Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP Tg2576 mouse model of Alzheimer's disease

Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in normal rodents. The purpose of this study was to determine if ciproxifan, an H(3) receptor antagonist, could alleviate the hyperactivity and cognitive deficits observed in a transgenic mouse model (APP(Tg2576)) of Alzheimer's disease. APP(Tg2576) mice displayed significantly greater locomotor activity than wild-type mice, but APP(Tg2576) mice provided with daily ciproxifan treatment showed activity levels that did not differ from wild-type mice. In the swim maze, APP(Tg2576) mice exhibited significantly longer escape latencies, but the APP(Tg2576) mice treated daily with ciproxifan had latencies that were indistinguishable from controls. In probe trials conducted one hour after the last training trial, ciproxifan-treated APP(Tg2576) mice spent more time near the previous platform location and made more crossings of this area than did saline-treated APP(Tg2576) mice. APP(Tg2576) mice also demonstrated a significant impairment in the object recognition task that was reversed by acute treatment with ciproxifan (3.0mg/kg). These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of Alzheimer's disease.     

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Spatial working memory and the ability of a cholinesterase inhibitor to enhance memory were assessed at 4, 10, and 16 months of ages in control and Ts65Dn mice, a partial trisomy model of Down syndrome, with possibly significant relationships to Alzheimer's disease as well. In addition, ACh release during memory testing was measured in samples collected from the hippocampus using in vivo microdialysis at 4, 10, and 22-25 months of age. When tested on a four-arm spontaneous alternation task, the Ts65Dn mice exhibited impaired memory scores at both 4 and 10 months. At 16 months, control performance had declined toward that of the Ts65Dn mice and the difference in scores across genotypes was not significant. Physostigmine (50 microg/kg) fully reversed memory deficits in the Ts65Dn mice in the 4-month-old group but not in older mice. Ts65Dn and control mice exhibited comparable baseline levels of ACh release at all ages tested; these levels did not decline significantly across age in either genotype. ACh release increased significantly during alternation testing only in the young Ts65Dn and control mice. However, the increase in ACh release during alternation testing was significantly greater in control than Ts65Dn mice at this age. The controls exhibited a significant age-related decline in the testing-related increase in ACh release. With only a small increase during testing in young Ts65Dn mice, the age-related decline in responsiveness of ACh release to testing was not significant in these mice. Overall, these results suggest that diminished responsiveness of ACh release in the hippocampus to behavioral testing may contribute memory impairments in Ts65Dn mice.     

Attention,spatial representation,and visual neglect: simulating emergent attention and spatial memory in the selective attention for identification model (SAIM)

The selective attention for identification model (SAIM) is presented. This uses a spatial window to select visual information for recognition, binding parts to objects and generating translation-invariant recognition. The model provides a qualitative account of both normal and disordered attention. Simulations of normal attention demonstrate 2-object costs and effects of object familiarity on selection, global precedence, spatial cueing, and inhibition of return. When lesioned, SAIM demonstrated either view- or object-centered neglect or spatial extinction, depending on the type and extent of lesion. The model provides a framework to unify (a) object- and space-based theories of normal selection, (b) dissociations within the syndrome of unilateral neglect, and (c) attentional and representational accounts of neglect.     

Reaction time and established risk factors for total and cardiovascular disease mortality: Comparison of effect estimates in the follow-up of a large, UK-wide, general-population based survey

Higher cognitive function is associated with faster choice reaction time (CRT), and both are associated with a reduced risk of mortality from all-causes and cardiovascular disease (CVD). However, comparison of the predictive capacity of CRT, an emerging risk factor, with that for established ‘classic’ risk factors for mortality, such as smoking, hypertension or obesity, is lacking. The purpose of this study was to compare the relative impact of CRT with a range of established risk factors for all-cause and CVD mortality. The UK Health and Lifestyle Survey (HALS) is a national sample survey of adults in England, Scotland, and Wales. In 1984/85, data on lifestyle factors, socioeconomic status, and health were collected for 9003 individuals. CRT data were available for 7414 individuals. With different predictor variables having differing coding structures, we used the relative index of inequality (RII) to explore the relation of a range of risk factors with mortality by computing the risk in disadvantaged (high risk; e.g., smokers) relative to advantaged (low risk; e.g., non-smokers) persons. During an average of 20 years of follow-up, there were 1289 deaths (568 ascribed to CVD). In age- and sex-adjusted models in which all-cause mortality was the outcome of interest, CRT mean (RII = 2.57, 95% CI = 1.98, 3.33) was the second most important predictor of death after smoking (RII = 3.03, 95% CI = 2.45, 3.75). For death from CVD, CRT mean (RII = 2.31, 95% CI = 1.55, 3.43) was again the second most important risk factor for death, behind systolic blood pressure (RII = 4.37, 95% CI = 3.03, 6.29). These analyses suggest that CRT, a moderately high correlate of intelligence, is an important risk factor for death from all-causes and CVD.     

Behavioral profile of L‐655,708, a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit,in social encounters between male mice

GABA‐A receptor is a transmembrane hetero‐oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. It is well‐known that the GABAergic system is involved in the modulation of aggression. However, the role of α5/GABA‐A receptors has not been explored. In this study, we examined the effect of L‐655,708 (0.625‐5 mg/kg), a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to an anosmic “standard opponent” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. L‐655,708 (5 mg/kg) exhibited an ethopharmacological profile characterized by a marked reduction of the time spent in offensive behavior (threat and attack) without affecting immobility, accompanied by a significant increase of avoidance/flee and nonsocial exploration behaviors, suggesting that the antiaggressive effect of the drug is unselective. Overall, this behavioral profile might indicate the existence of an anxiogenic‐like activity of L‐655,708 in mice. Aggr. Behav. 30:319–325, 2004. © 2004 Wiley‐Liss, Inc.