The conditioned place preference chamber is a paradigm widely used to explore the reinforcing effects of natural and pharmacological stimuli, including drugs of addiction. Combinations of floor and wall cues are available
In this variant, subjects are allowed to freely move between a compartment in which they were conditioned with either drug cues or neutral cues. The wall cues a (comes with maze) provide visual reinforcement
This dual chamber place preference allows for biased and unbiased conditioned place preference testing. A removable door (not shown) allows isolation into one compartment of the apparatus of the animal. Preference testing is then done by removing the door to allow the mouse to freely explore between the two compartments (as seen in the image)
- Visual pattern inserts are sandwiched between the clear interior layer and the outer grey layer. These visual pattern inserts do not interact with the mouse directly, preserving the life of the apparatus.
- Optional Standing Inserts (visualized) are for spatial place preference procedures. Please request separately.
Automated shock plates can be inserted anywhere in the CPP chamber
Automated heat plates can be inserted anywhere in the CPP chamber
Automated feeders/pellet dispensors can be inserted any point in the maze
Automated lickometers can be inserted any point in the maze
- Conductor Software
- Operant Builder
- Virtual Reality
Price & Dimensions
$ 1390+ Shipping and Handling (approx $150)
- Easy clean with 70% Ethanol
- No odors
$ 2290+ Shipping and Handling (approx $300)
- Easy clean with 70% Ethanol
- No odors
- Total(cm): Width 46 x Depth 27 x Height 30
- Compartments (cm): Width 20 x Depth 18 x Height 30
- Corridor(cm): Width 20 x Depth 7 x Height 30
- Doors(cm): Width 8 x Height 30
- Double walls Grey(Exterior)/Clear (interior)
- Total(cm): Width 86 x Depth 47 x Height 40
- Compartments (cm): Width 40 x Depth 34 x Height 40
- Corridor(cm): Width 25 x Depth 13 x Height 40
- Doors(cm): Width 10 x Height 40
- Double walls Grey(Exterior)/Clear (interior)
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.
Important/ Interesting facts
2.1. Interesting facts
The first ever study regarding place preference was conducted to examine the drive-reduction hypothesis of addiction learning in rodents, and Beach 1957 utilized a Y-choice maze for the procedure; an apparatus different from the modern day CPP apparatus (see section 3 for currently used CPP apparatus).
2.2. Closely Related Task
Self-administration (SA) task
2.3. Major Contributions made towards the task/apparatus
Many researchers have made significant contributions toward the CPP task, and a variety of different CPP apparatus have been used for studying the rewarding properties of drugs. Some of the prominent contributors are:
- BEACH H.D– Conducted first study discussing place preference
- NELLO A. ROSSI and LARRY D. REID– Introduced the concept of drug-paired conditioning.
- MARTIN D. SCHECHTER– Over 25 published papers. Also reviewed the trends in conditioned place preference in detail.
- Christopher L Cunningham– Over 75 published studies discussing the conditioning place preference task.
2.4. Applications in other laboratory animals
CPP model is highly applicable, and a number of other laboratory animals beside rodents have been tested for the rewarding effects of different drugs. For example, cocaine CPP has been demonstrated in chickens (Hughes et al. 1995). Chicken’s highly evolved visual system is sensitive to color and fine detail. Hughes et al. 1995 used visual stimuli as the CS to establish the CPP. Although originally designed for rodents, presently CPP behavior can also be evaluated in zebrafish by utilizing the Zebrafish Place Preference Test.
Apparatus and Equipment
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 Mazeengineers Apparatus Designs
Need Custom CPP variation? – Mazeengineers got you covered! We can make any custom CPP version. If you want to replicate an apparatus or plan to start from scratch, Mazeengineers is always there to handle your science. All we need from you is an overview, and the rest will be taken care of.
Documentation/ Scientific Research
The first documented work on place preference was way back in 1957. Two papers were published that year discussing place preference (Beach 1957; Garcia et. Al 1957). Beach examined the learning process under morphine addiction. He trained rats in a Y-choice discrimination box and associated one of the boxes with morphine. Although this study did not explicitly stress the rewarding properties of drugs and instrumental responses were involved, it surely had some conceptual similarities to the current versions of place conditioning methods. However, the study assessed evident place preference with morphine.
