class, animal species, and, in the case of rodents, strain. They can also vary among individual animals as a function of history of drug exposure, such environmental variables as ambient temperature (Finn et al., 1989), and the presence of a stimulus previously paired with drug exposure (Siegel et al., 1982).

Animal Care and Use Concerns Associated with Chronic Exposure to Addictive Agents

Studies of the effects of chronic exposure to addictive agents may involve prolonged or repeated exposure to high drug doses over a period of several days, weeks, months, or years. Such studies raise several issues that require consideration. One basic concern is whether extended periods of intoxication interfere substantially with normal feeding, drinking, and other activities (such as grooming) that are important for maintaining the health and well-being of animals. When that concern arises, consideration should be given to alternative methods of providing adequate nutrients and fluids, and of avoiding unsanitary cage conditions.

An additional concern in chronic studies is the possibility that long-term drug exposure will produce long-lasting tissue or functional changes that have adverse effects. In some cases, producing such changes is important to the scientific goals of the study, for example, a study designed to model neurologic deficits associated with Wernicke-Korsakoff syndrome.

In protocols involving prolonged or repeated drug exposure, criteria should be established for determining the duration of exposure and, if necessary, for terminating drug treatment earlier than planned. Daily observation of animals by someone familiar with the experimental protocol is important in such studies to ensure that decision-making is timely.

Physical Dependence and Withdrawal

In some studies of addictive agents, repeated or chronic drug exposure may produce physical dependence. Physical dependence is revealed by a characteristic withdrawal syndrome on termination of the drug regimen. The salient features and course of the withdrawal syndrome depend on the drug class, the animal species, and, in rodents, the strain (Metten and Crabbe, 1996; Way, 1993; Yutrzenka and Patrick, 1992). And the severity of withdrawal typically depends on the dosing regimen. Withdrawal signs may include irritability, activity changes, body-temperature changes, weight loss, tremor, and convulsive seizures. Drug withdrawal typically produces dysphoria and distress in humans (Jaffe, 1992), and investigators should consider the possibility that withdrawal may produce discomfort and distress in animals.

Whether or how withdrawal is treated in the laboratory will depend on the purpose of the experiment and the nature and extent of the withdrawal syndrome.

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