Dopamine/noradrenaline reuptake inhibition in women improves endurance exercise performance in the heat.

Catecholamine reuptake inhibition improves the performance of male volunteers exercising in warm conditions, but sex differences in thermoregulation, circulating hormones, and central neurotransmission may alter this response. With local ethics committee approval, nine physically active women (mean ± SD age 21 ± 2 years; height 1.68 ± 0.08 m; body mass 64.1 ± 6.0 kg; VO2peak 51 ± 7 mL/kg/min) were recruited to examine the effect of pre-exercise administration of Bupropion (BUP; 4 × 150 mg) on prolonged exercise performance in a warm environment. Participants completed a VO2peak test, two familiarization trials, and two randomized, double-blind experimental trials. All trials took place during the first 10 days of the follicular phase of the menstrual cycle. Participants cycled for 1 h at 60% VO2peak followed by a 30-min performance test. Total work done was greater during the BUP trial (291 ± 48 kJ) than the placebo trial (269 ± 46 kJ, P = 0.042, d = 0.497). At the end of the performance test, core temperature was higher on the BUP trial (39.5 ± 0.4 °C) than on the placebo trial (39.2 ± 0.6 °C, P = 0.021; d = 0.588), as was heart rate (185 ± 9 vs 179 ± 13, P = 0.043; d = 0.537). The results indicate that during the follicular phase of the menstrual cycle, an acute dosing protocol of BUP can improve self-regulated performance in warm conditions.

A dopamine/noradrenaline reuptake inhibitor improves performance in the heat, but only at the maximum therapeutic dose.

A maximal dose of bupropion has enabled subjects to maintain a higher power output than reported during the placebo session in the heat. Because this drug is taken in different doses it is important to know if there is a dose-response relationship with regard to exercise at high ambient temperature. Ten well-trained male cyclists ingested placebo (pla; 200 mg) or bupropion (50%, 75%, 100% of maximal dose: bup50: 150 mg; bup75: 225 mg; bup100: 300 mg) the evening before and morning of the experimental trial. Trials were conducted in 30 °C (humidity 48%). Subjects cycled for 60 min at 55% W (max) , immediately followed by a time trial to measure performance. Bup100 improved performance (pla: 33'42" ± 2'06"; bup100: 32'06" ± 1'54"; P = 0.035). Bupropion increased core temperature at the end of exercise, while heart rate was higher only in the bup100 trial (P < 0.05). No changes in rating of perceived exertion (RPE) or thermal sensation were found. Lower doses of bupropion were not ergogenic, indicating there was no dose-response effect. Interestingly, despite an increase in core temperature and improved performance in the maximal dose, there was no change in RPE and thermal sensation, suggesting an altered motivation or drive to continue exercise.

Emergence of topography in the developing hamster retinocollicular projection: axial differences and the role of cell death.

The precise ordering of the hamster retinocollicular projection is established over the first two postnatal weeks, coincident with developmental cell death. We have used quantitative retrograde labelling to define topographic precision in the early postnatal projection, to describe its refinement and to assess the contribution played by selective retinal ganglion cell death. The hamster's short gestation period allows the investigation of events occurring prenatally in other rodents. Discrete injections of fluorescent beads in the superior colliculus followed by isodensity contour analysis of labelled retinal cells reveals a dramatic decrease in the extent of retina labelled between postnatal days 2, 6 and 12 (P2, P6, P12): the 20% contour encloses 38.3%, 8.3% and 1.8% of the retina at these ages. Paired injections of two different tracers at variable rostrocaudal (R-C) separations at P2 produced complete overlap of label even when injections were separated by over 1 mm. This was not true for paired mediolateral injections at P2 that were separated by more than 500 microm. Analysis of the segregation of the two tracers ('nearest-neighbour analysis') shows topography improving with age so that by P12 injections separated rostrocaudally by more than 500 microm produced no overlap in the retina. To examine the contribution of selective ganglion cell death to topographic refinement, animals given paired R-C injections at P2 were allowed to survive until P12. Nearest-neighbour analysis reveals significantly more order in the P2-P12 retinae than after overnight survival. Thus, selective cell death plays a small but appreciable role in correction of topographical errors.

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Connections between cells of the internal capsule, thalamus, and cerebral cortex in embryonic rat.

