ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 micromol/kg/day). Continuous infusion of (-)-nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (-)-nicotine was required (62 micromol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies.     

Reduction in the number of NADPH-diaphorase-positive cells in the cerebral cortex and striatum in aged rats

Nitric oxide (NO) plays an important role as a diffusible messenger in learning and memory. To determine whether changes in NO production in the brain may be involved in aging-associated brain dysfunction, we measured the performance of aged rats in a radial arm maze task, and carried out histochemical examination of the changes in NADPH diaphorase (NADPH-d)-containing neurons in the brains of aged rats. The performance of aged rats (30 months old) in a radial arm maze task was significantly impaired compared to the performance of young rats (3 months old). The number of neurons containing NADPH-d reactivity in the cerebral cortex and striatum of aged rats was significantly reduced, by approximately 50 and 30 percent, respectively, compared to that in young rats. NO synthase activity in discrete brain regions of aged rats, i.e., in the cerebral cortex, striatum and hippocampus was not different from that in young rats, although the activity in the cerebellum of aged rats was significantly lower than that in young rats. These results suggest that the reduction in the number of NADPH-d-positive cells in the brains of aged rats may be involved in aging-associated learning impairment in rats.     

Preserved neuron number in the hippocampus of aged rats with spatial learning deficits

Hippocampal neuron loss is widely viewed as a hallmark of normal aging. Moreover, neuronal degeneration is thought to contribute directly to age-related deficits in learning and memory supported by the hippocampus. By taking advantage of improved methods for quantifying neuron number, the present study reports evidence challenging these long-standing concepts. The status of hippocampal-dependent spatial learning was evaluated in young and aged Long-Evans rats using the Morris water maze, and the total number of neurons in the principal cell layers of the dentate gyrus and hippocampus was quantified according to the optical fractionator technique. For each of the hippocampal fields, neuron number was preserved in the aged subjects as a group and in aged individuals with documented learning and memory deficits indicative of hippocampal dysfunction. The findings demonstrate that hippocampal neuronal degeneration is not an inevitable consequence of normal aging and that a loss of principal neurons in the hippocampus fails to account for age-related learning and memory impairment. The observed preservation of neuron number represents an essential foundation for identifying the neurobiological effects of hippocampal aging that account for cognitive decline.     

Brain aging: impaired coding of novel environmental cues

Studies of the spatial memory capacities of aged animals usually focus on performance during the learning of new environments. By contrast, efforts to characterize age-related alterations in spatial firing information processing by hippocampal neurons typically use an environment that is highly familiar to the animals. In the present study we compared the firing properties of hippocampal neurons in young adult and aged rats as they acquired spatial information about new environmental cues. Hippocampal complex spike cells were recorded while rats performed a radial arm maze task in a familiar environment and then recorded again after many of the spatial cues were changed. After the change in the environment, in aged rats 35-42% of place fields retained their original shape and location with respect to the maze center, although they usually rotated to another arm. By contrast, all place fields in young animals either disappeared or appeared in a new location. Some of the new place fields appeared in the new environment during the first 5 min of exploration, whereas others needed more than 30 min to develop fully. In the familiar environment spatial selectivity of place cells was similar in young and aged rats. By contrast, when rats were placed into a new environment, spatial selectivity decreased considerably in aged memory-impaired rats compared with that of young rats and aged rats with intact memory performance.     

Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input.

Studies using the selective cholinergic immunotoxin 192 IgG-saporin have demonstrated that lesions of the cholinergic input to the hippocampus from the medial septum/vertical limb of the diagonal band (MS/VDB) do not disrupt spatial learning in the water maze in young rats. However, age-related deficits in spatial learning correlate with the integrity of cholinergic neurons in the MS/VDB, suggesting that these neurons may be more crucial for spatial learning in aged rats. To investigate this hypothesis directly, we selectively lesioned these neurons in aged rats that demonstrated relatively intact spatial learning in an initial screening as well as in a comparison set of young rats. Intact and lesioned rats of both ages rapidly acquired a new place discrimination in a different spatial environment. These results indicate that the cholinergic input to the hippocampus is not differentially involved in spatial learning in aged rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypochord, an enigmatic embryonic structure: study of the axolotl embryo

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2-3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D2 receptor is more vulnerable to the effects of aging than the D1 receptor.     

