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((Short description|Pavlovian conditioning))
((technical|date=October 2012))

'''Conditioned place preference''' (CPP) is a form of [[Classical conditioning|Pavlovian conditioning]] used to measure the motivational effects of objects or experiences.<ref name="Tzschentke2007"/> This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of the context that surrounded the "encounter".<ref>((Cite journal |last1=Spencer |first1=Alexis C. |last2=Surnar |first2=Bapurao |last3=Kolishetti |first3=Nagesh |last4=Toborek |first4=Michal |last5=Dhar |first5=Shanta |date=2022-12-01 |title=Restoring the neuroprotective capacity of glial cells under opioid addiction |journal=Addiction Neuroscience |language=en |volume=4 |pages=100027 |doi=10.1016/j.addicn.2022.100027 |s2cid=250193516 |issn=2772-3925|doi-access=free ))</ref> 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.<ref>((Cite journal|last1=Childs|first1=Emma|last2=Wit|first2=Harriet de|title=Amphetamine-Induced Place Preference in Humans|journal=Biological Psychiatry|volume=65|issue=10|pages=900–904|doi=10.1016/j.biopsych.2008.11.016|pmid=19111278|pmc=2693956|year=2009))</ref> This paradigm can also be used to measure conditioned place aversion with an identical procedure involving aversive stimuli instead.  Both procedures usually involve mice or rats as subjects.<ref>Campbell J., Wood R., Spear L. (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav 68:487–493</ref><ref>Adriani 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.</ref> This procedure can be used to measure extinction and [[Wikipedia:School and university projects/Psyc3330 w12/Group09#Extinction and Reinstatement Procedures|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 is injected.<ref name="Prus, AJ. 2009">Prus, AJ., James, JR., Rosecrans, AJ.(2009). Methods of Behavioral Analysis in Neuroscience.  Augusta, CRC press.</ref> 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.<ref name="Prus, AJ. 2009"/>

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.<ref name="Human CPP">((cite journal | vauthors = Childs E, de Wit H | title = Amphetamine-induced place preference in humans | journal = Biol. Psychiatry | volume = 65 | issue = 10 | pages = 900–4 | year = 2009 | pmid = 19111278 | pmc = 2693956 | doi = 10.1016/j.biopsych.2008.11.016 | quote = This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.))</ref><ref>((Cite journal|last1=Castells|first1=Xavier|last2=Blanco-Silvente|first2=Lídia|last3=Cunill|first3=Ruth|date=2018|title=Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=8|pages=CD007813|doi=10.1002/14651858.CD007813.pub3|issn=1469-493X|pmc=6513464|pmid=30091808))</ref>
[[File:Conditioned Place Preference Apparatus.jpeg|thumb|405px|Conditioned place preference apparatus]]
[[File:Conditioned Place Preference - Floor Texture.JPG|thumb|300px|Different floor textures in conditioned place preference]]

==Conditioning procedure==
[[File:Infographic on Conditioned Place Preference.png|thumb|350px|Conditioned place preference protocol]]

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,<ref>Spyraki C, Fibiger HC, Phillips AG (1982) Attenuation by haloperidol of place preference conditioning using food reinforcement. Psychopharmacology 77:379–382.</ref> water,<ref>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</ref> sweet fluid,<ref>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</ref> novel toys,<ref>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</ref> social interaction,<ref>Calcagnetti DJ, Schechter MD (1992) Place conditioning reveals the rewarding aspect of social interaction in juvenile rats. Physiol Behav 51:667–672</ref> drug intoxication, drug withdrawal, foot shock, illness, wheel running<ref>Antoniadis EA, Ko CH, Ralph MR, McDonald RJ (2000) Circadian rhythms, aging and memory. Behav Brain Res (in press)</ref> or copulation.<ref>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.</ref>  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 [[Scientific control|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 (medicine)|saline]] or nothing to control for all elements of the procedure.<ref name="cunningham2006">Cunningham, C., Gremel, C. & Groblewski, P. (2006). Drug-induced conditioned place preference and aversion in mice. Nature Protocols, 1(4), 1662-1670.</ref>

===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.<ref name="cunningham2006"/>

===Steps to conditioning place preference or aversion===
Conditioned place preference involves three phases: [[habituation]], conditioning, and [[Preference tests (animals)|preference testing]].