On the other hand, Garcia et.al 1957 investigated that the avoidance behavior can be produced by irradiation where conditioning criteria involve consumption. Their apparatus consisted of a straight alley (30 x 4 x 5 inches) enclosed by an acrylic lid. They divided the alley into distinct compartments with the help of a 1-inch-high acrylic divider. Each compartment was distinct in terms of visual and tactile cues. One compartment was painted flat black and had a grid floor, while the other was painted flat white and had a mesh wire floor. The alley’s base was balanced on a fulcrum, and a micro-switch was located beneath each end for data collection (Garcia et.al 1957).
These published works were followed by limited research on place conditioning as only nine papers were published during the span of 1958-1974. The currently used apparatus and procedure were established by Kumar in 1972, followed by Ross and Reid in 1976. Kumar modified the procedure by introducing the subjects in the testing chamber right after the drug incorporation (Kumar 1972). Beach and Kumar administered a high dose of daily morphine to the subjects before the CPP test, and the same high dose was also employed for CPP induction, the subject’s conditioned responses may have been elicited by the relief of withdrawal rather than the rewarding effects of the drug under study (morphine).
In 1976, 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 (Bozarth 1987). They not only introduced the concept of drug-paired conditioning, but they were able to induce a conditioned response in rats at low doses of morphine productively. They used a 98 x 23 x 29 cm alley that was divided into three distinct compartments each separated by the middle compartment (8 x 23 x 29 cm) having guillotine doors on each side. The middle compartment was gray, had a solid floor, and served as a starting point for the animals during the testing procedure. On one side of the middle compartment was a black compartment with 1.3 x 2.5 cm with wire mesh floor, which they referred to as the black side. On the other side of the middle compartment was a white compartment with a 1.3 x 1.3 cm wire mesh floor, which they referred to as the white side. They claimed that the CPP paradigm could successfully access the drug’s affective consequences and the rewarding properties. (Rossi & Reid 1976)
Since then many studies probed the rewarding properties of different drug substances, and even natural reinforces as well. According to PubMed’s database, 3693 search results are obtained starting from 1978 to present by utilizing the search string, ‘’Conditioned place preference”, and the number is increasing is day by day (see Figure 1).
The three-chamber design is the most extensively used type of CPP; other apparatuses vary from this design by having a different number of compartments (e.g., two or four compartments) and shapes. The two-compartment apparatus requires a forced choice, whereas a three-compartment area offers a central choice area between the experimental chambers. There are also paradigms designed to assess place preference within an open field (Vezina and Stewart 1987a, b), or allowing for the association of the interoceptive effects of drugs with a unique environment.
4.1.3. Most recent Study Using the CPP apparatus
Presently, Huiwen Zhu et. al 2017 published the most recent study utilizing the CPP apparatus. They investigated the association of β-adrenoceptors (β-ARs), specifically β2-AR with drug reward mechanism and anxiety-like behavior. They employed a two- chambered, unbiased design. Each compartment had distinct wall and floor patterns.
Training Protocol/ How to use the apparatus
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)
Detailed Procedure of Conditioned Place Preference
18.104.22.168. 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).
22.214.171.124. 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.
126.96.36.199. Conditioning Phase
188.8.131.52.1. 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).
184.108.40.206.2. 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).
220.127.116.11. 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.
What can be evaluated? / Uses of the apparatus
4.3.1. Evaluation of CPP and CPA
The conditioned place preference model can be used to assess both CPP and CPA. Numerous drug substances have exhibited CPP behavior in rodents such as Bupropion (Ortmann 1985), Cocaine, Cocaethylene (Schechter 1995; Kushner 1997) Cathinone (Calcagnetti and Schechter 1992a)
On the contrary, many drug substances have depicted CPA behaviors in rodents such as Naloxonazine (Suzuki et al.1993a), Citalopram, Imipramine, and Amitryptiline. (Papp 1989). See Table 1 for detailed account.
