Biomedical subjects
P Mantyh
Publications and source records attributed to P Mantyh.
Beta-amyloid(1-40) effects on behavior and memory.
Beta amyloid 1-40 is a primary protein in plaques found in the brains of patients with Alzheimer's disease. There is evidence that unaggregated soluble beta-amyloid may be neurotoxic and may have behavioral effects on some types of memory. In the current study, the 1-40 fragment of beta-amyloid protein (beta A4), or vehicle, was bilaterally injected into the rostral hippocampus of rats performing under stable food-maintained schedules of reinforcement or under a delayed conditional discrimination procedure. Under the first procedure, rats were trained to stability under a multiple fixed interval 15 s, fixed ratio 30 reinforcement schedule. This reinforcement schedule has proven sensitive to low-dose drug effects. Acute bilateral hippocampal beta A4 (1.0, 2.0 and 3.0 microliters of 10(-3) M) administration did not significantly alter responding, compared to vehicle, under either reinforcement condition. Following the acute single-injection regimen, rats were administered chronic daily beta A4 (1 microliter of 10(-3) M), bilaterally, for 15 days. No significant changes in lever-pressing performance were observed during the chronic injection regimen, but performance declined significantly 30 days after termination of the chronic daily regimen. Histological examination revealed three of six rats showed positive reactions under Thioflavin S staining in and around the area of cannulae termination. The second assessment employed a delayed conditional discrimination procedure to evaluate the effects of intrahippocampal injections of beta A4 on short-term working memory. This conditional discrimination procedure assesses appropriate responding, dependent on a previously presented stimulus, after delays of various lengths have been imposed between the stimulus and the response opportunity.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of an exogenous beta-amyloid peptide on retention for spatial learning.
Three experiments assessed the effects of beta-amyloid 1-40 (beta A4) on spatial learning in Sprague-Dawley rats. In Experiment 1, rats were trained on a signaled footshock avoidance in a Y-maze. Rats received a single injection of beta A4 or vehicle in both sides of the hippocampus immediately after the fifth trial. The beta A4 group took significantly longer than the vehicle group to learn to avoid the shock when trained to criterion 1 week later, suggesting a detrimental effect of beta A4 on memory consolidation. Experiment 2 used a food reinforcer rather than shock relief under procedures similar to Experiment 1. Again, the beta A4 group took longer to learn the maze to criterion. This shocks that the effect in Experiment 1 was not specific to shock-maintained learning. In Experiment 3, rats were trained to retrieve a food pellet from each arm of an eight-arm radial maze. After training to criterion, beta A4 or vehicle was administered intrahippocampally 30 min before the daily session for 26 sessions. There were no acute or chronic effects of beta A4 injection on radial maze performance, and no aggregation of beta A4 or significant necrosis was observed upon postmortem histological analysis. These experiments suggest that single injections of beta A4 impair memory consolidation, but repeated injections of beta A4 over an extended period do not affect well-learned behavior.
Functional neurokinin 1 receptors for substance P are expressed by human vascular endothelium.
Substance P (SP), a neurotachykinin, is important in a number of inflammatory processes in which the endothelial cell also plays a critical role. SP receptors have previously been identified only on arterial endothelium, and the scant in vitro evidence for direct effects of SP on human endothelium is based on studies using nonarterial cells. To better understand SP's role in inflammation, we sought to identify functional SP receptors on human endothelium in situ and in culture. Autoradiographic ligand binding to human umbilical cord sections demonstrates the presence of SP binding sites with characteristics of the neurokinin 1 (NK-1) receptor (displacement by GTP analogues and the NK-1 specific antagonist CP-96,345) on human umbilical arterial, but not venous, endothelium. In culture, human umbilical venous endothelial cells (HUVECs) and human aortic endothelial cells express low levels of available SP binding sites. However, HUVECs, which are serum starved and refed, undergo a dramatic increase in SP binding. SP binding to starved/refed HUVECs induces a transient increase in intracellular calcium. This calcium flux is dose dependent over appropriate SP concentrations and can be blocked by NK-1 specific antagonists. The proinflammatory effects of SP may be mediated in part through the NK-1 receptor on endothelium.