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ALCOHOL (ETHANOL)

In rats and mice, an acute (a large) dose of alcohol prior to learning usually impairs memory of the training. The effect is heightened by the drug clonazepam, a BENZODIAZEPINE RECEPTOR AGONIST; it is lessened by bicuculline and picrotoxin, drugs that block receptors for the inhibitory NEUROTRANSMITTER GABA (GABA-A receptors). Such findings suggest that ethanol-induced amnesia is mediated by the benzodiazepine/GABA-A receptor complex. These findings are consistent with extensive evidence that benzodiazepines (see section below) induce amnesia in humans as well as in laboratory animals. Memory impairment induced by a large dose of alcohol is also lessened by physostigmine, the acetylcholinesterase inhibitor, suggesting that ethanol influences on memory involve cholinergic mechanisms.

Chronic administration of a high dose of ethanol to rats or mice over time induces memory impairment, accompanied by a decreased function of cholinergic systems in specific brain regions, including the hippocampus and neocortex. The syndrome can be reversed by an implant, into either BRAIN STRUCTURE, of fetal brain tissue that has high numbers of cholinergic cells or by giving oxotremorine, the cholinergic muscarinic agonist, prior to memory testing. Such findings suggest that the memory impairment resulting from chronic ethanol ingestion is associated with a deficit of brain cholinergic function.

Acute or chronic ethanol ingestion produces memory problems in humans. Large amounts of ethanol taken over a short period (hours or days) may cause a severe amnesia—a "blackout" for events occurring during and/or shortly before the period of intoxication. Some alcoholic blackouts may be caused partially by state-dependency—that is, during a later intoxication, individuals may sometimes remember experiences that occurred during a previous blackout. This phenomenon was illustrated in Charles Chaplin's 1931 film City Lights, in which the hard-drinking millionaire remembered Charlie only when under the influence of alcohol.

Paradoxically, experiments with human subjects indicate that low doses of ethanol administered immediately after learning enhance retention. Similar results have been obtained in studies using laboratory animals; however, it is not clear that effects seen in animals are due primarily to ethanol effects on brain processes underlying memory. They may reflect, at least in part, the aversive aftereffects of ethanol.

Clinical research shows that chronic ingestion of alcohol can produce three general categories of brain impairment that are associated with memory deficits: the Wernicke-Korsakoff syndrome, alcoholic dementia, and "nonamnesiac" or "non-Korsakoff" disorders. Wernicke-Korsakoff syndrome, the best known, is due to Vitamin B₁ (thiamine) deficiency, resulting from poor food intake during sustained periods of alcohol consumption. It involves an acute phase, with mental confusion and difficulty with eye movements and walking. Most people who recover from this acute phase after treatment with thiamine will have Korsakoff's syndrome, in which impairment of the ability to learn and remember new information (anterograde amnesia) as well as retention of recently acquired information (retrograde amnesia) occur, although apparently normal intellectual function and the ability to acquire and retain skill-based information, such as purely visual/motor tasks, appear to be relatively unaffected. Some improvement in the memory deficits may occur with prolonged abstinence from alcohol.

Alcoholic dementia differs from Korsakoff's syndrome in that it is characterized by severe memory impairment as well as major intellectual deterioration that can be difficult to distinguish from Alzheimer's Disease by clinical examination. Improvements are, however, often seen if patients abstain from alcohol.

It is not known whether the deficits seen in early alcoholic dementia and in Korsakoff's syndrome are accompanied by alterations in GABAergic or cholinergic functioning. The changes seen in late alcoholic dementia, like those of Alzheimer's Disease, involve multiple focal brain lesions, primarily in the temporal lobe but also in other brain regions, and involve deficits in glutaminergic, GABAergic, and cholinergic systems.

The third type of memory problem linked to alcohol ingestion has been variously referred to as "neurologically intact" or "neurologically asymptomatic" and is characterized by subtle impairments in dealing with abstractions, problem solving, and memory. Significant recovery with abstinence is typical.

BENZODIAZEPINES

BENZODIAZEPINES, which are used clinically in the treatment of ANXIETY and the induction of sleep, are among the most widely used (and abused) drugs. It has been known for several decades that benzodiazepines, including diazepam (Valium), triazolam (Halcion), and CHLORDIAZEPOXIDE (Librium) induce anterograde amnesia in humans. Studies using laboratory animals indicate that benzodiazepines impair memory when administered before training, but they generally do not impair memory when administered posttraining. The lack of posttraining effects may be due, at least in part, to the fact that benzodiaze-pines are absorbed slowly and are slow to reach peak concentrations in the brain following peripheral injections. The anterograde amnesia induced by benzodiazepines is not due either to alterations in sensory or motivational processes affecting learning or to state-dependency.

Benzodiazepines are known to act by modulating GABA-A neurotransmitter receptors on the benzodiazepine/GABA receptor complex. Their effects on memory appear to be mediated primarily by the brain structures designated as the amygdaloid complexand hippocampus. When administered acutely, either systemically or directly into specific brain regions, including the amygdaloid complexand the hippocampus immediately post-training, retention is enhanced by flumazenil, the benzodiazepine-receptor antagonist, and by the GABA-A-receptor antagonists bicuculline and picrotoxin. Findings indicating that the amnesia induced by peripherally administered benzodiaze-pines is blocked by GABAergic antagonists administered directly into the amygdaloid complex, as well as by lesions of the amygdaloid complex, provide additional evidence that this brain region is involved in benzodiazepine effects on memory. Although benzodiazepine-like substances are found in the brain, it is not yet known whether they are synthesized in brain cells or derived from food. Evidence that training experiences release these naturally occurring brain substances from synaptic vesicles in neurons suggests that they may play a role in modulating memory-storage processes.

MARIJUANA

In laboratory animals, both acute and chronic administration of marijuana extracts or of their active principles, the TETRAHYDROCANNABINOLS (THC), have been reported to impair the acquisition and retention of a very wide variety of tasks. It is not known whether these effects are due to influences on memory or simply to the sedative influences of the drug. There is some evidence suggesting that acute or chronic use of MARIJUANA impairs human memory. It is not known, however, whether such effects are due specifically to influences on brain processes underlying memory or to other influences on behavior. Cessation of marijuana use typically results in rapid recovery from the drug effects. Little is known about brain influences mediating marijuana effects on learning and memory.

OPIATES AND OPIOID PEPTIDES

The OPIATE drugs MORPHINE and HEROIN, administered posttraining, impair retention in laboratory animals. The memory impairment is not state-dependent: Administration of opiates prior to retention testing does not decrease the impairment. Opiate-receptor ANTAGONISTS, including NALOXONE and NALTREXONE, enhance memory and block the memory impairment produced by opiates. Endogenous opioid peptides (brain peptides that mimic the effect of morphine, heroin, and other opiates) also affect memory. The opioid beta-endorphin is released in the brain when animals are exposed to novel training situations. Memory impairment is induced by posttraining injections of beta-ENDORPHIN as well as by injections into several brain regions, including the amygdaloid complexand medial septum. Opiate antagonists administered into these brain regions enhance memory. Unlike the effects of opiate drugs, the memory impairment induced by beta-endorphin may be due, at least in part, to the induction of state-dependency: Under some conditions beta-endorphin administered (or endogenously released) prior to memory testing may lessen the memory impairment induced by a posttraining injection of the peptide.

Despite the widespread and long-standing use of opiate drugs by humans, there have been no systematic studies on the effect of morphine, heroin, or other opiates on human memory. Chronic opiate users do show memory deficits, but these may result from general deterioration rather than from any specific effect of the opiates. Acute administration of opiates (as in preanesthetic medication, for example) may induce a temporary amnesia. The failure of patients to remember experiences immediately prior to surgery may be due, at least in part, to an amnestic effect of the opiates used for ANALGESIA (PAIN suppression). The effect of opiate antagonists has been explored clinically in the treatment of dementias, but with limited success.

AMPHETAMINE

In laboratory animals, chronic administration of AMPHETAMINE prior to training impairs performance in many types of learning tasks. Such effects are typically obtained in experiments using high doses of amphetamine and complexlearning tasks. In contrast, extensive evidence, from studies using a variety of types of training tasks, indicates that acute posttraining injections of amphetamine produce dose-dependent enhancement of memory. Retention is also enhanced by direct administration of amphetamine into several brain regions, including the amygdaloid complex, hippocampus, and cau-date nucleus. Amphetamine is known to act by releasing the catecholamines epinephrine, norepinephrine, and dopamine from cells and block their reuptake. Amphetamine effects on memory appear to result primarily from influences on brain dopaminergic systems as well as influences on the release of peripheral catecholamines.

Amphetamine users often report that their "learning capacity" is enhanced by single doses of the substance. Since there are few systematic and well-controlled studies of the effects of amphetamine on memory in humans, however, it is not known whether such reports reflect subjective changes in perception and mood or effects on memory. Chronic amphetamine use is usually accompanied by a deterioration of memory function, an effect that subsides with cessation of use.

COCAINE

Despite the extensive use and abuse of COCAINE, little is known about cocaine effects on memory. Results of studies using rats and mice indicate that acute posttraining administration induces dose-dependent effects comparable to those of amphetamine: Memory is enhanced by low doses and impaired by higher doses. The brain processes mediating cocaine influences on memory have not been extensively investigated. The effects appear to be mediated by influences on adrenergic and dopaminergic systems. Also, as with amphetamine, users of cocaine report that memory is enhanced by acute doses and impaired by chronic use. Systematic, well-controlled studies of the effect of cocaine on human memory are lacking. The effects on memory and intellectual functioning of other drugs—such as PHENCYCLIDINE (PCP), BARBITURATES, NICOTINE, and INHALANTS—are considered in connection with these agents and in separate articles.

(SEE ALSO: ; ; Wikler's Pharmacologic Theory of Drug Addiction)

IVAN IZQUIERDO

JAMES L. MCGAUGH