|Response produced by||Response||Citations|
|Amphetamine||CPP||Asin et al (1985); Carboni et al (1989), Carr et al (1987, 1988); Clarke et al (1987); Costello et al (1987); Di Scala et al (1985); Gilbert et al (1983); Hiroi et al (1988); Hoffman et al (1988); Hoffman et al (1989); Kruszewska et al (1986); Leone et al (1987); Lett et al (1988); Mackey et al (1985); Mithani et al (1986); Nomikos et al (1988); Pettit et al (1987); Reicher et al (1977); Schenk et al (1986); Sherman et al (1980); Spyraki et al (1982); Spyraki et al (1988); Swerdlow et al (1984)|
|Cocaine||CPP||Bardo et al (1986); Issac et al (1984); Martin et al (1988); Michaelis et al (1987); Morency et al (1987); Mucha et al (1982); Nomikos et al (1988); Schenk et al (1986); Spyraki et al (1982); Spyraki et al (1985); Spyraki et al (1987)|
|Morphine||CPP||Advocat et al (1985); Bardo et al (1984), Bardo et al (1986)|
10-12 Barr et al (1985). Beach et al (1957), Bechara et al (1985); Bechara et al (1988); Bechara et al (1987); Blander et al (1984); Carboni et al (1989); Dymshitz et al (1987); Iwamoto et al (1986); Katz et al (1979); Kelsey et al (1987), Kruszewska et al (1986), Kumar et al (1972); Leone et al (1987); 62, Mackey et al (1985); Martin et al (1988); Mucha et al (1982); Nomikos et al (1988); Rossi et al (1976); Schwartz et al (1974); Sherman et al (1980); Shippenberg et al (1987, 1988); Spyraki et al (1988); Stapleton et al (1979); Vezina et al (1987); Vezina et al (1987); Zito et al (1988)
|Heroin||CPP||Amahic at el (1987); Bozarth et al (1987); Bozarth et al (1981); Dymshitz et al (1987); LeMoal et al (1988); Schenk et al (1985); Schenk et al (1983); Spyraki et al (1983)|
|Naloxone||CPA||Amahic at el (1987); Bechara et al (1987); Dymshitz et al (1987); Iwamoto et al (1986); Mucha et al (1985); Mucha et al (1985); Mucha et al (1987); Shippenberg et al (1988); Spyraki et al (1985)|
|Nicotine||CPP||Risinger and Oakes (1995); Calcagnetti and Schechter (1994b); Carboni et al. (1989); Acquas et al. (1989); Fudala et al. (1985); Fudala and Iwamoto (1986)|
|CPA||Risinger and Oakes (1995); Jorenby et al. (1990); Fudala et al. (1985)|
|Ethanol||CPP||Schechter (1992b); Risinger et al. (1994); Risinger and Oakes (1996a,b); Cunningham and Noble (1992a); Gevaerd and Takahashi (1996); Risinger et al. (1992a,b, 1996); Risinger (1997); Cunningham et al. (1992a, 1993, 1997); Kelley et al. (1997b)|
4.3.2. Evaluation of neural circuits involved in drug reward mechanism
Another favorable advantage of CPP is that it has substantial utility in scrutinizing the neural circuits involved in drug reward mechanism. For instance, microinjection of amphetamine into the nucleus accumbens produces approach response, while microinjection of amphetamine into the area postrema produces CTA (Carr and White 1983, 1986). Different reviews have demonstrated that microinjection of µ opioids into the ventral tegmental zone (VTA) produces CPP, while microinjection of κ opioids into the VTA, nucleus accumbens, medial prefrontal cortex or lateral hypothalamus produces avoidance behavior (Shippenberg and Elmer 1998). These place preference studies clearly signal that different neural circuits are involved in approach and avoidance behavior.
The CPP task can also serve to indicate the presence of lesions in rodents. For instance, lesions of NAS obstructed novelty-induced CPP (Pierce et al., 1990), and diazepam-induced CPP (Spyraki and Fibiger, 1988). Furthermore, the lesions of the VP prevented cocaine-induced CPP (Gong et al., 1997b). See Table 2 for studies involving lesions.
