DRUGS AND MEMORY

The psychopharmacological approach to the study of memory involves a systematic examination of the behavioral changes that occur following the administration of psychoactive drugs. This approach complements neuropsychological research in its neurobiological approach to the study of learning and memory. Most psychoactive drugs produce reversible effects in the central nervous system, allowing subjects to be used as their own controls. The ability to evaluate memory performance in both a drugged and an undrugged state is particularly useful in human studies, where the number of subjects can be limited. An additional advantage of this approach is that using the same subjects as both the control and experimental groups (within-subjects design) is a much more powerful way to detect small drug effects. Using a within-subjects experimental design is particularly useful for evaluating memory, because there can be substantial differences in baseline performance among individuals.

Studies of the effects of drugs on memory are valuable for several reasons. First, it is important to know whether a drug that is being used to relieve a particular condition can affect (usually impair) memory as a side effect (see Table 1). For example, agents that block the effect of acetylcholine, a neurotransmitter long known to modulate memory, are frequently used as part of the treatment for the movement disorders of Parkinson's disease. At high doses, anticholinergic drugs produce profound memory impairments. Second, experimental studies using drugs with defined mechanisms of action have helped to define the involvement of specific neurochemical systems in memory. One example is the class of drugs called benzodiazepines. These drugs facilitate the effects of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and impair memory. Unfortunately, not all agents that affect memory act discretely. Ethanol (alcohol) impairs memory by an unknown mechanism that appears to involve actions on several neurotransmitter systems and on nerve-cell membranes. Third, studies with drugs offer the possibility of helping to better define different types of memory. Fourth, drug studies offer the hope of developing treatments for diseases with symptoms of memory impairment, such as Alzheimer's disease.

Characteristics of Memory

There are several distinct memory systems in the brain. One useful classification scheme divides long-term memory into declarative (explicit) and non-declarative (implicit) categories. Declarative memory involves the conscious recall of facts or events (e.g., remembering a name), whereas nondeclarative memory is not conscious and is usually expressed through performance (e.g., riding a bicycle). Subtypes of memory within each of these systems rely on different brain regions and therefore involve different sets of neural connections and combinations of chemical neurotransmitters and second-messenger systems. In addition to distinctions based on neuroanatomy, there are separate processes governing short-term and long-term memory. This diversity implies that there are a number of sites where drugs can modulate memory and that different drugs should influence different types of memory.

There are at least three components of memory: acquisition, consolidation, and retention or retrieval. Each can be affected by drugs. The most frequently documented effects of drugs on learning and memory pertain to acquisition. In such studies researchers administer the drug before training begins. Arousal and attention influence acquisition, so sedatives usually impair memory, whereas stimulants usually enhance it. Mood and motivation also affect acquisition; agents that reduce either usually impair memory. At the most basic level, drugs can impair acquisition by interfering with sensory perception—blurring vision, for example. Possible drug effects on peripheral functions must be controlled for in experimental studies, especially when animals are used as subjects.

Administering the agent after training helps to disentangle the memory-altering properties of drugs from their effects on sensory or motor functions. This is the protocol used to study the effects of drugs on memory consolidation. If the drug has been metabolically eliminated by the time memory is tested, then posttraining treatments affect only consolidation, not acquisition or retention. Studies of consolidation in animals have provided valuable information about the biochemical mechanisms of memory formation and the intervals during which learning activates these mechanisms.

The research on drug effects on retrieval is not as extensive as that on acquisition or consolidation. Perhaps the best-known example of drug-induced alterations in retrieval comes from the literature on state-dependency. State-dependent retrieval refers to the ability of subjects to retrieve information better when they are in the same state as they were when the material was acquired. For example, if material was learned under the influence of a drug such as alcohol, retrieval under sober conditions is often worse than if the subject is again intoxicated. Some such effects hinge on the nature of the retrieval test, and not all results appear to depend on the state of the subject.

Drugs That Impair Memory

Many chemical compounds are known to impair memory; only a general overview of these agents is possible here. The initial question is whether a given compound can be considered a drug. At one end of the spectrum are commonly available agents that normally have another use. For example, sniffing the organic solvents (e.g., toluene) in glue will impair memory. At the other extreme are arcane chemical structures used only in scientific research. Most compounds mentioned here either have a role as medicines or are well known among scientists who study the neuropharmacology of memory.

The most pernicious drug-induced impairment of memory is the destruction of neurons in brain regions involved in memory formation. For example, domoic acid destroys neurons in the hippocampus, an area that is critical for the formation of long-term declarative memories. Other agents act by severely depleting levels of neurotransmitters in pathways that modulate memory. One example of this phenomenon is the recreational drug Ecstasy (MDMA), which impairs memory by reducing serotonin levels. While the effects of these types of treatments are long lasting, the memory impacts of most drugs are reversible.

Many drugs that impair memory act as neurotransmitter receptors. Usually they reduce the function of a particular neurotransmitter. For example, scopolamine blocks the receptor for acetylcholine, propranol blocks a class of receptors for norepinephrine, and dizoclipine (MK-801) blocks a subtype of glutamate receptors. Sedative drugs are the exception: Benzodiazepines (e.g., diazepam [Valium]) and barbiturates enhance the action of GABA, the primary inhibitory neurotransmitter in the brain, thus disrupting memory.

Long-term memory formation requires activation of certain enzymes such as protein kinases (e.g, PKC, PKA, CaMKII). This activation is controlled by several different neurotransmitters and can be affected by drugs that act at any of their receptors. Also, specific inhibitors of protein kinases impair memory. An important consequence of protein kinase activation is the initiation of new protein synthesis. Inhibitors of protein synthesis (e.g., cycloheximide or anisomycin) can disrupt long-term memory formation.

A given drug seldom uniformly impairs all types of memory. For example, ethanol and the benzodiazepine drugs affect mainly long-term memory, leaving short-term memory relatively unaffected. These drugs also preferentially disrupt declarative memory while leaving nondeclarative memory relatively intact.

There has been considerable interest in the possibility of using drugs in normal subjects to model clinical amnesias such as Korsakoff's syndrome or Alzheimer's disease. Knowledge of the neuropharmacology of a drug that would model a particular amnesic syndrome might suggest useful treatment strategies. The specific impairments seen in normal subjects treated with alcohol resemble those of patients with Korsakoff's syndrome, and it has been suggested that scopolamine mimics some of the features of the cognitive impairments seen in dementia patients. However, no drug treatment has been described that completely mimics the pattern of memory disruption induced by a specific disease.

Drugs That Enhance Memory

More drugs hinder memory than help it, so there is a lively interest in discovering memory-enhancing drugs, especially because many neurological diseases impair memory. Also, some memory loss occurs in old age even in healthy people. Finally, nearly everyone would like to have a better memory. An important unanswered question is whether enhancing "normal" memory is a reasonable possibility.

In general, the agents that enhance memory act in the opposite way from drugs that impair memory. For example, picrotoxin reduces the inhibitory effect of GABA receptors, while amphetamine causes the release of norepinephrine. Acetylcholinesterase inhibitors increase the effect of acetylcholine and are used to treat the memory deficits of Alzheimer's disease. All of these drugs are effective memory enhancers, but they all have have serious side effects.

Drugs can influence many aspects of brain function, including learning and memory. Most drugs adversely affect memory, although some can enhance it. There is an increasing need to develop safe and effective drugs to treat memory problems caused by aging or disease.

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Richard G.Lister

Herbert J.Weingartner

Revised byGregory M.Rose