Conditioned Place Preference

The conditioned place preference (CPP) is a widely used behavioral model which can evaluate the motivational properties such as the rewarding and aversive effects of drugs and natural substances as well (Suzuki 1999). Furthermore, it has been used to study the neural mechanism underlying the conditioned reward. For long, the rewarding properties of drugs were assessed by the conventional self-administration method. In the late 70’s, CPP paradigm revolutionized the methodological procedure to evaluate the motivational properties of drugs to compensate the methodological and interpretative ambiguities associated with the self-administration model. Since then, CPP has become one of the most frequently used models even surpassing the conventional self-administration method. Most importantly, it has opened avenues for understanding the neural mechanism of rewarding and aversive effects of drug substances, and for screening drugs for abuse liability.

In place conditioning tasks, animals are introduced to an apparatus having two distinct chambers, either through a doorway or smaller connecting chamber. Distinctions are made between these two chambers based on visual and tactile cues, including wall color and floor texture, but in some cases, other elements such as olfactory cues may also be used.

Subsequently, the affective state of the rodents is altered by the administration of a drug, or change in a physiological state. On alternate days, the drug or physiological state is paired with the other environment. After this conditioning trail, the animals are free to explore all the chambers, and they may depict an increase or decrease in the time spent in the chamber that was previously conditioned with the drug substance. A conditioned place preference (CPP) is said to occur if the animals spend considerably more time in the drug-paired compartment than the vehicle-paired compartment. This shift in preference may be attributed to the rewarding properties of the drug substances or the physiological situation that has evoked an approach response (Schechter & Calcagnetti 1993).

On the other hand, if the animals spend considerably longer time in the vehicle-paired compartment rather than the drug-treated compartment, then this is considered a conditioned place aversion (CPA). This reduced time spent in the drug conditioned chamber may be attributed to the aversive properties of the drug substances or the physiological situation that has evoked an avoidance response.  Usually, drugs of abuse like ethanol, cocaine produce CPP; while other drugs that elicit aversive effects, such as lithium chloride, produce CPA.

In CPP, the primary stimulus (drug) serves as an unconditioned stimulus (UCS). When it is paired with a secondary stimulus (visual, tactile, or olfactory cue) which acts as a conditioned stimulus (CS), an approach or avoidance behavior for the paired environment is elicited. Drug-induced CPP is based on the principle that when a primary reinforcer is paired with the secondary stimulus, the conditioned stimulus attains secondary reinforcing properties, which are apparently established due to a Pavlovian contingency. Interestingly, the CPP paradigm is not only restricted to drug substances, but the approach or aversive behavior can also be established using food (Bechara et.al 1992; Swerdiow et.al 1983), copulation (Miller et.al 1987), or water (Agmo et.al 1992) as primary reinforcers.

3.1 Apparatus Design

Classically, the CPP apparatus is of two types, namely the two-chamber design or three-chamber design. The two-chamber design comprises of two discrete compartments separated by a sliding guillotine door. In the three-chamber design, two large compartments are connected by a small central compartment usually called as the neutral chamber. In contrast to the two-chamber design, the three-chamber design consists of two guillotine doors present at the entry of the two large chambers from the central chamber.  However, sliding Plexiglas doors can also be used instead of guillotine doors. The sliding Plexiglas doors can be lowered or raised to gain access to each compartment. Each chamber has characteristic visual and tactile cue, and the base of the chambers is embedded with photocell beam for automated data collection. However, the locomotor activity of the subjects can also be recorded with the help of a video tracker such as Noldus Ethovision XT. While the inbuilt automated measurement method is common, the use of non-automated means such as hand scoring is still very much possible.

3.1.1. Two-chamber design

During conditioning period for the two-chamber design, the subject is introduced into one of the compartment after the incorporation of the drug substance, and it is confined there for the specific period of conditioning with the guillotine doors shut. On the test day, the subject is allowed to explore both the compartments freely, and the time spent in each compartment is recorded. This data is compared with the baseline preference for the chambers to determine the final place preference (Cunningham et.al 2006).

3.1.2. Three-chamber design

In Three-chamber design, the subject after incorporation of treatment is introduced into the neutral chamber and is allowed to access only one chamber during conditioning the period. On the test day, the subject is again placed into the neutral chamber and allowed to explore all the chambers freely for the determination of final place preference (Smith et.al 2016).