|Lesioned region||Response produced by||Response||Citations|
|NAS||Morphine||No CPP||Shippenberg et al. (1993)|
|U-69593 (CPA)||No CPA||Shippenberg et al. (1993)|
|Diazepam||No CPP||Spyraki and Fibiger (1988)|
|Novel environment||No CPP||Pierce et al. (1990)|
|CTOP (VTA) (CPA)||No CPA||Shippenberg and Bals-Kubik (1995)|
|CTOP (NAS) (CPA)||CPA||Shippenberg and Bals-Kubik (1995)|
|Naloxone (IP) (CPA)||CPA||Shippenberg and Bals-Kubik (1995)|
|VP||Cocaine||No CPP||Gong et al. (1997b)|
|Olfactory tubercle||Amphetamine||CPP||Clark et al. (1990)|
|Striatum||Morphine||CPP||Shippenberg et al. (1993)|
|U-69593 (CPA)||CPA||Shippenberg et al. (1993)|
|mPFC||Morphine||CPP||Shippenberg et al. (1993)|
|U-69593 (CPA)||CPA||Shippenberg et al. (1993)|
|Cocaine||CPP||Hemby et al. (1992b)|
|Visceral cortex||Morphine||CPP||Zito et al. (1988)|
|Morphine (CPA)||No CPA||Zito et al. (1988)|
|ICV||Methylphenidate||CPP||Martin-Iverson et al. (1985)|
|NAS||Amphetamine||No CPP||Olmstead and Franklin (1996)|
|Morphine||CPP||Olmstead and Franklin (1997a)|
|Sucrose||No CPP||Everitt et al. (1991)|
|Naltrexone (CPA)||CPA||Kelsey and Arnold (1994)|
|Striatum||Morphine||CPP||Olmstead and Franklin (1997a)|
|Food||CPP||White and McDonald (1993)|
|Striatum (ventromed.)||Sucrose||Reduced CPP||Everitt et al. (1991)|
|Striatum (dorsolateral)||Sucrose||CPP||Everitt et al. (1991)|
|VP||Sucrose||Reduced CPP||McAlonan et al. (1993)|
|Amphetamine||No CPP||Hiroi and White (1993)|
|Amphetamine (expr.)||CPP||Hiroi and White (1993)|
|Morphine||CPP||Olmstead and Franklin (1997a)|
|Amygdala (whole)||Cocaine||No CPP||Brown and Fibiger (1993)|
|Amygdala (lat. nucl.)||Morphine||CPP||Olmstead and Franklin (1997a)|
|Amphetamine||No CPP||Hiroi and White (1991b)|
|amphetamine (expr.)||No CPP||Hiroi and White (1991b)|
|Food||No CPP||White and McDonald (1993)|
|Amphetamine||CPP||Hiroi and White (1991b)|
|Amphetamine (expr.)||CPP||Hiroi and White (1991b)|
|Sucrose (expr.)||No CPP||Everitt et al. (1991)|
|Naltrexone (CPA)||Reduced CPA||Kelsey and Arnold (1994)|
|Endopiriform nucl.||Amphetamine||CPP||Hiroi and White (1991b)|
|Amphetamine (expr.)||CPP||Hiroi and White (1991b)|
|Ventral hippocampus||Amphetamine||CPP||Hiroi and White (1991b)|
|Amphetamine (expr.)||CPP||Hiroi and White (1991b)|
|Fornix||Morphine||Reduced CPP||Olmstead and Franklin (1997a)|
|Food||Enhanced CPP||White and McDonald (1993)|
|MD thalamus||Sucrose||Reduced CPP||McAlonan et al. (1993)|
|mPFC (prelimbic)||Cocaine||No CPP||Tzschentke and Schmidt (1998b)|
|Amphetamine||CPP||Tzschentke and Schmidt (1998b)|
|Morphine||CPP||Tzschentke and Schmidt (1998b)|
|mPFC (infralimbic)||Cocaine||CPP||Tzschentke and Schmidt (1998c)|
|Amphetamine||CPP||Tzschentke and Schmidt (1998c)|
|Morphine||No CPP||Tzschentke and Schmidt (1998c)|
|CGP37849||No CPP||Tzschentke and Schmidt (1998c)|
|Visceral cortex||Morphine||CPP||Mackey et al. (1986)|
|Lithium chloride (CPA)||CPA||Mackey et al. (1986)|
|PPTg||Cocaine||CPP||Olmstead and Franklin (1993, 1994, 1997a)|
|Cocaine (expr.)||CPP||Parker and van der Kooy (1995)|
|Amphetamine||No CPP||Bechara and van der Kooy (1989)|
|Heroin (low dose)||No CPP||Nader et al. (1994)|