====Habituation====
In the habituation procedure, the animal is given a chance to explore the apparatus.<ref name="cunningham2006"/> This is done to reduce the effects of novelty and usually consists of one five-minute trial.<ref name="cunningham2006"/>

====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.<ref name="cunningham2006"/> In this phase of the procedure the animal is only allowed access to one compartment of the apparatus.<ref name="Bardo, M. 2000">Bardo, M. & Bevins, R. (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology. 153, 31-43.</ref>  This compartment will become associated with the motivational effects of the unconditioned stimulus.<ref name="Tzschentke2007"/> 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.<ref name="Bardo, M. 2000"/> During the test, the time a subject spends in each compartment is measured in seconds.<ref name="cunningham2006"/> 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).<ref name="cunningham2006"/> Strength of conditioning is inferred by the magnitude of the difference or in the amount of time taken for the response to show [[Extinction (psychology)|extinction]].<ref name="cunningham2006"/>

===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.<ref name="cunningham2006"/> Alternatively, when the unconditioned stimulus is aversive, rodents will be more likely to escape and avoid the compartment that contains cues associated with it.<ref name="cunningham2006"/> The timing of presentation of the unconditioned stimulus can determine whether place preference or aversion will be conditioned.<ref name="Tzschentke2007"/>  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.<ref name="Tzschentke2007"/>  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.<ref name="Tzschentke2007"/>   The timing of these events can be manipulated by the experimenter in order to condition place preference or avoidance.<ref name="Tzschentke2007"/>

==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.<ref name="cunningham2006"/>  In some cases conditioning can occur with two stimulus-context pairings.<ref>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).</ref>  It allows both rewarding and aversive effects to be tested and it provides unique information about the motivational effects of unconditioned stimuli.<ref name="Tzschentke2007"/><ref name="cunningham2006"/> 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.<ref>Hughes RA, Baker MR, Rettig KM (1995) Cocaine-conditioned place preference in young precocial domestic fowl. Exp Clinical Psychopharmacology 3:105–111.</ref><ref>Meisel, R. & Joppa, M. (1993). Conditioned place preference in female hamsters following aggressive or sexual encounters. Physiology and behaviour, 56(5), 1115-1118.</ref>

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.<ref name="cunningham2006"/>  The testing is also sensitive to the effects of low drug doses.<ref name="cunningham2006"/> 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 [[Drug withdrawal|withdrawal]].<ref name="Bardo, M. 2000"/>  This can be done by varying the time of drug administration in relation to the presentation of the to-be-conditioned context.<ref>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).</ref>  The procedure also can be utilized to measure the neural circuits involved in drug reward.<ref>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).</ref>

===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.<ref>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.</ref>

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.<ref>Cunningham, C.L., Ferree, N.K. & Howard, M.A. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology 170, 409–422
(2003); Bevins, R.A. & Cunningham, C.L. in Tasks and Techniques: A Sampling of Methodologies for the Investigation of Animal Learning, Behavior, and Cognition (ed. Anderson, M.J.) ([[Nova Science Publishers, Inc.]], Hauppauge, NY, in the press).</ref> Thus a pretest is needed to define a possibly existing preference for one compartment. In a biased context, it is to show an absolute CPP to the initially non-preferred place. Otherwise, for instance, when anxiolytic drugs are used as the rewarding agent, we can interpret only relative place preference to be derived from the anxiolytic effect of the drug. On the other hand, with a biased design, we can distinguish between the anxiolytic and anti-aversive effects of drugs independently from potential genuine rewarding effects.<ref>Tzschentke T.M. in Progress in Neurobiology (1998): Measuring reward with the conditioned place preference paradigm: A comprehensive review of drug effects. Recent progress and new issues. p.216-217</ref>
<br />
In addition, individuals who will be handling animals must be trained to do this consistently so as to minimize stress on the animal.<ref name="cunningham2006"/>  It has been shown that stressful handling in rodents can weaken conditioning.<ref>Bechtholt, A.J., Gremel, C.M. & Cunningham, C.L. Handling blocks expression of conditioned place aversion but not conditioned place preference produced by ethanol in mice. Pharmacol. Biochem. Behav. 79, 739–744 (2004).</ref>

