Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of the context that surrounded the "encounter". By measuring the amount of time an animal spends in an area that has been associated with a stimulus, researchers can infer the animal's liking for the stimulus. This paradigm can also be used to measure conditioned place aversion (CPA) with an identical procedure involving aversive stimuli instead. Both procedures usually involve mice or rats as subjects.Campbell J., Wood R., Spear L. (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav 68:487–493Adriani W., Laviola G. (2002) Spontaneous novelty seeking and amphetamine-induced conditioning and sensitization in adult mice: evidence of dissociation as a function of age at weaning. Neuropsychopharmacology 27:225–236. This procedure can be used to measure extinction and reinstatement of the conditioned stimulus. Certain drugs are used in this paradigm to measure their reinforcing properties. Two different methods are used to choose the compartments to be conditioned, and these are biased vs. unbiased. The biased method allows the animal to explore the apparatus, and the compartment they least prefer is the one that the drug is administered in and the one they most prefer is the one where the vehicle (without the drug) is injected.Prus, AJ., James, JR., Rosecrans, AJ.(2009). Methods of Behavioral Analysis in Neuroscience. Augusta, CRC press. This method allows the animal to choose the compartment they get the drug and vehicle. In comparison, the unbiased method does not allow the animal to choose what compartment they get the drug and vehicle in. Instead, the researcher chooses the compartments.
Humans have also been shown to develop conditioned place preferences; for example, people taking therapeutic doses of amphetamine develop a CPP for where they consumed the drug.
The CPP effects of many drugs have been reviewed.
Conditioning procedure
As in Pavlovian conditioning, an initial neutral stimulus, in this case, environmental cues, is repeatedly paired with an unconditioned stimulus that naturally produces a response prior to conditioning (the unconditioned response). Over time and pairings, the neutral stimulus will come to elicit responses similar to the unconditioned response. In conditioned place preference, the unconditioned stimulus could be any number of things including food pellets,Spyraki C, Fibiger HC, Phillips AG (1982) Attenuation by haloperidol of place preference conditioning using food reinforcement. Psychopharmacology 77:379–382. water,Ågmo A, Federman I, Navarro V, Pudua M, Velazquez G (1993) Reward and reinforcement produced by drinking water: role of opioids and dopamine receptor subtypes. Pharmacol Biochem Behav 46:183–194 sweet fluid,Ågmo A, Marroquin E (1997) Role of gustatory and post ingestive actions of sweeteners in the generation of positive affect as evaluated by place preference conditioning. Appetite 29:269– 289 novel toys,Bevins RA, Bardo MT (1999) Conditioned increase in place preference by access to novel objects: antagonism by MK-801. Behav Brain Res 99:53–60 social interaction,Calcagnetti DJ, Schechter MD (1992) Place conditioning reveals the rewarding aspect of social interaction in juvenile rats. Physiol Behav 51:667–672 drug intoxication, drug withdrawal, foot shock, illness, wheel runningAntoniadis EA, Ko CH, Ralph MR, McDonald RJ (2000) Circadian rhythms, aging and memory. Behav Brain Res (in press) or copulation.Meisel RL, Joppa MA, Rowe RK (1996) Dopamine receptor antagonists attenuate conditioned place preference following sexual behavior in female Syrian hamsters. Eur J Pharmacol 309:21–24; Cunningham, C., Gremel, C. & Groblewski, P. (2006). Drug-induced conditioned place preference and aversion in mice. Nature Protocols, 1(4), 1662-1670; Bardo, M. & Bevins, R. (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology. 153, 31-43. The initially neutral environmental cues become associated with the motivational properties of the unconditioned stimulus leading to either approach or avoidance of the environment. Often in practice, there is a control and treatment group used to strengthen the ability to make causal claims from the results. The treatment group is administered the unconditioned stimulus while the control group is given saline or nothing to control for all elements of the procedure.Cunningham, C., Gremel, C. & Groblewski, P. (2006). Drug-induced conditioned place preference and aversion in mice. Nature Protocols, 1(4), 1662-1670.
Apparatus The conditioned place preference protocol makes use of an apparatus that contains two or more compartments or areas. These two compartments are designed so that the animal can discriminate between them. Differently patterned walls or floors or different types of floor textures may be used to ensure the animal can discriminate between the compartments.
Steps to conditioning place preference or aversion Conditioned place preference involves three phases: habituation, conditioning, and preference testing.
Habituation In the habituation procedure, the animal is given a chance to explore the apparatus. This is done to reduce the effects of novelty and usually consists of one five-minute trial.
