50% and a Clinical Global Improvement Scale rating of 'much' or 'very much' improved. By these criteria, nine of the subjects were classified as treatment responders. These responders had significantly greater decreases in normalized VLPFC and OFC metabolism than did non-responders. There were no significant effects of treatment response on change in the DLPFC or IFG in this sample. However, there was a positive correlation between change in HAM-D scores and change in normalized IFG and VLPFC metabolism. There were no significant interactions with laterality. On pre-treatment scans, lower metabolism in the left ventral anterior cingulate gyrus was associated with better treatment response. These findings implicate ventral prefrontal-subcortical brain circuitry in the mediation of response to serotonin reuptake inhibitors in MDD.     

Gabapentin modifies extracellular opioid peptide content in amygdala: a microdialysis study

Opioid peptide release was monitored in the amygdala and hippocampus of freely moving rats following a single oral administration of gabapentin using microdialysis. Extracellular opioid peptide levels were elevated above basal levels in the amygdala within the first 60 (54%) and 90 min (68%) after gabapentin administration. Levels returned to basal conditions 120 min following the treatment. No significant changes were detected in the hippocampus. The majority of immunoreactive material recovered from the amygdala following gabapentin administration was identified as Leu-enkephalin and Met-enkephalin by high performance liquid chromatography (HPLC) analysis. It is proposed that the enhanced opioid peptide release in the amygdala induced by gabapentin might be involved with the antiepileptic effects as well as with some adverse events produced by this drug.     

Structure-pulmonary toxicity/retention relationships of inhaled fluorocyclobutenes

Hexafluorocyclobutene (HFCB) and derivatives have been used as fumigants, refrigerants and polymerization monomers. When inhaled they produce a potentially fatal pulmonary oedema similar to that induced by perfluoroisobutene (PFIB), a by-product of Teflon manufacture. This study determined the relationship between the chemical structure, respiratory retention and toxicity of HFCB and five analogues in rats and mice. Retention in the rat was determined using a flow-through system combining nose-only exposure and plethysmography. Structural changes to HFCB modified retention. At concentrations of ca. 1 ppm, where uptake was independent of exposure time, the rate of uptake was increased by halogen substitution in the order 3-Br = 1-Br = 1-Cl > 3-Cl = 1-H > HFCB, and was a function of volatility. At concentrations of 6 or 30 ppm, the percentage retained and rate of uptake decreased with time. The total mass retained (micromol kg(-1)) was not proportional to inhaled concentration and was best described by the calculated partition coefficient (octane-water). No clear relationship between retention and reactivity was apparent. The contribution of volatility, partition coefficient and reactivity to the uptake process depended on inhaled concentration. The toxicity of the fluorocyclobutenes agreed with reactivity relationships based on electrophilicity (lowest unoccupied molecular orbital energy), carbanion stability and leaving-group mobility. Toxicity is based principally on the number of successive alkylations (1, 2 or 3) that can occur with tissue nucleophiles.     

Inflammation-induced changes in primary afferent-evoked release of substance P within trigeminal ganglia in vivo

Substance P (SP) is synthesized in a subset of nociceptive sensory neurons and is released from their peripheral and central terminals. Here we demonstrate with the use of in vivo microdialysis and radioimmunoassay techniques that SP is also released within trigeminal ganglia following intraganglionic application of KCl, veratridine or capsaicin, and after electrical stimulation of peripheral afferent fibers. Both the basal and KCl-evoked release of SP are shown to be dependent on extracellular calcium. Using the turpentine-induced model of unilateral orofacial inflammation we also show that both the basal and KCl-evoked release of SP within trigeminal ganglia are greatly increased on the inflamed side 48 h after induction of inflammation. Coupled with previous demonstrations of excitatory effects of SP on sensory neurons, these results suggest that SP fulfils the role of a non-synaptically released diffusible chemical messenger that may modulate the somatic excitability of neurons within sensory ganglia in inflammatory pain states.