There is debate over whether or not the results obtained from drug studies can be generalized to drug reward in humans.<ref name="Bardo, M. 2000"/>  It has been claimed that since the animal passively receives the drug, it cannot be compared.<ref>Dworkin, S. & Smith, J. in NIDA Research Monograph (ed. Harris, L.S.) 266–274. (US Department of Health and Human Services, Rockville, MD, 1988).</ref>

==Extinction and reinstatement procedures==

===Extinction===
Extinction in the conditioned place preference paradigm is the process by which the association of the place compartment with the paired [[aversive]]s or appetitive stimulus is greatly reduced, thus diminishing the place preference or aversion.<ref>Cherry, K. (2012). What is extinction? Retrieved from http://psychology.about.com/od/eindex/g/extinction.htm ((Webarchive|url=https://web.archive.org/web/20110821053337/http://psychology.about.com/od/eindex/g/extinction.htm |date=2011-08-21 ))</ref> Extinction occurs when the [[conditioned stimulus]] is presented on repeated trials without the presence of the appetitive or aversive stimulus. For example, if the animal had been given a reinforcing food stimulus when in one place compartment and established a preference for this place, the extinction process would be implemented by placing the animal in the compartment but not giving it the reinforcing food stimulus (unconditioned stimulus) while it was in the compartment. The extinction process can be used with [[knockout mice]] to establish whether certain receptors are particularly involved in the extinction process. Extinction is also used by researchers to study different forms of reinstatement.<ref>Bahi, A. (2012) The selective metabotropic glutamate receptor 7 allosteric agonist AMN082 prevents reinstatement of extinguished ethanol-induced conditioned place preference in mice.  Pharmacology Biochemistry and Behavior. 101, 93-100.</ref>

===Reinstatement===
Reinstatement is a method used in animal testing procedures including CPP and [[self-administration]]. It is often used to model the behavior of drug [[relapse]] in humans, although its [[Validity (logic)|validity]] is a topic of debate.<ref name="katz2003"/>  Reinstatement is the rapid reacquisition of an extinct behavior, which is caused by either the presentation of the [[unconditioned stimulus]], by stress, or by context cues. This shows that the process of extinction does not eliminate an association, since the association between the UCS and the CS can be rapidly reacquired.<ref>Bouton, M.(2007). Learning and Behavior. A contemporary synthesis. Massachusetts: Sinauer Associates, Inc. Publishers.</ref> In the context of conditioned place preference, after a place preference has been extinguished, the behavior is said to be reinstated when the animal quickly reacquires their place preference after repeated extinction trials have caused the preference to be extinguished. This has implications for research on drug relapse. There are two main modes of action for which reinstatement is often tested in the conditioned place preference paradigm. One is by introducing the animal (generally rats or mice are used) to stress. The other is by giving them a small dose of the unconditioned stimulus. In the case of CPP, when drugs are used to establish conditioned place preference, this is called drug priming.<ref name="Tzschentke2007">Tzschentke, T.(2007). Measuring reward with the conditioned place preference(CPP) paradigm: update of the last decade. Addiction Biology. 12, 227-462.</ref>