3.1.3. Two-chamber Versus Three-chamber Design

The added chamber (neutral chamber) in the three-chamber design is the only physical difference between both the designs.  This neutral chamber has its advantages and drawbacks as well. Its biggest advantage is the ease it provides to the experimenters which permit them to place the subjects in the center of the apparatus; a major problem with the two-chamber design as it is difficult to place the subject in the exact center of the apparatus. Conversely, the neutral chamber gives interpretational difficulties when the subjects make an association with the neutral chamber; they may show preference or aversion for the neutral chamber instead of the other two chambers. The two-chamber design is preferred in this regard as it excludes this pitfall by leaving the subject with two possible choices for the association.

3.2 Apparatus Designs

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4.2.1.  Experimental Design

The two major experimental designs used to condition animals under the influence of drugs or natural reinforcers are called the Biased and Unbiased experimental designs. (Schechter & Calcagnetti 1993)

4.2.2. Biased Design

In the biased procedure, animals are allowed to explore the CPP chamber for several days to determine their baseline place preference between the two compartments without the administration of drug substances. Rodents have the inherent ability to prefer dark over light, so they will choose a compartment with less light every time. This preference, if significant, may confound the interpretational results. However, this problem can be alleviated by balancing the stimuli between the two compartments. For instance, by fluctuating the intensity of external light reaching the two compartments, or by changing other sensory modality that would diminish the animal’s approach such as a dab of vinegar in the dark environment (Cunningham 2003).

Using this biased design, the animals choose a less-preferred compartment and a more-preferred compartment. For conditioning procedure, the animals are paired with one of the environments; a drug thought to have rewarding (drug treatment) properties is paired with the less-preferred environment, and the control treatment is paired with the more-preferred environment. This conditioning process is repeated for some days with multiple pairings of drugs with less-preferred side and an equal number of pairings of control treatment with the more-preferred side. In order to determine the final place preference, the animals (on a control treatment) are allowed to explore all the compartments once again freely.

On the test day, if the animals spend more time in the previously less-preferred environment during their baseline preference test, it can be inferred that the drug produces rewarding properties sufficient to elicit an approach response, thus depicting a place preference.

4.2.3. Unbiased design

In Unbiased design, the animals are trained to associate an environment with one or the other discrete state, i.e., after either drug or control treatment disregarding their initial preference of the stimulus cues present in one or the other environment. In their next session, they are trained to associate the stimulus cues of a second environment with the other condition. The design inherent in this procedure is to balance the number of subjects that receive one treatment in the first environmental pairing with the number of subjects that receive the second treatment in that first pairing. Following this design, the same subjects receive the opposite treatment on the second day of training.

The process comprises of two days that can be repeated a number of times after which the final place preference is determined by permitting the subjects to explore both environments freely. As the drug and control treatments are randomized between each of the two contexts, the choice of a preferred context during testing does not specify a bias at the time of baseline testing, which is usually seen in the biased design.

In addition, a third method can be employed, saline-injected control subjects are used to determine CPP. In this method, one group of animals is conditioned to one of the two environments, while the control group is given saline in both environments. CPP is then determined as the difference in duration spent in the drug-paired environment for conditioned animals compared to the saline-injected controls on the test day. The pre-testing phase for baseline place preference prior to conditioning may or may not be employed for this method. (Bardo et.al 1995)

4.2.4. Biased Versus Unbiased Design

The researchers have the choice to make the chambers either biased or unbiased depending upon their needs and ease. The biased design can be taken as a design in which the subjects prefer one chamber over the other during habituation. Conversely, in the unbiased design, the subjects prefer each chamber equally during adaptation. In general, the unbiased design is more advantageous as it permits researchers to determine CPP for the chamber paired with drug treatment on the test day. Furthermore, the data can be analyzed with great ease as the researcher simply notes and records differences in chamber preference as compared to the animal’s initial level of equal preference for both chambers during adaptation. (Lucke-Wold 2011)

4.2.2.1. Pre-training for CPP

The subjects are allowed to access all compartments of the apparatus for several days in order to eliminate the novelty-seeking behavior as it can be a confounding variable. CPP task, whether biased or unbiased follows the timeline of Pre-test, Conditioning, and Testing Phase. The pre-test may be separated from conditioning by 1-3 days; however, conditioning and the post-test day usually takes place on consecutive days. (Smith et al., 2016).