Conditioning In the conditioning phase, the unconditioned stimulus (e.g. morphine) is administered to the animal (usually a mouse or rat) in the treatment group. In this phase of the procedure the animal is only allowed access to one compartment of the apparatus.Bardo, M. & Bevins, R. (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology. 153, 31-43. This compartment will become associated with the motivational effects of the unconditioned stimulus. The environment will come to elicit an approach or avoidance-withdrawal depending on the nature of the unconditioned stimulus. The conditioning procedure usually consists of eight or more five-minute sessions.
Preference testing In the preference testing phase, the animal is allowed unrestricted access to all compartments of the apparatus. During the test, the time a subject spends in each compartment is measured in seconds. Modern protocols utilize commercial automated tracking systems to measure the time; however, manual measurement is also used. Statistical testing is used to determine whether a significant difference in time is present when compared to either a control group or the pre-conditioning time of the same group (baseline value). Strength of conditioning is inferred by the magnitude of the difference or in the amount of time taken for the response to show extinction.
Outcomes In the standard conditioned place preference procedure, when the unconditioned stimulus is rewarding, rodents will be more likely to approach the compartment that contains cues associated with it. Alternatively, when the unconditioned stimulus is aversive, rodents will be more likely to escape and avoid the compartment that contains cues associated with it. The timing of presentation of the unconditioned stimulus can determine whether place preference or aversion will be conditioned. For example, in trials testing drugs of abuse, if the animal experiences the initial pleasurable effects of the drug while in the conditioning context, the result will likely be conditioned place preference. However, if the animal is given the drug and then the experimenter implements a sufficient delay so that the animal is experiencing the negative aftereffects of the drug, conditioned place aversion is more likely to occur. The timing of these events can be manipulated by the experimenter in order to condition place preference or avoidance.
Advantages and disadvantages
Advantages There are numerous advantages of the conditioned place preference and aversion protocol. It is methodologically simple and only requires two to three weeks to perform all steps of the procedure. In some cases, conditioning can occur with two stimulus-context pairings.Cunningham, C.L., Tull, L.E., Rindal, K.E. & Meyer, P.J. Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect, sensitization to activating effect, but no change in rewarding effect. Psychopharmacology 160, 414–424 (2002). It allows both rewarding and aversive effects to be tested and it provides unique information about the motivational effects of unconditioned stimuli. Although the protocol is most often used with mice and rats, it can be adapted for use in other species such as birds and other rodents.Hughes RA, Baker MR, Rettig KM (1995) Cocaine-conditioned place preference in young precocial domestic fowl. Exp Clinical Psychopharmacology 3:105–111.Meisel, R. & Joppa, M. (1993). Conditioned place preference in female hamsters following aggressive or sexual encounters. Physiology and behaviour, 56(5), 1115-1118.
In drug testing the conditioned reward or aversive effects can be tested in a drug-free state where the animals will not be impaired due to drug use. The testing is also sensitive to the effects of low drug doses. Conditioned place preference is well suited to measure the temporal profile of drugs (the pattern of rewarding and aversive effects) as well as the aversive effects of withdrawal. This can be done by varying the time of drug administration in relation to the presentation of the to-be-conditioned context.Cunningham, C.L., Okorn, D.M. & Howard, C.E. Interstimulus interval determines whether ethanol produces conditioned place preference or aversion in mice. Anim. Learn. Behav. 25, 31–42 (1997); Fudala, P.J. & Iwamoto, E.T. Conditioned aversion after delay place conditioning with nicotine. Psychopharmacology 92, 376–381 (1987). The procedure also can be utilized to measure the neural circuits involved in drug reward.Carr, G.D., Fibiger, H.C. & Phillips, A.G. The Neuropharmacological Basis of Reward. (ed. Copper, J.M.L.S.J.) 264–319 (Clarendon Press, Oxford, 1989).
Disadvantages The conditioned place preference and aversion protocol are subject to several disadvantages and limitations. Perhaps the most significant disadvantage is that despite experimenters' best attempts to habituate animals to the procedure before conditioning, novelty-seeking effects can skew the data.Hughes RN (1968) Behavior of male and female rats with free choice of two environments differing in novelty. Animal Behavior 16:92–96; Bardo MT, Bowling SL, Robinet PM, Rowlett JK, Lacy M, Mattingly BA (1993) Role of D1 and D2 receptors in novelty-maintained place preference. Exp Clinical Psychopharmacology 1:101–109. Also, without a clear control of several variables that may interfere with the outcomes, such as the animal's strain, age, weight and housing, results from different studies may be difficult to compare, as the different outcomes may seem to contradict each other.
Another limitation of the procedure is the distinction between a biased and an unbiased CPP apparatus. Some authors indicate the importance of declaring in the publication, which type of CPP box has been used.Cunningham, C.L., Ferree, N.K. & Howard, M.A. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology 170, 409–422