====Primed induced reinstatement====

Primed-induced Reinstatement is a test in CPP whereby the unconditioned stimulus is given to the animal after the association between the UCS and CS has been extinguished. The administration of the UCS primes the association with the CS (place compartment) and stimulates the reacquisition of the place preference. Drugs of abuse such as cocaine and heroin have a particularly strong ability to be reinstated through priming, which is known as drug-primed reinstatement. Drug-primed reinstatement is thought to renew the incentive value of the place compartment because of the motivational effects of the drug.<ref name="brown2010">Brown RM, Short JL, Lawrence AJ (2010) Identification of Brain Nuclei Implicated in Cocaine-Primed Reinstatement of Conditioned Place Preference: A Behaviour Dissociable from Sensitization. PLoS ONE 5(12): e15889. ((doi|10.1371/journal.pone.0015889))</ref>  Drug-primed reinstatement has been tested in CPP primarily with [[psychostimulants]] and [[opiates]].<ref name="Tzschentke2007"/> Reinstatement with drug primes depends on the dose of the drug that is given to the animal. Small administrations of the drug-prime will generally not produce reinstatement whereas higher doses will. One area of the brain that is linked to reinstatement of place preference through drug priming is the lateral [[habenula]]<ref name="brown2010"/> Drug-primed reinstatement of cocaine has shown to also be reinstated by administration of similar psychostimulants including methamphetamine and methylphenidate<ref>Itzhak, Y., Martin, J.(2001). Cocaine-induced Conditioned Place Preference in Mice: Induction, Extinction and Reinstatement by Related Psychostimulants. Neuropsychopharmacology. 26(1), 130-134.</ref> All three of these psychostimulants increase the amount of [[dopamine]] in the [[nucleus accumbens]] by blocking [[reuptake]] of dopamine, which is presumed to mediate the drug's rewarding effects.  This is also the case with morphine. Administration of morphine, heroin, and cocaine induce reinstatement or morphine-induced CPP.<ref name="Xiu, NJ. 2002">Lu, L., Xiu, NJ., Ge, X., Yu, W., Su, WJ., Pei, G., Ma., L.(2002). Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization. Psychopharmacology. 159, 125-132.</ref>

====Stress induced reinstatement====

In the conditioned place preference paradigm, stress has been shown to reinstate conditioned place preferences in rats after the preference had been extinguished. This has implications for research on addiction because of the effect that stress has on human relapse behavior. Stress-induced reinstatement in CPP occurs when the animal is exposed to stress after a place preference has been extinguished. This exposure leads to reinstatement of the place preference. Common stressors used in these paradigms include foot shock and noise<ref>Lu, L., Shepard, J., Hall, F., Shaham, Y. (2003). Effect of Environmental stressors on opiate and psychostimulant reinforcement, reinstatement, and discrimination in rats: a review. Neuroscience and Behavioral Review. 27, 457-491.</ref>  Some studies have shown that when drugs of abuse are used as appetitive stimuli, exposure to stress can reinstate place preference that has been extinguished over two weeks.<ref>Wang, B., Luo, F., Zhang, W., Han, J.(2000). Stress or drug priming induces reinstatement of extinguished conditioned place preference. NeuroReport. 11(1221), 2781-2784.</ref>

When rats experience stress in the form of foot shock or noise, changes occur in the [[noradrenergic|norepinephrine]] system and the [[hypothalamic-pituitary-adrenal axis]]. These changes have a high impact on the reinstatement of conditioned place preference.  Stress stimulates the release of [[corticotropin-releasing hormone]] (CRH) from the rat's [[hypothalamus]] which leads to a series of changes through the pituitary gland in the brain to release [[glucocorticoids]] from the [[adrenal glands]]. CRH also stimulates the release of neurotransmitters in the hypothalamic regions of the brain to mediate stress-induced changes in brain activity<ref name="Erb, S. 2001">Erb, S., Salmaso, N., Rodaros, d., Stewart, J.(2001). A role for the CRF-containing pathway from the central nucleus of the amygdala to the bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine-seeking in rats. Psychopharmacology. 158, 360-365.</ref> This system plays a key role in the reinstatement of conditioned place preference. CRH acts as a neurotransmitter in regions of the brain including the bed nucleus of the [[stria terminalis]] and the [[amygdala]]. Reinstatement of conditioned place preference has shown to be blocked when antagonists for CRH receptors are injected into the BNST.<ref name="Erb, S. 2001"/> In other words, the effects of stress on reinstatement can be inhibited by blocking the receptor sites for CRH in certain areas of the brain. The neurotransmitter [[noradrenaline]] also plays a role in stress-induced reinstatement.<ref>Mantsch, J., Weyer, A., Vranjikovic, O., Beyer, C., Baker, D., Caretta, H.(2010). Involvement of the noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: Role of b-2 receptors. Neuropsychopharmacology. 35(2), 2165-2178.</ref> Blockage of certain noradrenergic receptors inhibits stress-induced reinstatement. Furthermore, disinhibition of areas of the brain that inhibit the release of noradrenaline also nullifies the effect of stress-induced reinstatement. Together, the noradrenaline and CRH systems play a key role in the stress-induced reinstatement of conditioned place preference and provide knowledge of the neurochemical basis of stress-induced relapse.

