Neurotransmitters In Memory Processing And Appropriate Synaptic Function

Since AzD is characterised by an impairment of memory, which is a normal brain function, then a consideration of which NTs and brain circuitry are implicated in the laying down and retrieval of memory may provide an indication of not only which NTs we should expect to be affected in AzD but also which need to be manipulated to therapeutic advantage. Again, most evidence points to ACh and glutamate.

® I 23456789 10 Days of test (training)

Figure 18.3 Acquisition of the water maze task as an index of learning and memory. In this example rats were trained daily to find a platform just submerged below water in a circular (150 cm) glass tank painted black and the time taken to reach it recorded. Young (4-month) saline-treated rats (o) quickly learnt and from day 6 consistently swam to the platform in less than 10 s. By contrast, aged (22-month) rats (■) took significantly longer to acquire the task and by day 10 were still taking about 30 s. The anticholinesterase drug tacrine (30mgkg~' daily.ip) given to such aged rats (•) significantly reduced the time to acquire (6 days) and perform the task (20 s). Adapted from Yavich et al. (1996)

® I 23456789 10 Days of test (training)

Figure 18.3 Acquisition of the water maze task as an index of learning and memory. In this example rats were trained daily to find a platform just submerged below water in a circular (150 cm) glass tank painted black and the time taken to reach it recorded. Young (4-month) saline-treated rats (o) quickly learnt and from day 6 consistently swam to the platform in less than 10 s. By contrast, aged (22-month) rats (■) took significantly longer to acquire the task and by day 10 were still taking about 30 s. The anticholinesterase drug tacrine (30mgkg~' daily.ip) given to such aged rats (•) significantly reduced the time to acquire (6 days) and perform the task (20 s). Adapted from Yavich et al. (1996)

ACETYLCHOLINE

ACh is implicated in memory for two main reasons:

(1) It has been known for many years that antimuscarinic drugs like hyoscine, which enter the brain, cause amnesia when used clinically, e.g. pre-operatively, to reduce bronchial secretions. In experimental studies in both humans and animals they disrupt both the acquisition and the performance of learned behaviour. Anti-cholinestrase drugs have the opposite effect. It is by no means certain, however, that the memory defects induced by antimuscarinics are identical to those seen in AzD.

(2) Exocytoxic lesions of the nucleus basalis with excitatory amino acids such as quisqualic and ibotenic reduce cortical ChAT activity and impair memory performance in animals. Unfortunately although quisqualate is more effective than ibotenic in reducing ChAT, it has less effect on memory (acquisition of passive avoidance), suggesting some additional effect of ibotenic acid not concerned with the ACh. Nevertheless, the memory defect induced by ibotenic acid is similar to that obtained with hyoscine and can be reversed, as studies in the rat water maze test show, by implanting fibroblasts with high ChAT activity in the cortex to secrete ACh. Anticholinesterase inhibition and foetal brain grafts containing cholinergic neurons have also been shown to partially reverse the effects of lesions of the nucleus basalis.

So if ACh is involved in memory function, what does it do? Any attempt to answer that question has to follow some consideration of how memory is thought to be processed. Many neuroscientists believe that memory is achieved by changes in the strength of synaptic connections (activation) between neurons and that increases in such synaptic activity somehow reinforce the pattern of neuronal activity during the memorising of an event so that it can be more easily restored later. One form of such plasticity is long-term potentiation (LTP), which has been mostly studied in the hippocampus where, as in other areas associated with memory, there is the appropriate complex synaptic morphology.

That the hippocampus is important for memory is generally accepted. This is not because it is a site of major degeneration in AzD, that finding can only be used to account for the memory loss if memory is known to be dependent on the hippocampus, but because lesions of that region are known to impair memory. Case reports in the medical literature are rightly mistrusted but few people have felt inclined to disregard the evidence presented by one 27-year-old male mechanic who underwent bilateral hippocampal removal for intractable epilepsy in Montreal in 1953. While that condition was improved the operation has not been repeated because memory loss was almost total, so while he appeared to behave reasonably normally (and still does), he cannot remember where he lives, what he has just eaten or the person he met a few minutes previously.

Long-term potentiation can be defined as the increased effectiveness (potentiation) of synaptic transmission which may last for hours (possibly days) and is triggered experimentally by a brief burst of high-frequency stimulation of presynaptic inputs so that the response to any following input is much greater than normal. It was first demonstrated in vivo (Bliss and Loma 1973) but much studied in vitro. There is considerable debate as to whether the potentiation is of pre- or postsynaptic origin, or both, and while neurons can discharge spontaneously at an appropriate tetanic frequency (e.g. 200 Hz) it is not known how this may arise in normal neurophysiological processing. So to what extent LTP is essential to the memory process is unclear but there is no disputing the fact that despite all the evidence for the involvement of ACh in memory, antimuscarinic drugs do not affect LTP. ACh does, however, have the ability to partially depolarise neurons by reducing K+ efflux (Chapter 6) and so make them more likely to fire repetitively to an incoming impulse. On the other hand, LTP is blocked by glutamate NMDA antagonists.

GLUTAMATE

As outlined above, changes in glutamate levels and function in AzD are much less clear-cut than for ACh, despite the fact that the lost pyramidal cells presumably use glutamate as a NT. On the other hand, glutamate, unlike ACh, does appear to be essential for LTP and if that is important in the memory process then so is glutamate. LTP is increased by NMDA agonists as well as being blocked by NMDA antagonists, which also decrease learning in animals. Such drugs have not been risked in patients but phencyclidine, which has been used as an anaesthetic (and drug of abuse), is known to cause amnesia and has been found to directly block NMDA receptor channels.

OTHER NTs

Just as there is less degeneration of monoamine than cholinergic neurons in AzD, so they have less influence on memory function. Generally in both animals and humans, increases in NA activity (a1 agonists, a2 antagonists) improve cognition although both positive and negative effects have been reported with a2 agonists and cardiovascular effects cannot be ruled out in all these studies. 5-HT3 antagonists such as zacopride and ondansetron have been shown to produce some improvement in cognitive performance in animal and human studies. Removal of the posterior pituitary in rats shortens retention of a conditioned avoidance response, an effect which can be overcome by the administration of vasopressin. Variable but generally weak positive effects on cognition have been seen with this peptide in humans. Opioids tend to impair and their antagonists improve memory in animals (see McGough, Introlni-Collison and Castellano 1993).

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