The aim of our study is to understand the development of the earliest connections in the mammalian pallium by documenting the distribution of cells and fibres labelled from the dorsal and ventral thalamus, internal capsule, perirhinal, and dorsal cortex during the period between embryonic day (E) 14 and 17 by using carbocyanine dye tracing in fixed embryonic rat brains. Dye placed in the thalamus of E14 brains backlabels cells in the thalamic reticular nucleus and within the primitive internal capsule. Both anterograde and retrograde tracing confirmed that the first corticofugal projections reach the internal capsule by E14. At E15-E16, after the first cortical plate cells have migrated into the lateral cortex, some cells of the cortical plate and subplate and marginal zone, are backlabelled from the internal capsule, but still not from the dorsal thalamus, even with very long incubation periods. Crystal placement into the perirhinal cortex at E14-E15 labels numerous cells within the internal capsule, whereas no such cells are revealed from dorsal cerebral cortex until E17, suggesting that internal capsule cells establish early connections with the perirhinal and ventral but not dorsal cortex. We propose that the growth of axons from cortex to dorsal thalamus is delayed in two regions: first from E14-E15 at the lateral entrance of the internal capsule and then, from E16, closer to the thalamus, probably within the thalamic reticular nucleus. Subplate projections reach the proximity of the diencephalon at an early stage, but they might never enter the dorsal thalamus.

Embryonic development of connections in turtle pallium.

We are interested in similarities and conserved mechanisms in early development of the reptilian and mammalian thalamocortical connections. We set out to analyse connectivity in embryonic turtle brains (Pseudemys scripta elegans, between stages 17 and 25), by using carbocyanine dye tracing. From the earliest stages studied, labelling from dorsal and ventral thalamus revealed backlabelled cells among developing thalamic fibres within the lateral forebrain bundle and striatum, which had similar morphology to backlabelled internal capsule cells in embryonic rat (Molnár and Cordery, 1999). However, thalamic crystal placements did not label cells in the dorsal ventricular ridge (DVR) at any stage examined. Crystal placements into both dorsal and lateral cortex labelled cells in the DVR and, reciprocally, DVR crystal placements labelled cells in the dorsal and lateral cortices. Retrograde labelling revealed that thalamic fibres arrive in the DVR and dorsal cortex by stage 19. The DVR received projections from the nucleus rotundus and the dorsal cortex exclusively from the perirotundal complex (including lateral geniculate nucleus). Thalamic fibres show this remarkable degree of specificity from the earliest stage we could examine with selective retrograde labelling (stage 19). Our study demonstrates that axons of similar cells are among the first to reach dorsal and ventral thalamus in mammals and reptiles. Our connectional analysis in turtle suggests that some cells of the mammalian primitive internal capsule are homologous to a cell group within the reptilian lateral forebrain bundle and striatum and that diverse vertebrate brains might use a highly conserved pattern of early thalamocortical development.

Manufacture and release characteristics of Elvax polymers containing glutamate receptor antagonists.

Implantable sustained-release polymers offer an alternative to osmotic minipumps for the local delivery of drugs to specific brain areas. Here we describe the production of Elvax polymers containing a range of glutamate receptor antagonists and the quantitative characterization of their release properties. Sections of Elvax (200 or 400 microns), prepared by a dimethyl sulphoxide-based method, containing the NMDA antagonist MK-801 or the non-NMDA antagonist CNQX exhibited similar release profiles: an initial 2-week burst followed by a slow decline in release rate over the next 6 weeks. Differences in slice preparation method and thickness or drug concentration and solubility all led to alterations in the level of drug release, but not the overall exponential nature of the release curve. Elvax sections prepared by an aqueous method containing the NMDA antagonists CPP or APV displayed more constant but much lower levels of release than those from the dimethyl sulphoxide-based method. The in vitro release characteristics were compared with in vivo release of MK-801 and the close correspondence observed indicates that the in vitro release data is an accurate predictor of the drug release behaviour of implanted Elvax slices.

Postnatal changes in the uncrossed retinal projection of pigmented and albino Syrian hamsters and the effects of monocular enucleation.

Anterograde and retrograde tracing techniques have been used to study the uncrossed retinal projection in neonatal pigmented and albino Syrian hamsters. The total number of retinal ganglion cells projecting ipsilaterally peaks at postnatal days 2-4 (P2-P4) and declines to adult values by P12. The change in cell numbers has a similar time course in albino and pigmented animals. Although the population of uncrossed cells in the temporal retina of albino hamsters is always less than that in pigmented hamsters, no difference between the colour phases was found for the population of uncrossed cells in nasal retina. Differential cell death also contributes to the adult albino decussation pattern in hamsters: The relative loss of cells from temporal retina in albinos (72%) is greater than that in pigmented animals (56%). The additional loss in albinos does not appear to depend on binocular interactions: The same proportion (30%) of uncrossed cells is "rescued" from death by neonatal monocular enucleation in both colour phases. Flat-mount preparations showing the distribution of uncrossed fibres reveal that a distinct focus of terminals emerges in rostral superior colliculus, which is topographically appropriate for a binocular mapping, at the peak of uncrossed ganglion cell numbers (P4). Comparison of uncrossed terminal distributions and ganglion cell death reveals considerable refinement of the terminals prior to the main phase of cell death. Monocular enucleations performed some time after birth have a greater effect on uncrossed terminal distributions than on cell death. These observations suggest that independent mechanisms may be involved in the regulation of terminal distributions and of cell numbers in the developing uncrossed retinal pathways.