4.2.2.2. Pre-Test/Habituation Phase

The subjects are allowed to explore all the compartments freely. During pre-testing phase, baseline place preference is assessed and recorded. Baseline data is determined in terms of the average amount of time spent in each compartment over 3–5 days.

This procedure is same for both biased and unbiased design. The main aim of this phase is to determine the baseline place preference so that it can be exploited later. In the case of a biased design, the baseline preference will serve to determine the less and more preferred side. Conversely, for unbiased design, this baseline preference data will be used to compare results obtained after the final place preference.

4.2.2.3. Conditioning Phase

4.2.2.3.1. Conditioning for Unbiased design

On the first day of the conditioning phase, the subject should receive drug treatment and then placed into a specific compartment for 30 minutes. On the next day, the subject should receive control treatment and place into the opposite compartment for 30 minutes. This alternate scheme of drug and control treatment should be repeated for eight days. The locomotor activity is recorded with the help of the photocells (Huiwen Zhu et.al 2017).

4.2.2.3.2. Conditioning for Biased Design

The subjects are initially divided into equal groups. One group should be conditioned on their non-preferred side (as determined by the baseline place preference) whereas the other group is randomly assigned to the side in which their respective conditioning should take place. All subjects from both groups are then randomly divided into groups that either receive drug or control treatment. The conditioning period for biased design is usually repeated for four days. On the conditioning day, each subject is injected with its respective treatment and confined into the pre-determined chamber for a period of 30 minutes. After the conditioning procedure, the subjects are safely removed from the conditioning chamber and placed into their home cages (Blander et.al 1984).

4.2.2.4. Testing Phase

In the testing phase, the final place preference is recorded. The subjects should be placed in the central chamber after the administration of control treatment, and allowed to explore freely for 15 to 30 minutes. This testing procedure is repeated on three consecutive days. The final place preference is recorded as a mean of the locomotor activity and the time spent in each compartment following the three testing days.

The time spent in each compartment can either be recorded manually or automatically. For the automatic collection of data, two prominent techniques i.e. the use of microswitches, or a video tracking device are employed. The latter technique involves the placement of the CPP apparatus on a fulcrum in such a fashion that the weight of a rat in one end compartment causes the microswitch to close, thus resulting in automatic time calculation. Whereas the former technique simply involves a video tracker such as Noldus Ethovision XT  to collect data. Furthermore, the base of the chambers is embedded with photocell beam for automated data collection.

4.6.1. Strengths

• The most promising advantage of the CPP paradigm is its ability to assess both the preference and aversion of the substance within a single test.
• The drug substance may have effects beyond the rewarding/aversive domain that may influence the time spent by the subject in the previously drug-paired side. This problem is resolved by the CPP model as it determines the baseline and final place preference in an animal that is drug-free.
• The motivational properties of the different drugs can be assessed by minimal quantities (low doses) of drugs when compared to other behavioral methods that assess motivational properties. This capacity makes CPP as one of the most sensitive behavioral test.
• While there are superior methods of assessing factors that contribute to drug addiction, namely drug self-administration, CPP is a simple and much more accessible approach to measuring reward function. It is amenable to several manipulations and could be used to test both subject’s place preference and aversion to certain substances. There is also less stress to the subject as treatment is administered.
• One of the greatest advantages of the CPP is that it is well suited for evaluating locomotor activity concurrently with the drug reward. Furthermore, it also helps to investigate the neuronal circuits involved in drug reward. It is still one of the very simple and dynamic models that have been developed in an attempt to understand the complexities of human addictions clearly.
• CPP is preferred over the self-administration experiments in terms of the dose-effect curves. CPP characteristically yields a monophasic dose-effect curve, whereas self-administration experiments yield inverted U-shaped dose-effect curves. (Yokel 1987; Stafford et al. 1998).
• The CPP task is highly preferred because it is completed within a short period of time. The likelihood exists that a CPP or CPA can be shown in as meager as one drug pairing (Bardo et.al 1986; Iwamoto 1988; Mucha et.al 1982) and when different pairings are utilized, these pairings can be directed either on more than once or twice a day without diminishing the overall strength of conditioning (Calcagnetti et.al 1992).
• The equipment needed to regulate the CPP model has turned out to be exceptionally refined with devices that not just permit automation of the time spent on a specific side, additionally the capacity to quantify the actions of subjects while it is physically present in a specific environment with the help of video tracker such as Noldus Ethovision XT. The applications of CPP model overshadow the equipment expenses as the results are highly reproducible.
• The subjects can be tested in the drug-free state, where there is no disruption of its behavior, additionally, the impacts of pharmacological antagonists can be determined without disruptions. By incorporating the antagonist amid conditioning (drug-environment pairings) and just later testing (when the animal is drug-free) for potential impacts of the antagonist upon the agonist used to condition the subject, allows reliable measure of the agonist-antagonist associations to be resolved. Furthermore, this task can be adjusted to evaluate the rewarding properties of different physiological states, e.g., access to a sexually responsive mate (Mehrara et.al 1990) or to another juvenile rodent as a playmate (Calcagnetti et.al 1992b). The CPP-test can also assist to determine the drug effects upon physiological states (Bardo et.al 1990).
• CPP gives a reliable measure of the rewarding and aversive properties of drugs and the other physiological treatments. This notion is further strengthened as the CPP’s verdict about the rewarding and aversive properties is also confirmed by other behavioral models that measure drug rewarding and aversive properties as well. Drugs that have seemed to yield place preference in the CPP task have also shown rewarding properties in other behavioral models as well. In this way, drugs of abuse, and physiological treatments, for example, access to sustenance, are able to produce CPP and have rewarding properties in operant behavioral models. On the other hand, agents such as lithium chloride, and physiological treatments such as irradiation depicts CPA, and these treatments elicit avoidance behavior in other behavioral paradigms as well.