|Heroin (high dose)||CPP||Nader et al. (1994)|
|PPTg||Morphine (IP) (in naive|
|No CPP||Bechara and van der Kooy (1992a,b);|
Nader and van der Kooy (1994, 1997)
|Morphine (VTA) (in|
|Morphine (IP) (in|
|Morphine (VTA) (in|
|Food (satiated animals)||No CPP|
|Morphine withdrawn in|
depend animals (CPA)
|CPA||Bechara and van der Kooy (1992a)|
|Hunger in food-depr.|
|CPA||Bechara and van der Kooy (1992a)|
|Saccharin solution||No CPP||Stefurak and van der Kooy (1994)|
|PAG||Cocaine||CPP||Bechara and van der Kooy (1989);|
|Cocaine (expr.)||CPP||Olmstead and Franklin (1993, 1994);|
|Amphetamine||CPP||Parker and van der Kooy (1995)|
|Morphine||Reduced CPP||Olmstead and Franklin (1997a)|
|Med. parabrach. nucl.||Morphine||CPP||Bechara et al. (1993)|
|Morphine withdr. in|
depend. animals (CPA)
|No CPA||Nader et al. (1996)|
|NAS (electrolytic)||Morphine||No CPP||Kelsey et al. (1989)|
|Striatum (electrolytic)||Amphetamine||Enhanced CPP||Hiroi and White (1991a)|
|Cocaine||Enhanced CPP||Gong et al. (1995)|
|Mediobasal arcuate||Morphine||CPP||Mucha et al. (1985)|
|Hypothalamus||U-50 488H (CPA)||CPA||Mucha et al. (1985)|
|(radiofrequency)||Naloxone (CPA)||reduced CPA||Mucha et al. (1985)|
|Lithium chloride (CPA)||No CPA||Shippenberg et al. (1988b)|
|Connection of sulcal||mPFC self-stimulation||Enhanced CPP||Robertson and Laferriere (1989)|
|and mPFC (knife cut)||Lithium chloride (CPA)||Enhanced CPA||Schalomon et al. (1994)|
|mPFC (aspiration)||Cocaine||CPA||Isaac et al. (1989)|
|Orbital PFC (aspirat.)||Cocaine||No CPP||Isaac et al. (1989)|
|Precentral PFC (asp.)||Cocaine||No CPP||Isaac et al. (1989)|
|Central NA depletion|
|Diazepam||CPP||Spyraki and Fibiger (1988)|
|Central 5-HT depl.||Mianserin (CPA)||Enhanced CPA||Rocha et al. (1993b)|
|(ICV 5,7-DHT)||FG 7142 (CPA)||No CPA||Rocha et al. (1993b)|
|Ethanol (CPA)||CPA||Bienkowski et al. (1997b)|
|NAS 5-HT depl.||Diazepam||No CPP||Spyraki et al. (1988)|
|(5,7-DHT)||Morphine||Reduced CPP||Spyraki et al. (1988)|
|Amphetamine||CPP||Spyraki et al. (1988)|
|Adrenalectomy||Morphine||Enhanced CPP||Suzuki et al. (1995a)|
|Cocaine||CPP||Suzuki et al. (1995a)|
|Olfact. Bulbectomy||Cocaine (expr.)||No CPP||Calcagnetti et al. (1996)|
|Vagotomy||Morphine (low dose)|
|No CPA||Bechara and van der Kooy (1987)|
|U-50 488H (CPA)||CPP||Bechara and van der Kooy (1987)|
4.3.3. Evaluation of the hereditary nature of addictive drugs
The CPP model is not only confined to testing, but it can also help to assess the hereditary nature of the addictive drugs. Schechter, 1992a produced lines of rodents through selective pairing. The parent rodents depicted weak or strong cocaine-induced CPP over three generations. Their successive line was either aversive to cocaine manifested by the little locomotor response to cocaine or strongly addicted to cocaine manifested by strong locomotor activation induced by cocaine, respectively.
4.3.4. Evaluation of the effects of Natural Reinforcers and Hormones
One of the biggest advantages of the CPP paradigm is that non-drug reinforcers can be evaluated for their motivational properties. See Table 3 for studies involving hormones and natural reinforcers.
