Drugs to treat age-related neurodegenerative problems. The final frontier of medical science?
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Aged↗
Biomedical subjects
R T Bartus
Publications and source records attributed to R T Bartus.
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↗
The effects of blood sludging upon short-term memory in rats and rhesus monkeys: an evaluation of its role in age-related cognitive declines.
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Aging↗
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↗
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↗
Four stimulants of the central nervous system: effects on short-term memory in young versus aged monkeys.
Aged Rhesus monkeys and young control monkeys were tested in a delayed-response procedure to assess the effects of central-nervous-system (CNS) stimulants on short-term memory (STM). Previous research had established that the aged monkeys showed specific impairments of STM in this procedure. Four different CNS stimulants (methylphenidate, magnesium pemoline, a pentylenetetrazole/niacin mixture, and caffeine) were chosen for evaluation on the basis of their relevancy to current geriatric-psychopharmacologic research. Four different doses of each of the four CNS stimulants were given to each monkey, counter-balanced for possible order effects. Methylphenidate and caffeine impaired the performance of both age groups in this non-human primate cognitive task, even at relatively low dose levels. Magnesium pemoline produced fewer adverse effects and some evidence of improving STM in the aged monkeys, although not within the levels of statistical significance. The pentylenetetrazole/niacin mixture produced a three-way interaction involving age, dose and retention interval. This reflected the fact that although no definite effects were noted under the zero-sec control condition, statistically significant age-related deficits did occur in the STM-dependent retention interval as the dose varied. The data demonstrate that, of these four CNS stimulants, none radily improves (and often may impair) performance of tasks requiring STM. Thus the results of this study offer little support for the hypothesis that general CNS stimulation may constitute significant therapy for cognitive impairments associated with advanced age.
Aging↗
Short-term memory in the rhesus monkey: effects of dopamine blockade via acute haloperidol administration.
The effects of dopaminergic blockade on recent or short-term memory (STM) were evaluated in test-sophisticated rhesus monkeys. Each monkey was tested under several doses of the antidopaminergic haloperidol (0.006 to 0.05 mg/kg), in an automated, delayed-response procedure. The same procedure and test apparatus had previously been used to demonstrate profound STM impairments in aged rhesus monkeys and strikingly similar deficits in young monkeys given the anticholinergic scopolamine. The results of this study do not support the notion that dopaminergic mechanisms play a critical role in primate STM. Although significant impairments in delayed-response accuracy were observed with the higher doses of haloperidol, this impairment was unrelated to the duration of the retention interval, implying a more general, non-mnemonic dysfunction. Since the qualitative nature of this deficit to dissimilar to, and not as specific as that previously found in aged rhesus monkeys (or young monkeys given scopolamine), it is suggested that age-related changes observed in the dopaminergic system are less likely to be responsible for the aged STM impairments than comparable age-related changes in the cholinergic system.
Animals↗
Evidence for a direct cholinergic involvement in the scopolamine-induced amnesia in monkeys: effects of concurrent administration of physostigmine and methylphenidate with scopolamine.
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Animals↗
Aging in the rhesus monkey: debilitating effects on short-term memory.
The performance of aged rhesus monkeys (18 years and older) was compared to that of young control monkeys (three to five years old) in three experiments designed to define and evaluate the presumed short-term memory impairment associated with aging. An automated, indirect delayed-response procedure was used with special emphasis directed toward controlling or eliminating potentially confounding variables such as attention, motivation, learning disabilities, etc. It was shown that the aged monkeys do suffer from a profound a specific impairment in short-term memory (STM), performing normally on the shortest dealy interval and showing progressively greater impairment as the retention interval was increased. A subsequent study varied deprivation level and demonstrated that it is unlikely that differences in motivation could account for the age-related STM deficits observed on the delayed-response task. Further studies indicated that alterations in stimulus availability did not differentially affect the performance of the two age groups to any measurable extent, suggesting that differences in stimulus processing abilities are neigher necessary nor sufficient conditions for the deficit found in the first experiment. These results suggest that the delayed-response deficity in old monkeys is directly related to age-associated changes in those areas of the nervous system which are important for the expression of short-term memory.
Aging↗
Primate information processing under sodium pentobarbital and chlorpromazine: differential drug effects with tachistoscopically presented discriminative stimuli.