4.6.2. Limitations

• For long there has been a lingering criticism on CPP regarding what exactly is being evaluated by the CPP task. The likelihood exists that subjects are not depicting a drug-environmental paired preference, but rather are influenced by the locomotor activating and sedative actions of the drugs. For example, the increased activity as manifested by the stimulant drug may change the interoceptive state of the subject in a specific environment in order to enhance the exploratory activity and, accordingly, uplift its acquaintance with the drug-paired environment. Conversely, after control treatment in a particular environment, the subject may associate less exploration with this environment. On the test day, the subjects will be well-suited to enter a place that they have explored comprehensively.
• A confounding variable associated with the CPP test dwells in the likelihood that the signs of the conditioning environment stay novel to the subject because of the drug effects. The subject may spend more time in the drug combined side during testing because of the novelty of encountering that side in a drug-free state.
• Shortfalls in performance produced by drug-state reliance might be viewed as another constraint innate in the CPP test. The animals are trained in one state in that they encounter the drug effects in a specific context and, later, they are tested in an alternate state (drug-free). The likelihood exists that the failure to express a preference for the drug combined environment is innate in the way that training and testing happen in different interoceptive states.
• Another likely mechanism underlying the CPP response could be the anxiolytic properties of the drug as opposed to the rewarding effects of drugs. So, if a drug decreases subjects’ neophobia to a least preferred side, it will then be slanted to spend more time on that side.
• The likelihood exists that the drug may be producing an avoidance behavior for the favored environment, while the drug meddles with the subject’s capacity to recollect its introduction to the drug-conditioned environment.

• The conditioned place preference (CPP) is a widely used behavioral model which can evaluate the motivational properties such as the rewarding and aversive effects of drugs and natural substances as well.
• A conditioned place preference (CPP) is said to occur if the animals spend considerably more time in the drug-paired compartment than the vehicle-paired compartment.
• Rossi and Reid developed the concept of drug-paired conditioning to measure drug induce affective state (approach or avoidance behavior) as a measure of the rewarding properties of drug substances.
• In CPP, the primary stimulus (drug) serves as an unconditioned stimulus (UCS). When it is paired with a secondary stimulus (visual or tactile cue) which acts as a conditioned stimulus (CSS), an approaching or aversive behavior for the paired environment is elicited
• CPP continues to be very popular because of its numerous applications.
• Classically, the CPP apparatus is of two types, namely the two-chamber design or three-chamber design.
• The two major experimental designs used to condition animals under the influence of drugs or natural reinforcers are called the Biased and Unbiased experimental designs.
• CPP task, whether biased or unbiased follows the timeline of Pre-test, Conditioning, and Testing Phase.

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