|Effects produced by||Effects||References|
|LHRH||CPP||De Beun et al. (1991a, 1992a)|
|Testosterone||CPP||De Beun et al. (1992b); Alexander et al. (1994)|
|Estradiol||CPA||De Beun et al. (1991b)|
|CRF||CPA||Cador et al. (1992)|
|Rough-and-tumble play||CPP||Calcagnetti and Schechter (1992b)|
|Home cage odors||CPP||Hansen (1993)|
|Pups (for maternal rats)||CPP||Magnusson and Fleming (1995); Fleming et al. (1994)|
|Social play||CPP||Crowder and Hutto (1992a)|
|Successful aggression||CPP||Martinez et al. (1995)|
|Male/female interaction||CPP||Meisel and Joppa (1994); Paredes and Alonso (1997); Meisel et al. (1996); Oldenburger et al. (1992); Hughes et al. (1990); Mehrara and Baum (1990); Miller and Baum (1987)|
|Ejaculation||CPP||Agmo and Berenfeld (1990); Agmo and Gomez (1993)|
|Water||CPP||Crowder and Hutto (1992a); Agmo et al. (1993); Perks and Clifton (1997)|
|Sucrose solution, saccharin solution||CPP||Papp et al. (1991); Agmo et al. (1995); Perks and Clifton (1997); Agmo and Marroquin (1997); Stefurak and van der Kooy (1992, 1994)|
|Food||CPP||Lepore et al. (1995); Papp (1988a, 1989); Papp et al. (1991); Cheeta et al. (1994); Willner et al. (1994); Guyon et al. (1993); Muscat et al. (1992); Perks and Clifton (1997); Maes and Vossen (1993); Chaperon et al. (1998)|
|Novel environment||CPP||Carr et al. (1988); Bardo et al. (1989, 1990, 1993); Parker (1992); Laviola and Adriani (1998)|
4.3.5. Evaluation of aversive/emotional domain of pain
In recent years, the aversive/emotional domain of pain has been evaluated by the conditioned place preference model. Basically, the CPA produced by a painful stimulus is paired with a distinct compartment. The conditioned place preference model has been used for both inflammatory pain stimulus and neuropathic pain models (Tzschentke 2007).
It has been demonstrated that inflammation induced by unilateral injection of formalin or carrageenan into the plantar surface of the hind paw of rats reduced the CPP effects of morphine (Suzuki et al. 1999d). Furthermore, the subcutaneous injection of a 2.5% formalin solution into the hind paw of rats produces CPA. Formalin injection also produced clear nocifensive behavior (paw licking, lifting, flinching, etc.) during the conditioning phase. (Johansen, Fields & Manning 2001). A study induced neuropathic pain by partially ligating the sciatic nerve and demonstrated the reduced approach behavior response to morphine (Ozaki et al. 2002).
4.3.6. Studies involving the genetically modified animals
One of the striking advantages of CPP paradigm is its application in the studies concerning the genetically modified subjects. Some of the prominent studies involving the dopaminergic and cholinergic pathways, opioids, ethanol, and natural rewards are as follows.
18.104.22.168. Studies involving the dopaminergic pathway in genetically modified animals
Surprisingly, cocaine and methylphenidate (dopaminergic drugs) can produce an evident CPP effect in dopamine transporter (DAT) knockout mice. Furthermore, cocaine has also demonstrated CPP effect in SERT knockout mice as well (Sora et al. 1998).
Later, cocaine was tested in DAT/SERT double-knockout mice (Sora et al. 2001). They investigated that mice heterozygous for the DAT knockout and homozygous for the SERT knockout still exhibited cocaine-induced CPP, while mice homozygous for the DAT knockout and hetero- or homozygous for the SERT knockout did not exhibit cocaine-induced CPP.
These studies revealed an underlying interplay between Dopamine active transporter (DAT) and Serotonin transporter (SERT) in mediating the rewarding effects of cocaine. The role of the N-acetyltransferase (NAT) was demonstrated by Xu et al. 2000. They investigated that NAT knockout mice showed enhanced approach behavior when compared with wild-type rats.
Another interesting study demonstrated that amphetamine-induced CPP is retained in DAT knockout mice. (Budygin et al. 2004)
Later, it was confirmed that interaction with the DAT is vital for mediating the rewarding effects of cocaine Chen et al. 2006. They produced a knockout mouse line having a functional DAT, but insensitive to cocaine. In these mice, no cocaine-induced CPP was established, locomotor activity was diminished, and the cocaine-induced dopamine release in the nucleus accumbens was reduced significantly. However, amphetamine produced CPP response similar to that observed in wild-types in these lines.
Monoamine transporter mechanisms fundamental for cocaine reward were further studied by Hall et al. 2002) who observed CPP effects of fluoxetine, nisoxetine, and cocaine in single and multiple transporter knockout mice.
