Anticholinesterase-Induced Amnesia and Its Temporal Aspects

Deutsch, J. A.; Hamburg, Martin D.; Dahl, H. A.

doi:10.1126/science.151.3707.221

Cited by 104 publications

(23 citation statements)

References 5 publications

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“…The first two experiments (8,9) show that facilitation or block of a memory can be obtal ed with the same dose of anticholinester simply as a function of time of injectin riginal learning, as might be expected yaptic change formed the substrate of memory. In the first experiment, rats were trained on a simple task (10).…”

Section: Pharmacological Tools To Investigate Hypothesismentioning

confidence: 79%

The Cholinergic Synapse and the Site of Memory

Deutsch

1971

Science

693

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A simple hypothesis can explain the results obtained to date if we disregard those results when we wait 30 minutes after original learning to inject. The hypothesis is that, as a result of learning, the postsynaptic endings at a specific set of synapses become more sensitive to transmitter. This sensitivity increases with time after initial learning and then declines. The rate at which such sensitivity increases depends on the amount of initial learning. If the curve of transmission plotted against time is displaced upward with anticholinesterases then the very low portions will show facilitation, and the high portions will cause block (Fig. 8). The middle portions will appear unaffected (unless special experimental tests are made). If the curve of transmission is displaced down with anticholinergics, then the middle portion will appear unaffected and only the very early or late components will show block. The results are evidence that synaptic conductance is altered as a result of learning. So far it seems (i) that cholinergic synapses are modified as a result of learning and that it probably is the postsynaptic membrane that becomes increasingly more sensitive to acetylcholine with time after learning, up to a certain point. (ii) After this point, sensitivity declines, leading to the phenomenon of forgetting. (iii) There is also good evidence that there is an initial phase of declining sensitivity to cholinesterase or increasing sensitivity to anticholinergics. This could reflect the existence of a parallel set of synapses with fast decay that serve as a shortterm store. (iv) Increasing the amount of learning leads to an increase in conductance in each of a set of synapses without an increase in their number. (v) Both original learning and extinction are subserved by cholinergic synapses.

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Section: Pharmacological Tools To Investigate Hypothesismentioning

confidence: 79%

The Cholinergic Synapse and the Site of Memory

Deutsch

1971

Science

693

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“…As suggested by Deutsch and colleagues (Deutsch et al, 1966;Deutsch, 1971), the ability of cholinomimetics to enhance learning or memory processes may be determined by a number of factors, foremost being the timing of drug administration with respect to the "strength" of the memory trace. The data with regard to the cognitive enhancing effects of cholinomimetics in the treatment of Alzheimer's related deficits are inconsistent.…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, Pang and Nocera (1999) reported a disruption of T-maze performance in young rats given intraseptal oxotremorine in both control and IgG saporin-lesioned rats. These somewhat contradictory findings recall that the effects of both centrally and peripherally administered cholinomimetics vary as a function of several parameters (Deutsch et al, 1966;Deutsch and Rocklin, 1967;Hamburg, 1967;Deutsch, 1971; see also Schildein et al, 2000). Foremost of these is the timing of treatment with respect to the to-be-remembered event, or the strength of the trace at the time of drug administration.…”

Section: Introductionmentioning

confidence: 89%

Intraseptal infusion of the cholinergic agonist carbachol impairs delayed‐non‐match‐to‐sample radial arm maze performance in the rat

2004

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The medial septal nucleus regulates the physiology and emergent functions (e.g., memory formation) of the hippocampal formation. This nucleus is particularly rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive enhancing drugs. A large number of studies have demonstrated that direct intraseptal drug infusions can produce amnestic or promnestic effects. While a few studies have examined the effects of direct intraseptal infusion of cholinomimetics on spatial memory performance (with drug "on-board" at the time of testing), the effects of post-acquisition infusions have not been assessed. We hypothesized that post-acquisition intraseptal infusion of cholinomimetics, by promoting hippocampal theta and suppressing the occurrence of hippocampal sharp waves, may disrupt the long-term retention and consolidation of memory. The present study examined the effects of intraseptal infusion of the cholinergic agonist carbachol in a delayed-non-match-to-sample radial maze task. Treatments were administered immediately following (within 1 min) the sample session with a retention session 2 h later. Carbachol infusions (12.5-125 ng in 0.5 microl) produced a linear dose-dependent decrease in correct entries and increase in retroactive errors, without any change in proactive errors or latency-per-choice. These findings suggest that post-acquisition intraseptal cholinergic treatments can produce amnesia. These findings are discussed with regard to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related cognitive decline and Alzheimer's dementia.

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“…Though much of this stimulation work is intriguing, it is plain that Deutsch, Hamburg, and Dahl 1966, Deutsch and Leibowitz 1966, Wiener and Deutsch 1968 have reported that various changes in retention are a function of changes in cholinergic systems, which can be manipulated by anti-cholinergic and anti-cholinesterase drugs injected into the hippocampus. In a recent study George and Mellanby (1974) have shown that the carrier used in such studies (peanut oil) can, by itself, affect memory.…”

Section: Stimulation Studies 371mentioning

confidence: 99%