Decreased duration of Ca(2+)-mediated plateau potentials in striatal neurons from aged rats

1. The influence of age on striatal neuron Ca2+ physiology was studied through an analysis of intracellularly recorded Ca(2+)-mediated plateau potentials. In vitro brain slices from young and aged rats were treated with the K+ channel blocker tetraethylammonium (30 mM) to facilitate the expression of plateau potentials. A sample of neurons was also filled with biocytin and post hoc correlations were performed between morphology and physiology. 2. Testing of sampling parameters in neurons from young rats revealed that tetrodotoxin did not affect the amplitude or duration of plateau potentials. The membrane potential induced during plateau testing and the rate of plateau potential generation, however, had to be held constant because these variables affected plateau potential duration. 3. A significant age-related decrease was found in the duration of Ca(2+)-mediated plateau potentials that could not be explained by alterations in the activation or inactivation properties of the plateau potential. Investigation into relationships between cell morphology and plateau potential duration revealed a number of correlations. Soma size and dendritic length were correlated with plateau potential duration, independent of age (hierarchical regression), and an age-related decrease in dendritic length but not in soma size was found. Spine density and plateau potential duration were also correlated, but the significance depended on the variance associated with age. These data indicate that the extent of somadendritic membrane (including spines) affects plateau potential duration in striatal neurons and that dendrite and spine loss in aged animals may contribute to age-related decreases in plateau potential duration. 4. The response to replacement of Ca2+ with Ba2+ was age dependent, with Ba2+ causing a greater increase in the duration of plateau potentials in young neurons. These data rule out an increase in Ca(2+)-mediated inactivation of Ca2+ channels as a primary cause for the shortening of plateau potentials in aged neurons. Our morphological findings suggest that dendritic regression in aged neurons may have reduced the number of Ca2+ channels participating in plateau potential generation, but other mechanisms related to changes in the type of Ca2+ channel expressed and possible differences in their inactivation kinetics may also contribute to the age-related change in plateau potential duration.     

Estradiol's effects on learning and neuronal morphology vary with route of administration.

Estrogen's effects on performance and neuronal morphology are variable, and the reasons for this variability are not yet understood. In this study, the authors compared the effects of 2 delivery routes of 17 β-estradiol on spatial learning and dendritic spine densities in young ovariectomized rats; estradiol was administered by implanted capsules or by daily oral gavage. Estradiol treatment via capsules improved performance in the radial-arm water maze and increased spine densities on dendrites of CA1 pyramidal neurons in the hippocampal formation. In contrast, daily oral administration of estradiol did not affect either measure. These data demonstrate that estradiol delivery is a critical variable in animal studies and that clinical studies comparing the effects of different estradiol treatment routes on cognition are warranted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reactivity to novelty in cognitively-impaired and cognitively-unimpaired aged rats and young rats

Two distinct populations of aged, Long-Evans rats can be identified on the basis of performance in the Morris water maze task. Aged (24 month) unimpaired rats perform similarly to young (six month) animals. Aged, impaired rats display latencies to find the submerged platform greater than two standard deviations from the mean of the young animals. A hallmark of efficient cognitive processing is the ability to cope with environmental change. Consequently, the present studies were conducted to assess if aged, impaired animals display differential reactivity to repeated exposure to novel stimuli. Reactivity was assessed by examining the degree of (i) consumption of a novel gustatory/olfactory stimulus (sweetened milk), (ii) pain inhibition induced by exposure to a novel hot-plate (48.5 degrees C) apparatus and (iii) exploratory behaviour in an elevated plus maze and a novel open field. Aged, impaired rats exhibited lower milk consumption on day one and protracted reactivity (lower consumption over days two to eight) in comparison to aged, unimpaired and young animals. Aged, impaired rats were more reactive to novelty on the hot plate test (as indicated by longer paw lick latencies); this novelty-induced pain inhibition did not habituate in aged, impaired rats following repeated plate exposures. The degree of exploratory behaviour in both the plus maze and the open field was reduced in aged, impaired rats. This effect was not entirely a consequence of deficient affective mechanisms, as measures of anxiety (e.g., time in open arms, time in inner squares) were not different among aged impaired, aged unimpaired and young animals. These results are the first to demonstrate that behavioural deficits observed in aged, impaired animals extend beyond the impairments observed in the water maze. This behavioural profile is attributed, in part, to heightened anxiety. In addition, the impairments observed in aged, impaired animals may also reflect a reduced sensitivity to the positive incentive properties of novel stimuli.     