It can be inferred from all these studies that in a situation where DAT is lacking, NAT and SERT play a significant role in facilitating the rewarding effects produced by monoaminergic uptake blockers. Conversely, in the presence of DAT, SERT and NAT contributes towards attenuating rather than potentiating the rewarding effects in order to balance the overall effects of drugs such as cocaine.
22.214.171.124. Studies involving the Opioids drugs in genetically modified animals
DAT knockout mice exhibited a stronger CPP response to morphine when compared with wild types (Spielewoy et al. 2000). However, unlike controls, the DAT knockout mice did not exhibit a morphine-induced hyperlocomotion. Additionally, morphine-induced analgesia was undisturbed in the genetically modified mice, while the behavioral manifestation of naloxone-induced withdrawal was reduced. Morphine produced higher extracellular levels of dopamine and a higher rate of c-Fos transcription in the NAS shell in DAT knockout mice compared with controls. Therefore, the enhanced rewarding effects of morphine in DAT knockout mice may be associated with the amplified morphine- induced dopaminergic activity within the NAS shell. Overexpression of the glutamate transporter GLT-1 produced by adenovirus-mediated gene transfer eliminated morphine-induced CPP in the NAS shell (Fujio et al. 2005).
126.96.36.199. Studies involving Ethanol in genetically modified animals
In homozygous D2 receptor knockout mice, ethanol failed to produce CPP, whereas the approach behavior was elicited in wild-type and heterozygous mice at this dose (Cunningham et al. 2000). Conversely, deletion of the D3 receptor had no impact on ethanol-induced CPP (Boyce-Rustay & Risinger 2003).
In female MOR (mu opioid receptor) knockout mice, ethanol (2 g/kg IP) did not produce a CPP, regardless of whether the animals were heterozygous or homozygous for the receptor deletion (Hall et al. 2001). On the contrary, no effect of MOR deletion was found (in male mice) on the CPP response to 2 and 4 g/kg IP ethanol (Becker et al. 2002).
Preproenkephalin knockout mice showed normal ethanol-induced CPP as well as wild type-like ethanol consumption and preference (Koenig & Olive 2002). In a similar fashion, pre prodynorphin knockout mice showed normal ethanol-induced CPP. Interestingly, female (but not male) mutant mice showed reduced ethanol consumption and preference compared with wild types (Blednov et al. 2006).
Ethanol-induced CPP was absent in hetero- and homozygous mice lacking the NMDA receptor NR2A subunit (Boyce-Rustay & Holmes 2006). Mice lacking the β2-subunit of the GABA-A receptor depicted a diminished CPP response to ethanol, while mice lacking the β1-subunit of the GABA-A receptor did not differ from wild-type animals in their CPP response to this dose of ethanol. (Blednov et al. 2003).
188.8.131.52. Studies involving the cholinergic pathway in genetically modified animals
In 2002, Berrendero, Kieffer & Maldonado found that in MOR (mu opioid receptor gene) knockout mice nicotine failed to produce CPP. The anti-nociceptive effects of nicotine and the expression of mecamylamine-precipitated nicotine withdrawal were also weakened.
The CPP produced by (0.5 mg/kg sc) nicotine was also lacking in pre proenkephalin knockout mice, and mecamylamine-precipitated withdrawal was also lessened in the subjects (Berrendero et al. 2005).
In monoamine oxidase A- knockout mice, a dose of nicotine (0.2 mg/kg sc) that produced approach response in wild-type subjects produced avoidance response (Agatsuma et al. 2006).
Nicotine failed to produce CPP effects in mice lacking the tissue plasminogen activator t(PA) or the protease activated receptor-1 (PAR1) (Nagai et al. 2006a)
184.108.40.206. Studies involving Natural Rewards in genetically modified animals
In male wild-type mice, sexual activity with females with intromissions alone, or with intromissions and ejaculation both produced CPP. However, in dopamine D5 receptor knockout mice, only sexual encounters with intromissions and ejaculation, but not with intromissions alone, produced CPP (Kudwa et al. 2005).
The approach behavior induced by food was integral in hetero and homozygous Dbh knockouts, the enzyme transforming dopamine to noradrenaline (Jasmin et al. 2006; Olson et al. 2006b).
The mice lacking AMPA receptor subunit GluR2 did not produce food-induced CPP, whereas the mice lacking the AMPA receptor subunit GluR1 produced food-induced CPP (Mead et al. 2005).
