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Brain Function and Psychotropic Drugs$

Heather Ashton

Print publication date: 1992

Print ISBN-13: 9780192622426

Published to Oxford Scholarship Online: March 2012

DOI: 10.1093/acprof:oso/9780192622426.001.0001

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Drugs and memory

Drugs and memory

Chapter:
(p.215) 10 Drugs and memory
Source:
Brain Function and Psychotropic Drugs
Author(s):

Heather Ashton

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780192622426.003.0010

Abstract and Keywords

Increasing interest has focused recently on the possibility of pharmacological treatment for memory disorders. Drugs, of course, cannot be expected to replace degenerated neurones, but they might theoretically improve the function of surviving neurones in chronic diseases, hasten neuronal recovery in acute conditions, and perhaps prevent further neuronal damage in both. Such measures are unlikely to have specific effects on memory, but may produce general improvement in mental efficiency. In other circumstances it is advantageous to facilitate forgetting. For example, the use of amnesic drugs as preoperative medication may not only calm the patient but also forestall the laying down of unpleasant memories.

Keywords:   memory disorders, pharmacological treatment, neurones, neuronal recovery, mental efficiency, unpleasant memories

Increasing interest has focused recently on the possibility of pharmacological treatment for memory disorders. Drugs, of course, cannot be expected to replace degenerated neurones, but they might theoretically improve the function of surviving neurones in chronic diseases, hasten neuronal recovery in acute conditions, and perhaps prevent further neuronal damage in both. Such measures are unlikely to have specific effects on memory, but may produce general improvement in mental efficiency. In other circumstances it is advantageous to facilitate forgetting. For example, the use of amnesic drugs as preoperative medication may not only calm the patient but also forestall the laying down of unpleasant memories.

Drugs for improving memory

Central nervous system stimulants

Central nervous system stimulants such as amphetamine and caffeine can improve performance of normal subjects in certain tasks, particularly in the presence of fatigue or boredom. In general these drugs may influence memory by improving arousal and attention, but it is doubtful whether they can contribute much to the treatment of memory disorders.

Methyl-phenidate over a range of doses has been reported to impair performance in memory tasks by disrupting attention during learning (Squire and Davis 1981), but to facilitate the learning of a pictorial paired-associate task in hyperactive children (Shea 1982). Facilitation of word-list recall has been observed after d-amphetamine in depressed patients and in normal children (Squire and Davis 1981). Pemoline and other central nervous system stimulants reviewed by Judd et al. (1987) have also been claimed to increase general performance, although not specifically memory, in fatigued or elderly subjects, and to reverse the sedative effects of central nervous system depressants.

Cholinergic agents

The demonstration of central cholinergic degeneration in Alzheimer’s disease suggested a therapeutic potential for cholinergic agents. Drachman (1978; Chapter 8) showed that the memory defects produced (p.216) by anticholinergic agents were similar to those which develop in old age and could be reversed by physostigmine. A parallel between dopamine replacement in Parkinson’s disease and acetylcholine replacement in Alzheimer’s disease was immediately suggested. However, early hopes (Corkin 1981) have been somewhat dashed by later findings of considerable deficits in cholinergic receptors in Alzheimer’s disease, as well as deficits in many other neurotransmitter systems and widespread neuronal degeneration (Chapter 9; Fibiger 1991). Treatment with cholinergic agents, if it is to be effective, must probably be started early in the disease and continued for long periods, perhaps for life. Coyle et al. (1983b) point out that functional deficits caused by degeneration of the cholinergic system, which is normally phasically active, with rapid neuronal discharge rates conveying spatially and temporally coded information (Chapter 8), may not be amenable to pharmacological correction.

Trials with several cholinergic agents including acetylcholine precursors, anticholinesterases and cholinergic agonists have been reported, although there have been few well-designed, large-scale, long-term studies (Squire and Davis 1981; Zeisel et al. 1981; Kendall 1987). The results available suggest only limited therapeutic benefit. Dietary supplements of choline and lecithin increase the synthesis and concentration of acetylcholine in the rat brain, and possibly in humans. Corkin (1981) reviewed 11 studies in which choline was administered for periods of 2 weeks to 3 months to patients with Alzheimer dementia. No overall changes were seen although individual patients showed improvement in some memory tests. Levy et al. (1983) reported the preliminary results of a double blind trial of a preparation containing 90 per cent phosphatydyl choline in 52 patients with early Alzheimer dementia. A significant improvement in a test of general cognitive function and in a paired associate learning test was found in patients taking the drugs for 6 months. Pomara and Stanley (1982) raise the possibility that long-term treatment with cholinergic precursors might lead to receptor desensitization and eventually produce the opposite effect from that intended.

Of the anticholinesterases, physostigmine has been used in a number of studies reviewed by Mohs and Davis (1987). Significant improvement in some aspects of memory was found in a few subjects, but the utility of this drug is limited by adverse effects and the fact that it has a short half-life and a narrow effective dose range which needs individual titration (Castleden 1984). Intravenous infusion of physostigmine was shown to increase cerebral blood flow in the posterior parietal region, especially in the left hemisphere, in patients with Alzheimer’s disease (Geaney et al. 1990). Oral tetrahydroaminoacridine (THA, tacrine), a potent centrally acting anticholinergic agent, has been used in some trials, either alone (Summers et al. 1986) or combined with lecithin (Kaye et al. 1982; Chatellier and Lacamblez 1990; Eagger et al. 1991). Early reports seemed (p.217) encouraging in a few patients but the results were modest overall. Tacrine has other effects, including a central stimulant action and can also produce adverse effects (Byrne and Arie 1989).

Cholinergic receptor agonists have been investigated. The results, reviewed by Gray et al. (1989), in general show a clinically relevant response only in a minority of patients. Nicotine by various routes has been advocated (e.g. Sahakian et al. 1988) but there is no evidence that cigarette smoking, the most effective method of nicotine administration (Chapter 7), has therapeutic or prophylactic effects in Alzheimer’s disease. Some authors (Quirion et al. 1989; Gray et al. 1989) suggest that centrally acting selective antagonists of muscarinic (M2) autoreceptors or specific muscarinic (M1) receptor agonists, might have a therapeutic potential, and some such drugs are under trial.

An alternative approach is the use of agents which increase acetylcholine release. Sarter et al. (1988, 1990) point out that acetylcholine release and choline uptake are largely under the control of GABAA receptors, and cite evidence that residual cholinergic neurones in Alzheimer’s disease are subject to increased GABA inhibition. These observations suggest a therapeutic potential for drugs which inhibit GABAA receptors. Some beta-carbolines, such as ZK 93 426, combine antagonist and inverse agonist actions at GABAA receptors (Chapter 4). This drug has indirect cholinomimetic effects and has been shown to increase vigilance and information processing in normal subjects (Sarter et al. 1990). As yet data on the use of such drugs in Alzheimer patients is lacking, and adverse effects such as anxiogenesis (Dorow et al. 1983; Chapter 3) may prove a limiting factor. Acetylcholine release in the cortex also appears to be under serotonergic control, via 5-HT3 receptors (Table 3.1), and it has been suggested that antagonists of these receptors (such as ondansetron) may be of value in states of impaired cortical cholinergic function (Barnes et al. 1989).

Drugs which increase cerebral blood flow or enhance cellular metabolism in the brain

In cerebral arteriosclerosis, which occurs to some degree in about 30 per cent of patients with senile dementia, cerebral blood flow is reduced and areas of brain tissue are hypoxic. Several drugs have been tested for their ability to relieve cerebral hypoxia in animals. It was found, however, that many of the drugs, although vasodilators, also stimulated cerebral metabolism. This action is probably more important than vasodilatation since cerebral vascular tone depends largely on local factors and sclerotic blood vessels in anoxic areas are likely to be already maximally dilated. Recent efforts have therefore been directed towards developing (p.218) drugs which increase neuronal oxidative activity, in the hope of improving neural function both in cerebrovascular disease and Alzheimer’s disease.

Papaverine, procaine, cyclandelate

Papaverine produces vasodilatation by a direct action on arterial smooth muscle. It may also have some dopamine receptor blocking activity and may inhibit phosphodiesterase, resulting in raised tissue concentrations of cyclic AMP, which may stimulate neuronal metabolism (Scott 1979). Papaverine reduces the symptoms of cerebral ischaemia due to arterial spasm. Its effects in arteriosclerotic dementia or other dementias of old age are controversial although some trials have reported favourable results (Branconnier and Cole 1977). Beneficial effects when they occur are modest and are not restricted to memory functions. Similarly, procaine may have beneficial effects on mood and general performance in senile dementia (Ban 1978).

Dihydrogenated ergot alkaloids

Co-dergocrine mesylate (Hydergine) is a mixture of dihydrogenated derivatives of the constitutent alkaloids of ergotoxine. These substances block adrenergic receptors and act as partial agonists/antagonists at dopaminergic and serotonergic sites (Castleden 1984). They may increase the microcirculation in the brain but their major action appears to be on neurone metabolism. Co-dergocrine is reported to inhibit the action of Na/K ATPase, adenylate cyclase, and phosphodiesterase in brain cells, thus decreasing the breakdown of ATP and cyclic AMP, improving the energy balance of the cell, and enhancing cyclic AMP-mediated effects (Meier-Ruge et al. 1975). These changes are thought to account for an ‘activating’ effect on the EEG observed in hypoxic rats and elderly patients. Cerebral oxygen consumption is also reported to be increased by hydergine in patients with cerebrovascular disease (Sandoz 1977). Several placebo controlled double blind with dihydrogenated ergot alkaloids studies reviewed by Castleden (1984) have shown significant but limited improvement in general and cognitive functioning in geriatric patients.

Naftidrofuryl and other vasodilators

Naftidrofuryl is a vasodilator with sympatholytic and local anaesthetic properties; it is also said to stimulate brain metabolism (Scott 1979). It has been used in a number of small studies in patients with mixed dementias and may be modestly effective in improving cognitive performance in some patients (Castleden 1984).

Other vasodilator drugs which also stimulate cell metabolism include isoxsuprine, vinca alkaloids, nicergoline, and cinnarizine. Some studies (p.219) have suggested that they are of therapeutic value and these are reviewed by Nicholson 1990.

Piracetam and other nootropic drugs

The term nootropic was applied to the compound piracetam, a cyclic derivative of GABA, which was claimed to be the first of a new class of drugs which enhance learning and memory by a selective effect on brain integrative mechanisms in the telencephalon (Giurgea 1976). Several more effective congeners, reviewed by Nicholson (1990) have since been developed. These drugs are reported to have rather dramatic effects on learning and memory in rodents. They facilitate information acquisition and enhance memory retrieval (Sara et al. 1979) in normal animals and in animals with impaired cognitive function induced by hypoxia, hyper-capnia, scopolamine and cycloheximide. In addition, they enhance long-term potentiation, facilitate interhemispheric transfer of information (Bureseva and Bures 1976), and protect the brain from various physical and chemical injuries. Their mode of action is not known, but they are thought to increase the release of dopamine (Rago et al. 1981) and possibly of acetylcholine (Nicholson 1990).

Despite their promising pharmacological profile in animals, there is little evidence that nootropic drugs are therapeutically effective in dementia in man. Piracetam has been investigated in a number of clinical trials in patients with impaired mental function of mixed aetiology (Barnas et al. 1990). It has been reported to produce variable degrees of improvement in general mental function in cerebrovascular disease, post-concussional syndrome, senile and presenile dementia, chronic and acute alcoholism, and alcohol withdrawal syndromes, to shorten the duration of coma following drug intoxication, and to hasten recovery after neurosurgery. As a treatment for senile dementia, piracetam has received little support, eight out of 13 studies reviewed by McDonald (1982) showing no difference between drug and placebo. However, trials with a combination of piracetam and choline in Alzheimer’s dementia may be worth pursuing (Castleden 1984).

Vasopressin

In spite of the demonstrable effects of vasopressin on memory in animals and the suggestion that it may be involved in human memory (Chapter 8), the use of vasopressin or its synthetic analogues for treatment of memory disorders in man has met with variable success. Vasopressin is usually administered by nasal catheter or as a nasal spray and treatment must usually be continued daily for some weeks before a measurable response occurs. Occasional reports have noted improvement after vasopressin in learning ability in the alcoholic amnesic syndrome (Le Boeuf (p.220) et al. 1978) and partial reversal of retrograde amnesia due to head injury (Oliveros et al. 1978) or electroconvulsive therapy (Weingartner et al. 1981). Vasopressin has also been reported to improve learning and memory in patients with primary affective disorders (Gold et al. 1979b; Weingartner et al. 1981). Kovacs et al. (1982) claim that memory defects occurring in diabetes insipidus, in which there is a lack of endogenous posterior pituitary hormones, can be reversed with vasopressin or its derivatives.

Opioid antagonists

Considering the probable importance of opioid peptides in a physiological amnesic system and the proven effects of naloxone on memory in animals (Chapter 8), it is perhaps surprising that there is little published data on the effects of opioid antagonists on memory in man. Naloxone does not appear to improve memory in normal subjects but Reisberg et al. (1983) conducted a double blind, placebo controlled, multiple dose trial of naloxone in seven patients with Alzheimer’s dementia. They noted significant improvement in tests of digit span and recall as well as in general cognitive function. In isolated cases, naloxone has been reported to reverse neurological defects associated with cerebral ischaemic attacks (Bousigue et al. 1982; Baskin and Hosobuchi 1981).

Nmda receptor antagonists

The importance of NMDA receptors in learning and memory has been mentioned in Chapter 8. Although agonists of these receptors can enhance learning and memory in animals (Collingridge and Bliss 1987), these substances are neurotoxic (Rothman and Olney 1987), and do not appear to offer a viable approach to the treatment of dementia. However, it has been suggested that excessive NMDA receptor activation may be a causative factor in neurodegenerative diseases including Alzheimer’s disease (Maragos et al. 1987). Thus NMDA receptor antagonists could possibly retard the progression of such conditions (Nicholson 1990). Several non-competitive NMDA receptor antagonists are under investigation. These agents have anxiolytic and other benzodiazepine-like actions (Stephens et al. 1986; Moreau et al. 1989) which might be helpful in early Alzheimer’s disease in which anxiety as well as deterioration of memory is often prominent, but their utility may be limited since they also impair memory (Venables and Kelly 1990; Wozniack et al. 1990) and are likely to produce psychotomimetic effects by interaction with phencyclidine/sigma opioid receptors (Sonders et al. 1988; Herberg and Rose 1989; Piercy et al. 1988).

A more promising approach might be the use of calcium entry blockers (p.221) (Wauquier 1984; Izquierdo 1990b), since the neurotoxic effect of NMDA receptor activation is thought to be due to excessive intracellular Ca2+ concentrations (Choi 1988). Other measures which may delay the onset or progression of neural degeneration include aluminium chelators (Cowburn and Blair 1989), free radical trapping agents (Calne et al. 1986) and calcium supplements (Deary and Hendrickson 1986).

Drugs for forgetting

The amnesic effects of certain drugs can sometimes be put to clinical use as preoperative medication or during minor surgical procedures.

Benzodiazepines

The amnesic effects of intravenous diazepam, flunitrazepam and lorazepam (4 mg) given preoperatively to healthy females undergoing minor gynaecological operations were assessed against a saline control by George and Dundee (1977). All the drugs produced an anterograde amnesia as tested by recognition of cards shown to the patients at various times after drug administration. There was no retrograde amnesia. The amnesia was accompanied by sedation, although the patients were rousable, and the sedation far outlasted the amnesic effects. Many other studies (reviewed by Curran 1986) have confirmed these findings and benzodiazepines are now routinely used as preoperative medication and for minor surgical procedures (Dundee et al. 1984). Of the benzodiazepines, midazolam appears to produce optimal amnesia (Hennessy et al. 1991). The sedative effects of benzodiazepines can be reversed by the antagonist flumazenil (Chapter 4) but there is much less effect on the amnesia, suggesting that these two actions of benzodiazepines are separate (Curran and Birch 1991).

Studies of benzodiazepine effects on memory in healthy subjects suggest that they exert dose-related effects on various stages (acquisition, retention, recall), and that acquisition is impaired at lower doses than retrieval (Liljequist et al. 1978; Ghoneim et al. 1981). In some subjects with high state anxiety single doses of oral diazepam may actually improve memory (Desai et al. 1983). This result is not surprising in view of the known interactions of psychotropic drugs with starting state and personality.

Anticholinergic drugs

Atropine and scopolamine primarily block the actions of acetylcholine at muscarinic receptors, although at high doses they may also have some (p.222) nicotinic receptor blocking action. Both muscarinic and nicotinic receptors appear to be involved in cholinergic transmission at cortical and subcortical levels in the brain. While the depressant effects of atropine and scopolamine are usually ascribed to central muscarinic blockade, stimulant effects may result from other actions. The drugs cause an increase in acetylcholine turnover which may result in the activation of nicotinic receptors in the brain (Weiner 1980a). The mixed stimulant/depressant effects of these drugs depend on dose and on individual susceptibility. Since cholinergic systems are involved both in arousal (Chapter 2) and memory (Chapter 8), amnesic effects of anticholinergic drugs could result from disruption of either or both of these systems.

In the clinical setting, therapeutic doses of scopolamine (0.6 mg) usually produce drowsiness, euphoria, amnesia, fatigue, and dreamless sleep with decreased REM activity (Weiner 1980a). This action is useful when scopolamine is employed for preanaesthetic medication or as an adjunct to anaesthetic agents. However, some patients respond to the same doses with excitement, restlessness, hallucinations, and delirium. The excitatory effects are most common in patients with severe pain, occur regularly with high doses, and are also seen with high doses of atropine.

Several investigators have compared the effects of scopolamine (0.8 mg IM, 1 mg SC), methscopalamine, a peripherally acting muscarinic blocker (0.5 mg IM, 1 mg SC), and normal saline on the performance of normal subjects in multiple memory tests (Caine et al. 1981; Drachman 1978). From both studies, it appeared that the effects of scopolamine on memory were not global and not due simply to non-specific central nervous system depression, although the subjects were drowsy. Scopolamine impaired initial memory acquisition and retrieval, but even at these doses there was no decrement in immediate memory and no decrease of attention or initial signal detection in an auditory vigilance task. Caine et al. (1981) suggest that the amnesic effect of scopolamine was on definable neuropsychological processes, especially encoding of new information and retrieval of well-learned old information. The effect of scopolamine was presumed to be mediated via cholinergic mechanisms since it was reversed by physostigmine, but not by amphetamine.

Future prospects

While the use of drugs for forgetting has reached a considerable degree of sophistication, the use of drugs to improve memory remains problematic. Despite intense interest in the pharmacology of memory over the past few years (Chapters 8 and 9), and considerable advances in understanding, it appears that the subject has hardly reached the stage of direct clinical application to memory disorders. From experience to (p.223) date, it seems unlikely that drugs which influence neurotransmitter or modulator function will have major effects in clinical conditions—although possibly the development of drugs with specific sites of action in the brain is worth striving for. Drugs which improve cerebral oxygenation and stimulate neuronal metabolism and possibly calcium channel antagonists may be of more value in dementias and other amnesic syndromes if used early enough, but again specificity in site of action is so far lacking. The greatest hope for the future would seem to lie in drugs which stimulate neuronal plasticity, and such drugs are still in their infancy. However, information on nerve growth factor and other polypeptide growth factors is increasing (Greene 1984; Levi-Montalcini and Calissano 1986; Thoenen 1991). Since adult neurones are capable of increasing their dendritic aborizations (Chapter 8), it might be possible with such substances to encourage surviving neurones to take over the function of degenerated neurones in human dementias. Finally there remains the distant prospect of brain implantation with living embyronic or cultured neurones (Katzman 1986; Gage et al. 1984).

The possibility of using drugs to improve cognitive function in normal subjects opens another uncharted field, but there is a growing ‘recreational’ use of vasopressin, piracetam and ondansetron for this purpose.