Sodium pentobarbital and chlorpromazine were evaluated for the degree to which they differentially reduce the speed or efficiency with which sensory information can be processed. Rhesus monkeys were tested under comparable doses of sodium pentobarbital and CPZ on a visual discrimination problem with varying durations of tachistoscopically presented stimulus information. When unlimited stimulus information was available, no effects of the two drugs were observed at the doses used, but as the duration of stimulus presentation was progressively decreased, the effects of sodium pentobarbital became more severe, whereas CPZ did not differe from the saline control an any presentation duration. While previously published literature indicates that CPZ impairs performance by intermittantly blocking sensory input or transmission, the present data provide the first direct behavioral confirmation that barbiturates impair performance by retarding the rate at which sensory stimuli can be processed and utilized.
Animals↗
Frontal decortication in rhesus monkeys: a test of the interference hypothesis.
Four monkeys with dorsolateral frontal ablations and 3 unoperated controls were run on discrimination problems which sequentially presented both relevant and irrelevant visual stimuli prior to the opportunity for a choice response. As previously reported, monkeys with undamaged brains performed significantly better on those problems presenting relevant information first, being unaffected by later occurring irrelevant stimuli. Contrary to the behavior of the normal monkeys, monkeys with lesions of the dorsolateral frontal cortex were severely impaired when irrelevant stimuli were presented after the relevant stimuli had been processed, but before the opportunity to respond had occurred. In other words, the frontal monkeys performed just the opposite of the normals in these procedures, even though the relevant and irrelevant stimuli were manipulated within the usual temporal definitions of the two-choice discrimination trial. These data demonstrate that the presentation of irrelevant stimuli before the choice response can significantly impair frontally decorticated monkeys and that this impairment does not require the use of a long temporal delay preceding the opportunity to respond. For this reason the data were interpreted as rather direct support of the interference hypothesis of frontal dysfunction. On the basis of these and other data discussed, it was concluded that one function of the dorsolated frontal cortex involves the suppression of interfering stimulus events interposed between the information necessary to guide behavior and the behavior itself.
Animals↗
Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine.
Two separate experiments were conducted to evaluate the effects of the anti-cholinergic scopolamine on primate visual discrimination and short-term memory (STM). In the first experiment it was shown that relatively mild doses of scopolamine severly impaired visual discrimination performance, even though the test procedure provided strong stimulus control. This deficit in visual discrimination suggested that previous research which used the delayed matching to sample procedure (DMS) to evaluate the role of cholinergics in primate STM may have confounded an accurate measure of specific STM effects because the DMS is inherently dependent on accurate visual discrimination. Therefore, the second experiment evaluated the effects of scopolamine on STM, using an automated apparatus and test procedure designed to minimize the discrimination component and other confounding variables present in the earlier research. In this second experiment, an indirect delayed response (DR) procedure was used, measuring the monkeys' ability to recall simple stimulus events over retention intervals of 0, 2.5, 5, and 10 sec. The monkeys were tested under 2 doses of the anti-cholinergic scopolamine and their performance was compared to that obtained on several nondrug control days. Contrary to earlier reports using the DMS, a clear interaction of drug and retention interval occurred in this situation. Under scopolamine, greatest impairments occurred on the longest delays, with little or no effect with zero second retention. Furthermore, the impairments observed on the longer delays were even greater with the highest dose of scopolamine. These data, therefore,support the notion that cholinergic mechanisms play an important role in the expression of STM in primates.
Acetylcholine↗
Effect of nitrogen narcosis on cortical and subcortical evoked responses in the cat.
Four cats were chronically implanted with gross, monopolar electrodes in the lateral geniculate nucleus (LGN), pretectum-superior colliculus (P-SC), primary visual cortex (VI), and secondary visual cortex (VII). Following recovery and preliminary testing, the animals were dived in a dry hyperbaric chamber to the sea water equivalent of 103 m (i.e. 340 ft.) where visual evoked responses were recorded. No decrements in the amplitude of the visual evoked response were found at the LGN, but significant decreases did occur at the other three sites. These data suggested: 1) that the effects of nitrogen narcosis on the visual system are primarily central, and not simply peripheral in nature; 2) that these effects are not limited to the visual cortical mantle; and 3) that the narcosis apparently influences structures involving different anatomical levels of the brain which presumably mediate various types of visual processes. The findings were discussed as they relate to current ideas concerning the underlying neurological causes and behavioral effects of nitrogen narcosis.
Animals↗