Valverde et al. (2004) reported that in CREB knockout mice, the CPP response to food was normal. Food-induced CPP was also unaffected (normal) in mice lacking the immediate early gene Zif268 (Valjent et al. 2006a).
In male mice lacking the aromatase enzyme (leading to estrogen deficiency), an anesthetized estrous or non-estrous female, or soiled bedding from estrous females, did not produce CPP (in contrast to the wild types) (Pierman et al. 2006).
In a transgenic mouse line (CN98) expressing a truncated and active form of calcineurin (resulting in an increase of the enzymatic activity of calcineurin of approximately 75% in the hippocampus), which shows deficits in the transition of information from short- to long-term memory, produced food-induced CPP. Although, amphetamine and morphine failed to do so. (Biala et al. 2005).
4.3.7. Evaluation of Extinction and Reinstatement
The extinction and reinstatement of different drug substances can also be assessed with the aid of the CPP paradigm (Yossef and Julio, 2002). Recently, there has been a major shift, and many researchers have opted the extinction-reinstatement approach for place conditioning. In extinction-reinstatement approach, the conditioned response (usually approach behavior or CPP) becomes extinguished with frequent exposure to the conditioned stimulus in the absence of the unconditioned stimulus. The initial response in the shape of the expression of the approach behavior or CPP can be reinstated by the unconditioned stimulus (usually a drug priming injection), by stressors or by conditioned cues.
Extinction of previously established drug-induced approach behavior or CPP can be accomplished either by repeated exposure to the preferred compartment without drug exposure or by pairing both the drug and non-drug compartments with vehicle (saline) treatment. The efficiency of CPP extinction is dependent upon several factors such as the number of pairings or injections, the number of extinction sessions, and the extent of the extinction period (Mueller et.al 2002; Brabant et.al 2005; Sakoori 2007)
Reinstatement of drug seeking and taking behavior in the laboratory animals is hypothesized to be related to drug relapse phenomena in humans. The reinstatement model had been used to determine the behavioral and neural mechanisms underlying relapse (Shaham et.al 2003; Epstein et.al 2006). Using the CPP procedure, numerous studies have also revealed that both drug-priming injections and stressors could reinstate previously reduced CPP performance (Mueller et.al 2000; Sanchez et.al 2001; Lu et.al 2002; Kreibich et.al 2004; Bardo 1984; Calcgnetti et.al 1993). This phenomenon can be a specific reflection of relapse to drug-seeking behavior that is usually observed in drug-addicted individuals.
A sample data can be visualized by comparing the performance of rodents in black versus white compartment. It is evident from the graph that there is a marked place preference for the black compartment during the testing phase which is obvious by the mean time spent in all four testing trials by the subject in the black compartment. See figure 2a
Figure 2a represents the mean time spent by a subject in the white or black compartment.
Another sample data can be visualized by plotting the CPP and CPA with respect to the time spent in the drug-paired compartment. It is evident from the graph that Cocaine and Bupropion induces CPP, whereas Citalopram induce CPA behaviors. See Figure 2b
Yet another sample data represents the impact of lesions/injuries on the CPP behavior. For instance, diazepam induces CPP behavior, but in case of nucleus accumbens septa (NAS) lesion, diazepam-induced CPP is obstructed. The suppression of cocaine- induced CPP behavior may be the indication of VP (ventral pallidum) lesion. Figure 2c
4.5 Extent to which it is applicable to human studies/ Translational study
The CPP paradigm has been rigorously criticized as it has not been validated as a protocol for measuring drug reward in humans. Unfortunately, not even a single paper was published until 2008. In 2009, Emma Childs and Harriet de Wit validated a place preference technique in humans based on the principle procedure followed for the laboratory animals. One of their aims was to demonstrate the translational capacity of the CPP procedure in humans like non-humans. They concluded that healthy human volunteers depicted preference for a room previously associated with the drug of abuse (amphetamine).
Since then, humans have established a CPP using food, drugs, or music, all primary reinforcers (Astur et al., 2014; Childs & de Wit, 2009; Molet et al., 2013. In 2016, Astur and co-workers established a conditioned place preference in humans utilizing the secondary reinforcers such as drug paraphernalia.
Strength and Limitations
- 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.
- 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.
Summary and Key Points
- 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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