Background

The conditioned place preference (CPP) paradigm has been used for decades to examine the role of genes, histone modifications, signaling pathways, and brain regions in drug-associated memory and reward (see Tzschentke, 1998; Malvaez et al., 2009). It incorporates classical conditioning to assess the rewarding effects of contextual cues that have been associated with a drug (for reviews see Schechter and Calcagnetti, 1993; Everitt et al., 1999; Bardo and Bevin, 2000). There are various CPP chamber designs and configurations, depending on the specific research question being addressed (Bardo and Bevin, 2000). However, the most commonly used designs are the two-compartment or three-compartment chambers. Both chambers types rely on the ability of mice to differentiate between two compartments that contain distinct olfactory, tactile, and visual cues. The three-compartment design contains an additional compartment, between the two larger compartments, that does not contain olfactory or tactile cues, and is used only for the entry and removal of mice at test. Here, we describe the equipment setup, key parameters, and data collection in the three-compartment CPP paradigm using adult mice. The focus of this protocol is on cocaine CPP. However, this paradigm can be used for other drugs of abuse (e.g., other psychostimulants, opioids, and nicotine).

The three-compartment design allows mice to choose whether to enter either the cocaine or saline-paired compartments or remain in the center compartment. Conversely, the two-compartment chambers require mice to be placed in either the saline-paired or the cocaine-paired compartments to begin the test. This has the potential to introduce bias for the compartment in which the mice is place at post-test. Using tactile, olfactory and visual cues allows mice to form a memory for each context that does not rely on one sensory system. Therefore, the likelihood that mice with sensory deficits (e.g., poor vision) will fail to acquire a drug-associated preference is reduced. Other variations of the task (e.g., olfactory only) can require four cocaine pairings, which results in eight total injections when the saline injections are included. Acquisition in our task requires two cocaine pairings (four total injections) for robust cocaine CPP, which reduces the likelihood that stress and irritation at the site of injection will be significant factors in the experiment. Furthermore, if both the control and experimental groups equally acquire a preference, the posttest day of the CPP task can serve as the first day of an extinction experiment. This subsequent extinction experiment would allow the experimenter to examine the persistence of the acquired cocaine-associated memory. Overall, the CPP paradigm provides an adaptable, quick, and inexpensive method of assessing drug reward in adult mice.