H-7 stimulates desmosome formation and inhibits growth in KB oral carcinoma cells

Groups of old and young rats were administered three tests of spatial learning and memory that are known to be sensitive to hippocampal dysfunction: the radial arm maze (RAM), spatial non-matching-to-sample (SNMTS), and a spatial vs. local cue-preference task. Old rats performed worse than young rats on the RAM and SNMTS tasks; on the cue-preference task, young rats were biased to use spatial cues, whereas old rats exhibited strong preferences for distinct, local cues. Peripheral injections of glucose (100 mg/kg) improved performance by old rats on the RAM and SNMTS, which correlated with measures of glucose metabolism. Glucose treatment did not affect old rats performance on the cue-preference task. There was evidence that glucose-treatment improved performance of young rats in the RAM test, but not the other tests. The results extend the range of tasks on which glucose-induced cognitive enhancement has been demonstrated in aged rats, and provides further evidence that memory loss resulting from hippocampal dysfunction is especially amenable to glucose treatment.     

Hereditary primary childhood glaucomas

Experimental autoimmune encephalomyelitis (EAE) was induced in young (2-3 month old), middle-aged (12-13 month old) and geriatric (24-26 month old) Lewis (JC) rats by active immunisation with myelin basic protein (MBP) in complete Freund's adjuvant (CFA). It was found that aged Lewis (JC) rats developed a more chronic form of EAE than younger rats of the same strain, a phenomenon observed in both male and female rats despite males developing more severe disease than females at all ages. Middle-aged recipients also developed more severe disease than young recipients when EAE was induced by the adoptive transfer of lymphocytes from actively immunised young donors, suggesting that disease chronicity in middle-aged animals is a property of the central nervous system (CNS) milieu. Histological studies demonstrated that disease chronicity did not correlate with the number of inflammatory lesions in the CNS, young animals containing substantial numbers of CNS lesions following recovery and lesions being largely absent from middle-aged animals which still exhibited signs of disease. No significant differences were found in the degree of fibrin deposition or demyelination between young and middle-aged or symptomatic and asymptomatic animals. However, astrocytic hypertrophy was found to correlate with manifestation of disease in both young and middle-aged animals and in particular with disease chronicity in middle-aged animals. In parallel studies, no significant differences were found in the levels of the inflammatory mediators tumor necrosis factor (TNF)-alpha, prostaglandin E (PGE)2, reactive nitrogen intermediates (RNI) and corticosterone in young and middle-aged animals. However, markedly elevated corticosterone levels were found in both young and middle-aged animals with the development of clinical signs which returned to baseline levels with the resolution of clinical signs. Elevated levels of RNI were evident in animals immediately prior to and during the early stages of symptomatic EAE. Although these results suggest that nitric oxide may play a role in the pathogenesis of disease, whereas corticosterone may play a role in the immunoregulation of the disease, these factors cannot explain differences in disease chronicity evident in middle-aged animals.(ABSTRACT TRUNCATED AT 400 WORDS)     

Single enrichment variables differentially reduce age-related memory decline in female mice.

The authors sought to determine how different elements of enrichment, for example, cognitive stimulation and voluntary exercise, differ in their ability to improve memory throughout the lifespan. Young, middle-aged, and aged female C57BL/6 mice received 24-hr exposure in their home cages to toys alone (cognitive stimulation), running wheels alone (exercise), or both toys and running wheels (complex enrichment) for 4 weeks prior to and then throughout spatial water maze testing. As expected, spatial memory became progressively worse with age. Exercise alone improved spatial water maze performance in young mice, whereas both exercise alone and complex enrichment improved spatial maze performance in middle-aged mice. All enrichment treatments improved spatial maze performance in aged mice. These data suggest that exercise is the most effective element of enrichment in young female mice and that both cognitive stimulation and exercise are necessary to reliably improve spatial water maze performance in aging female mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility

The present study examined the performance of rats with neurotoxic lesions centred in the thalamic nucleus medialis dorsalis on standard and modified versions of the eight arm radial maze test. In Experiment 1, the thalamic lesions produced a borderline deficit in acquisition of the standard task, but subsequently had no effect when a delay was interposed after the first four arms had been entered. The same lesions had no effect on T-maze alternation, but they did impair radial-arm maze performance when intramaze and extramaze cues were set against each other. In Experiment 2, lesions of the dorsomedial thalamus impaired acquisition of the standard radial-arm maze task, but combining the results from Experiments 1 and 2 showed that this acquisition deficit was confined to those animals in which bilateral damage extended into the adjacent anterior thalamic nuclei. In addition, lesions of the dorsomedial thalamus disrupted radial-arm maze performance when the task was modified to compare working memory and reference memory and increased activity and exploration. These changes were not associated with anterior thalamic damage. Finally, the thalamic lesions did not affect performance on a test of spontaneous object recognition. It is concluded that lesions of medialis dorsalis do not disrupt spatial memory but do affect other processes that can interact with task performance. These include a failure of extramaze cues to overshadow intramaze cues, a change in activity and exploration levels and deficits in with-holding spatial responses.     

Brain aging: changes in the nature of information coding by the hippocampus

Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information.     

Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat

6-Hydroxydopamine-induced nerve terminal lesion of the nigrostriatal system may provide a partial lesion model of Parkinson's disease useful for the assessment of neuroprotective treatments and behavioral recovery after therapeutic intervention. The aim of the present study was to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra and the associated behavioral and neurochemical consequences of intrastriatal injections of 6-hydroxydopamine in young adult rats. Four groups of rats were stereotaxically injected in the right striatum with graded doses of 6-hydroxydopamine ranging from 0 to 20 mu g. Structural and functional deficits were quantified by tyrosine hydroxylase-immunoreactive nigral cell numbers, striatal dopamine content, skilled paw use, and drug-induced rotation. The results show that striatal 6-hydroxydopamine lesions produce dose-dependent decreases in striatal dopamine levels and tyrosine hydroxylase-immunoreactive cell numbers in the ipsilateral substantia nigra, accompanied by a significant long-lasting atrophy of the remaining dopaminergic neurons. Paw reaching test scores on the side contralateral to the lesion were non-linearly correlated with dopaminergic neuronal cell loss and exhibited a clear symptomatic threshold such that impaired paw use appeared only after >50% loss of nigral dopamine neurons or a reduction of 60-80% of striatal dopamine levels. The behavioral, cellular, and neurochemical effects of the nerve terminal lesion thus bear some resemblance to the early stages of Parkinson's disease, where the severity of motor impairment is correlated with the loss of dopamine in the striatum and dopaminergic neuronal loss in the substantia nigra. Rats with intrastriatal 6-hydroxydopamine lesions thus provide a model of progressive dopamine neuron degeneration useful not only for the exploration of neuroprotective therapeutic intervention but also for the study of mechanisms of functional and structural recovery after subtotal damage of the nigrostriatal dopamine system.     

Selective memory impairments produced by transient lidocaine-induced lesions of the nucleus accumbens in rats.

Reversible lidocaine-induced lesions of the nucleus accumbens (NAC) impaired performance on the spatial win-stay, but not on the cued win-stay, radial arm maze task. Pretraining lesions on the former task did not affect foraging for 4 pellets during either the training or test phases. In contrast, lesions given prior to the test phase significantly disrupted retrieval of 4 pellets on the 8-arm maze. Comparable deficits also were observed in rats trained to forage for 4 pellets on an 8-arm maze without prior win-shift experience. State-dependent drug effects were ruled out by replicating the disruptive effects of lidocaine infusions into the NAC on spatial win-shift performance in rats receiving this treatment prior to both training and test phases. These results suggest that the NAC may interact with the hippocampus to guide foraging behavior requiring memory of previous spatial locations on a maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related deficits on the radial maze and in fear conditioning: hippocampal processing and consolidation

Young adult, middle-aged, and old male F-344 rats were assessed for their hippocampal ability. This was accomplished by examining the animals on two different paradigms, each incorporating a simultaneous measure of hippocampal-dependent and -independent processing. The animals were fear conditioned and then tested for retention of the conditioning context and tone. This was followed by an 8-arm radial maze task which combined spatial working and cued reference memory elements. The two paradigms are compared in terms of task demands, potential confounds, and validity for aging studies. The results indicate that the performance of the animals on the two tasks is correlated. Age-related deficits limited to the hippocampal aspects of the above tasks were found, with no deficits found in the analogous but hippocampus-independent aspects of these tasks. The function of the hippocampus in incorporating new memories is time-related. Therefore, the possibility of age-related changes in consolidation was examined. It has previously been shown on the fear conditioning paradigm that the hippocampus is involved in retention of the aversive context for approximately 28 days. In the present study, an attempt was made to test the animals for retention of the conditioning context both early into the period of consolidation (10 days) and after consolidation should have been completed (52 days). The results indicate that, initially, the old animals show comparable retention to young rats. When examined later, young animals showed a stronger retention of the conditioning context than they had previously. The aged rats, however, did not seem to benefit from this additional period of time and in fact showed a decrease in retention of the conditioning context. The data are interpreted in terms of consolidation, alternative explanations of the data are presented, and suggestions are given for future research. Finally, the implications of such age-related changes in hippocampal consolidation on learning and memory are discussed.     

Identification and characterization of CDS2, a mammalian homolog of the Drosophila CDP-diacylglycerol synthase gene

The technique of intracranial microdialysis was used to investigate the effects of aging on the striatal dopaminergic system of the anesthetized Fischer 344 rat. Microdialysis probes were implanted into the striatum of young (2-8 months) and aged (24-28 months) urethane anesthetized rats. Striatal dialysate levels were analyzed for dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and serotonin (5-HT) by high performance liquid chromatography with electrochemical detection. As compared to the young animals, basal extracellular levels of DA and DOPAC were significantly decreased in two groups of aged animals. Stimulation with excess potassium added through the microdialysis probe produced a robust overflow of DA in the young and aged rat striatum, but the evoked overflow of DA was not diminished in the aged rat striatum as compared to young animals. In contrast, d-amphetamine-evoked overflow of DA was again robust in young and aged animals, but was greatly decreased in the aged rat striatum as compared to the signals recorded in the young rats. Taken together with previous reports, these data support the hypothesis that a major change in the regulation of DA release that occurs in aging involves changes in the function of the neuronal uptake of DA, which may be a compensatory property of DA neurons in senescence.     

VIP neurons in the human SCN in relation to sex, age, and Alzheimer's disease

The brains of 46 control subjects and 21 Alzheimer's disease (AD) patients were studied to determine whether there are age-related or AD-related changes in the vasoactive intestinal polypeptide (VIP) neuron population of the human suprachiasmatic nucleus (SCN). The number of VIP expressing neurons in the SCN of females, ranging in age from 10-91 years, did not change during normal aging. In males, however, the number of VIP neurons in the SCN was highest in the young subjects (10-40 years of age), after which, a dramatic decrease occurred in middle-aged subjects. This resulted in an age-dependent sex difference in the VIP cell population of the SCN: young males had twice as many VIP expressing SCN neurons as young females, whereas in the middle-aged groups, the females had twice as many VIP SCN neurons as the males. A significant decrease in the number of VIP expressing neurons in the SCN was found in female presenile AD patients, i.e., those younger than 65 years.