Table 1.

Modeling addiction in animals.

Locomotor sensitization: Locomotor sensitization describes the progressive increase in locomotor activity that usually follows repeated, intermittent drug exposure. Sensitization can persist for months or even years following withdrawal, and as such it is considered to be an indication of enduring drug-induced plasticity (Steketee, 2003). Although it is most commonly studied in relation to psychostimulants, sensitization has also been characterized in response to opiates, nicotine and ethanol (Shuster et al., 1977; Kalivas and Duffy, 1987; Robinson et al., 1988; Benwell and Balfour, 1992; Cunningham and Noble, 1992). Cross-sensitization between different drugs of abuse has also been shown to exist, suggesting that common mechanisms underlie the development of this phenomenon despite these drugs having distinct pharmacological actions in the brain (Vezina and Stewart, 1990; Itzhak and Martin, 1999; Beyer et al., 2001; Cadoni et al., 2001).

Conditioned place preference (CPP): CPP is an indirect measure of drug reward based on classical (Pavlovian) conditioning principles (Tzschentke, 1998). The CPP apparatus consists of two distinct environments, one of which is paired with a drug, and with repeated pairing the drug-paired environment acquires secondary motivational properties which can elicit approach behavior. An animal is said to have obtained a place preference if it spends more time in the drug-paired environment when given a choice. This paradigm is used to measure conditioned drug reward and associative learning.

Operant self-administration: Animals can be trained to self-administer most drugs that are commonly abused by humans. This is usually achieved using operant boxes where an instrumental task such as a lever press or nose poke results in the delivery of a drug or natural reward. Reward delivery can be paired with a discrete cue such as a tone or light, or passive contextual cues.

Extinction/reinstatement: Extinction describes a reduction in conditioned drug-seeking behavior after it is repeatedly non-reinforced (Myers and Davis, 2002). Extinction can be performed in the context of CPP, where an animal is repeatedly exposed to the drug-paired environment in the absence of the drug. Once a CPP is extinguished, it can be reinstated by drug priming (Mueller and Stewart, 2000) or exposure to stressors (Sanchez and Sorg, 2001; Wang et al., 2006). Operant self-administration behavior can also be extinguished by removal of drug reinforcement, and subsequently reinstated by non-contingent exposure to the drug (Dewit and Stewart, 1981), exposure to cues or contexts previously associated with the drug (Meil and See, 1996; Weiss et al., 2000; Crombag and Shaham, 2002), or exposure to stress (Shaham and Stewart, 1995; Erb et al., 1996; Shepard et al., 2004). These same factors are known to precipitate drug craving and relapse in human addicts, and as such reinstatement attempts to model relapse-like behavior in animals.