Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats

Stimulation of either GABA(A) or GABA(B) receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol) stimulated responding but a higher dose (660 pmol) induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol) also stimulated intake of freely available chow. Muscimol (220-660 pmol) was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol) induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A) or GABA(B) receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food

Neural circuits of eating behaviour: opportunities for therapeutic development

Understanding of the neural and physiological substrates of hunger and satiety has increased rapidly over the last three decades, and pharmacological targets have already been identified for the treatment of obesity that has moved from pre-clinical screening to therapies approved by regulatory authorities. Initially, this review describes the way in which physiological signals of energy availability interact with hedonic and rewarding properties of food to modulate the neural circuitry that supports eating behaviour. This is followed by a brief account of current and promising targets for drug development and a review of the wide range of preclinical paradigms that model important influences on human eating behaviour, and can be used to guide early stages of the drug development process

Shear dynamics in Bianchi I cosmologies with R^n-gravity

We give the equations governing the shear evolution in Bianchi spacetimes for general f(R)-theories of gravity. We consider the case of R^n-gravity and perform a detailed analysis of the dynamics in Bianchi I cosmologies which exhibit local rotational symmetry. We find exact solutions and study their behaviour and stability in terms of the values of the parameter n. In particular, we found a set of cosmic histories in which the universe is initially isotropic, then develops shear anisotropies which approaches a constant value.Comment: 25 pages LaTeX, 6 figures. Revised to match the final version accepted for publication in CQ

Galactic populations of radio and gamma-ray pulsars in the polar cap model

We simulate the characteristics of the Galactic population of radio and $\gamma$-ray pulsars using Monte Carlo techniques. At birth, neutron stars are spatially distributed in the Galactic disk, with supernova-kick velocities, and randomly dispersed in age back to $10^9$ years. They are evolved in the Galactic gravitational potential to the present time. From a radio luminosity model, the radio flux is filtered through a selected set of radio-survey parameters. $\gamma$-ray luminosities are assigned using the features of recent polar cap acceleration models invoking space-charge-limited flow, and a pulsar death valley further attenuates the population of radio-loud pulsars. Assuming a simple emission geometry with aligned radio and $\gamma$-ray beams of 1 steradian solid angle, our model predicts that EGRET should have seen 7 radio-loud and 1 radio-quiet, $\gamma$-ray pulsars. With much improved sensitivity, GLAST, on the other hand, is expected to observe 76 radio-loud and 74 radio-quiet, $\gamma$-ray pulsars of which 7 would be identified as pulsed sources. We also explore the effect of magnetic field decay on the characteristics of the radio and $\gamma$-ray pulsar populations. Including magnetic field decay on a timescale of 5 Myr improves agreement with the radio pulsar population and increases the predicted number of GLAST detected pulsars to 90 radio-loud and 101 radio-quiet (9 pulsed) $\gamma$-ray pulsars. The lower flux threshold allows GLAST to detect $\gamma$-ray pulsars at larger distances than those observed by the radio surveys used in this study.Comment: 38 pages, 11 figures, accepted for publication v565 n1 Ap

Spring 1984 Conference Issue

Research Update (page 3) Low Management Kentucky Bluegrass Cultivar Trials (5) Nitrogen Leaching Losses from N Fertilizer Applied to Turf (8) Fifty-third Annual Turf Conference and Eighth Industrial Show (10) Liquid Versus Dry Nitrogren Fertilizer Applications on Kentucky Bluegrass (13) Growth Retardant, Embark (16) Fungicides: The Good, The Bad and The Ugly (18

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Improved human observer performance in digital reconstructed radiograph verification in head and neck cancer radiotherapy.

Purpose: Digitally reconstructed radiographs (DRRs) are routinely used as an a priori reference for setup correction in radiotherapy. The spatial resolution of DRRs may be improved to reduce setup error in fractionated radiotherapy treatment protocols. The influence of finer CT slice thickness reconstruction (STR) and resultant increased resolution DRRs on physician setup accuracy was prospectively evaluated. Methods: Four head and neck patient CT-simulation images were acquired and used to create DRR cohorts by varying STRs at 0.5, 1, 2, 2.5, and 3 mm. DRRs were displaced relative to a fixed isocenter using 0–5 mm random shifts in the three cardinal axes. Physician observers reviewed DRRs of varying STRs and displacements and then aligned reference and test DRRs replicating daily KV imaging workflow. A total of 1,064 images were reviewed by four blinded physicians. Observer errors were analyzed using nonparametric statistics (Friedman’s test) to determine whether STR cohorts had detectably different displacement profiles. Post hoc bootstrap resampling was applied to evaluate potential generalizability. Results: The observer-based trial revealed a statistically significant difference between cohort means for observer displacement vector error (p = 0.02) and for Z-axis (p < 0.01). Bootstrap analysis suggests a 15% gain in isocenter translational setup error with reduction of STR from 3 mm to ≤2 mm, though interobserver variance was a larger feature than STR-associated measurement variance. Conclusions: Higher resolution DRRs generated using finer CT scan STR resulted in improved observer performance at shift detection and could decrease operator-dependent geometric error. Ideally, CT STRs ≤2 mm should be utilized for DRR generation in the head and break neck

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials