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Biomedical subjects

R T Bartus

Publications and source records attributed to R T Bartus.

At least 91 records · Page 5Linked to original sources
PubMed1983

Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat.

The nucleus basalis magnocellularis (NBM) is the name given to a group of cholinesterase-reactive neurons in the ventromedial corner of the globus pallidus of the rat. This cell group appears to be the major extrinsic source of cortical acetylcholine and is believed to be homologous to the nucleus basalis of Meynert in primates. The excitotoxin ibotenic acid (2.4 micrograms/0.4 microliter) was infused bilaterally into the ventromedial globus pallidus. These lesions depleted frontal cortical choline acetyltransferase (CAT) by a third. Neurotoxic lesions of the dorsolateral globus pallidus did not affect cortical CAT activity. Neither lesion affected the rats' performance on a battery of psychomotor tasks or on tests of shock sensitivity. Rats with NBM lesions were mildly impaired in the acquisition of a one-way active avoidance response, but did not differ from the other groups on extinction of the task. The NBM lesioned rats exhibited a severe deficit in the retention of a passive avoidance response. This effect was visible both 24 hours and one hour after training. Experimental controls suggested that the poor performance of the NBM lesioned rats involves a deficit in learning and/or memory of the training trial. Lesions of the dorsolateral globus pallidus also produced an impairment of passive avoidance retention, but this impairment was not as severe as that following NBM lesions. These results are discussed as they relate to the behavioral role of cholinergic innervation of the cortex, and the development of animal models for disorders involving cortical cholinergic deficiencies, including senile dementia of the Alzheimer's type.

Acetylcholine↗
PubMed1982

The cholinergic hypothesis of geriatric memory dysfunction.

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

Acetylcholine↗
PubMed1982

Neuropeptide effects on memory in aged monkeys.

The effects of several neuropeptides were evaluated using a non-human primate model of age-related memory impairments. Several doses of ACTH4-10, lysine vasopressin, arginine vasopressin, oxytocin and somatostatin were each tested in several aged monkeys. Because data from a large number of non-drug control sessions was collected before, during and after this study, it was possible to define the normal range of control performance for each monkey and statistically determine whether a change in performance under any single dose of drug reflected a significant change from the particular monkey's normal baseline performance. Although none of the neuropeptides produced consistent group effects, evaluations of individual subjects against their own baseline performance revealed reliable changes at certain doses. Arginine vasopressin appeared to produce the best overall effects with three of the five monkeys exhibiting reliable changes in performance from baseline. These same three monkeys also responded positively to the lysine form. Oxytocin impaired memory in three of the six aged monkeys tested over a wide range of doses. Three of six aged monkeys performed better under ACTH4-10 compared to baseline; however, in two of these cases only a single dose was effective. The performance of only one subject was improved under somatostatin, and this was at a single dose only. The data reported here provide evidence for neuropeptides producing behavioral improvement in non-human primates using an appetitive task, eliminating a popular criticism that the data in this literature has depended too heavily on the testing of rodents in shock-motivated tasks. Additionally, the improvements observed in this study involve a behavior that it naturally impaired by age and one which has many operational similarities and some empirical relevance to measures of recent memory in humans. However, these positive findings must be tempered by the lack of robust effects and high individual variation observed.

Adrenocorticotropic Hormone↗
PubMed1981

Presynaptic cholinergic mechanisms in brain of aged rats with memory impairments.

Presynaptic cholinergic mechanisms were investigated in various brain regions of aged Fisher 344 rats with documented 24 hr retention deficits measured in a single-trial passive avoidance tasks. Sodium-dependent high affinity choline uptake was found to be decreased by 22% in hippocampus of 23-26 month old animals as compared to 6 month old controls. Prior depolarization of hippocampal or cortical synaptosomes with K+ resulted in stimulation of choline uptake which was similar in aged rats and young controls. No age-related differences were observed either in hippocampal, cortical, striatal acetylcholine or choline concentrations, or in the activity of choline acetyltransferase in hippocampus. Synthesis of acetylcholine in hippocampal and cortical slices under basal conditions, as well as under K+-stimulated concentrations, did not differ in the two age groups examined. These neurochemical findings are consistent with an age-related decrease in hippocampal cholinergic neuronal activity without an actual loss in cholinergic neuron number. It is further suggested that this reduction in cholinergic neuronal activity may be related to the deficit in cognitive performance observed in aged Fisher rats.

Acetylcholine↗
PubMed1981

Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats.

In an attempt to gain some insight into possible approaches to reducing age-related memory disturbances, aged Fischer 344 rats were administered either vehicle, choline, piracetam or a combination of choline or piracetam. Animals in each group were tested behaviorally for retention of a one trial passive avoidance task, and biochemically to determine changes in choline and acetylcholine levels in hippocampus, cortex and striatum. Previous research has shown that rats of this strain suffer severe age-related deficits on this passive avoidance task and that memory disturbances are at least partially responsible. Those subjects given only choline (100 mg/kg) did not differ on the behavioral task from control animals administered vehicle. Rats given piracetam (100 mg/kg) performed slightly better than control rats (p less than 0.05), but rats given the piracetam/choline combination (100 mg/kg of each) exhibited retention scores several times better than those given piracetam alone. In a second study, it was shown that twice the dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not enhance retention nearly as well as when piracetam and choline (100 mg/kg of each) were administered together. Further, repeated administration (1 week) of the piracetam/choline combination was superior to acute injections. Regional determinations of choline and acetylcholine revealed interesting differences between treatments and brain area. Although choline administration raised choline content about 50% in striatum and cortex, changes in acetylcholine levels were much more subtle (only 6-10%). No significant changes following choline administration were observed in the hippocampus. However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%). No measurable changes in striatum or cortex were observed following piracetam administration. The combination of choline and piracetam did not potentiate the effects seen with either drug alone, and in certain cases the effects were much less pronounced under the drug combination. These data are discussed as they relate to possible effects of choline and piracetam on cholinergic transmission and other neuronal function, and how these effects may reduce specific memory disturbances in aged subjects. The results of these studies demonstrate that the effects of combining choline and piracetam are quite different than those obtained with either drug alone and support the notion that in order to achieve substantial efficacy in aged subjects it may be necessary to reduce multiple, interactive neurochemical dysfunctions in the brain, or affect activity in more than one parameter of a deficient metabolic pathway.

Acetylcholine↗
PubMed1981

Age-related differences in behavior across the life span of the C57BL/6J mouse.

C57Bl/6J mice, representing four divergent age groups (ranging from 3 months to 31 months) were each tested on a number of behavioral procedures, selected to sample a wide spectrum of behaviors. The evaluation demonstrated that, as with other mammalian species, not all behaviors in the mouse are affected by old age. Most severely impaired was retention of a single-trial passive avoidance task, most probably reflecting a deficit in memory ability. One tests of motor function, the most demanding tasks revealed the greatest debilitating effects of age, paralleling the effects of task difficulty previously reported in numerous learning studies. Finally, a deficit in the ability to modify preexisting habits in a T-maze learning situation was observed, corroborating reports of increased perseveration in aged humans and nonhuman primates. The similarity of these results across the life span of the C57 mouse with those previously reported for other aged mammalian species demonstrates that certain common types of behaviors seem to be impaired selectively by increased age across mammalian species and raises the possibility that common neurological etiologies may exist for these behavioral deficits.

Aging↗
PubMed1980

Brain cholinergic dysfunction and memory in aged rats.

Age related alterations in mnemonic ability and in the functional status of muscarinic receptors were evaluated and compared to biochemical measures of pre and post-synaptic cholinergic functioning. Retention of a single trial passive avoidance task was considerably disturbed as a function of aging. The functional status of muscarinic receptors, as measured by the ability of microiontophoretically applied acetylcholine to stimulate the firing of hippocampal pyramidal cells, was similarly disturbed in aged rats. A small, but significant decrease in muscarinic receptors was detected in the dorsal hippocampi of these same aged rats, while choline acetyltransferase activity did not change. When considered with prior psychopharmacological studies, these data suggest that specific muscarinic receptor impairments may play a critical role in the memory disturbances associated with old age.

Acetylcholine↗
PubMed1980

Localization of cellular changes within multimodal sensory regions in aged monkey brain: possible implications for age-related cognitive loss.

Young (4 to 7 years) and aged (18 to 28 years) rhesus monkeys were sacrificed and various neuromorphometric analyses performed to determine age differences in gross topography, cell population and patterns of cellular degeneration. Two brain regions implicated for their role in age-related cognitive disturbances, the hippocampus and the gyri bordering the principal sulcus in the frontal cortex were selected for these comparisons. Reliable morphometric differences between age groups were observed in both neural areas. One significant difference observed in the hippocampus was a reduced mean depth of the pyramidal layer of the CA-1 zone in the aged monkeys. Also, the mean number of neurons per transverse section in the CA-1 zone of the pyramidal layer was significantly less in the aged monkeys, and in certain instances cell gaps were observed in this region. In the lateral principal gyrus of the frontal cortex, the number of neurons in full-depth "cores" was lower in the old monkeys, glial count was higher and the ratio of neurons to neuroglia, therefore, lower in the older monkeys. Further, the mean area of the principal gyri, measured planimetrically from the apex of the medial gyrus to that of the lateral gyrus was significantly smaller in the aged monkeys. These findings indicate that significant age-dependent cellular differences occur in brain areas thought to be functionally involved in the particular cognitive behaviors most severely impaired in aged monkeys. These differences in brain morphology may, therefore, help provide some leads into the types of neurological changes contributing to the severe cognitive disorders suffered by the elderly.

Aging↗
PubMed1980

Age-related alterations in the rodent brain cholinergic system and behavior.

Pre- and postsynaptic cholinergic markers were studied in various brain regions of mice and rats aged 6 to 30 months in an attempt to determine whether alterations in this transmitter system occur during the normal aging process. Reliable decreases in cholinergic receptor binding and choline acetyltransferase (CAT) activity were found in the cerebral cortex and corpus striatum. These alterations in the cholinergic system were typically more consistent and robust than changes involving glutamic acid decarboxylase, and enzyme marker for GABA neurons. No statistically significant changes in any markers were found in the hippocampus of either species. Significant age-related changes in retention of passive avoidance learning and locomotor activity were also observed in these same animals. These findings demonstrate that changes in the cholinergic system occur naturally in aged mice and rats and that both the loss of cholinergic receptors and decrease in cat activity may contribute to the motor and mental impairments that often accompany old age.

Aging↗
PubMed1979

Physostigmine and recent memory: effects in young and aged nonhuman primates.

The effect of physostigmine on recent memory was evaluated in young and aged rhesus monkeys. All aged monkeys had previously shown impaired memory. The performance of the young monkeys treated with physostigmine was similar to that recently reported for young humans--no effects at low doses, some improvement at a restricted range of doses, and deficits at the highest dose. Although the aged subjects also improved at the same general doses, their overall response as a group was much more variable than that of the younger subjects. The performance of some aged monkeys was impaired by low doses that did not affect young monkeys. Continued improvement was observed in some aged monkeys at the highest dose, which typically impaired young monkeys. These variable effects across aged subjects suggest that physostigmine cannot easily or reliably be used as an agent for treating geriatric cognition. Nevertheless, the differential age-related effects suggest that appropriate manipulation of the cholinergic system may eventually be developed to alleviate some of the cognitive impairments suffered by aged subjects.

Acetylcholine↗
PubMed1979

Recent memory in aged non-human primates: hypersensitivity to visual interference during retention.

The effect of irrelevant visual information presented during retention of recent memory was investigated in young and aged monkeys. The monkeys were required to remember the location of a visual stimulus over short durations, during which time, on certain trials, irrelevant visual stimulation was presented. It was found that although the young monkeys performed as well with or without the irrelevant stimulation, the aged monkeys were significantly impaired when irrelevant stimulation was presented. Thus, these data provide direct support for the notions that aged subjects suffer a decreased ability to suppress visual stimuli from interfering with accurate behavior, and that this disability contributes to the memory impairments reported with old age. When considered with previous research in humans and non-human primates, these results suggest that this disability to suppress sensory interference may reflect a general effect of aging which may contribute to many other age-related behavioral impairments. Finally, it was suggested that the striking similarities of the behavioral profile now established for the aged monkey to that of younger monkeys suffering destruction of the frontal cortex (and anatomically related subcortical sites) offers the heuristic possibility that these two syndromes share a common neurological etiology.

Aging↗
PubMed1979

Aging in the rhesus monkey: effects on visual discrimination learning and reversal learning.

The behavior of aged rhesus monkeys (18 years and older) was compared to that of young monkeys (3 to 6 years old) to evaluate their relative abilities to learn a series of visual discrimination and discrimination reversal problems. Using a subject-paced, automated experimental procedure designed to optimize stimulus control and facilitate execution of choice responses, no consistent age-related differences were observed in the ability to learn new color and pattern discrimination problems of varying difficulty. However, a severe and consistent deficity on reversal learning did occur. A detailed analysis of this deficit revealed that not only did the aged monkeys take longer to extinguish the old habit and return to chance performance, but they continued to display a deficit in establishing accurate performance at above-chance levels as well. Since no reliable age differences were observed on the original discrimination learning problems, these data suggest that aging impairs mechanisms involved with response rigidity and/or susceptibility to intertrial proactive interference, more severely than those involved with the simple formation of new associations.

Aging↗