===Relapse===

Research on stress and drug-primed reinstatement has implications for the treatment of addiction research in humans. Reinstatement studies on stress and drug primes provide evidence for their role in relapse behavior in humans.<ref name="katz2003">Katz, JL, Higging, ST(2003). The validity of the reinstatement model of craving and relapse to drug use.Psychopharmacology.168, 21-30.</ref> In addition to conditioned placed preference, animal testing using [[self-administration]] procedures has also been used to examine potential causes of relapse in humans. Stress and drug primes have also been shown to contribute to relapse behavior in humans.<ref>Stewart, J.(2000). Pathways to relapse: the neurobiology of drug and stress-induced relapse to drug taking. Journal of Psychiatry and Neuroscience.25(2), 125-136.</ref> With the knowledge that stress and drug primes contribute to relapse behavior, measures to avoid stressful situations can help addicts avoid returning to their addictive behaviors. Drug priming is thought to induce relapse in humans because of its effects on the reward circuits of the brain. Repeated drug exposure is thought to sensitize the rewarding effect of the drug and exposure to the drug after extinction can reintroduce this rewarding effect. These effects play a key role in the persistence of drug-seeking behaviors.<ref name="Xiu, NJ. 2002"/> Researchers use the reinstatement procedure to test the ability of certain drugs to [[:wikt:inhibit|inhibit]] these different types of reinstatement. One such drug that has been shown to have attenuating effects on reinstatement is [[mecamylamine]]. This is a selective [[nicotinic acetylcholine receptor]] [[antagonist]] which, if administered after extinction trials, can block the reinstatement of the conditioned place preference for nicotine and opiates.<ref>Biala, GG., Staniak, NN., Budzynska, BB.(2010). Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats. Naunyn-Schmied Arch Pharmacol. 381, 361-370.</ref> Although direct causal linkages cannot be assumed between reinstatement in the conditioned place preference procedure and relapse in humans, it provides a solid first step in the process of creating drugs that may one day be used to treat relapse in humans.

==Knockout mice==
[[File:Maus-cat.jpg|thumb|230px|Knockout mice are used to demonstrate behavioural or physiological differences]]
[[Knockout mice]] are genetically modified mice that have had certain genes selectively removed. The removal of certain genes allows researchers to study the effects of certain genes missing and the implications of missing genes on physiology and behavior.

===Cocaine===
Genetic knockouts of the dopamine transporter failed to eliminate the conditioned place preference of cocaine, implying there may be different mechanisms of cocaine's reinforcing properties.<ref name="sora2001">Sora, I., Hall, F.S., Andrews, A.M., Itokawa, M., Li, X.F., Wei, H.B., Wichems, C., Lesch, K.P., Murphy, D.L., & Uhl, G.R. (2001). Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proceedings of the National Academy of Sciences of the United States of America, 98, 5300–5305.</ref> Mice lacking the [[noradrenaline transporter]] and [[serotonin transporter]] separately or at the same time demonstrated an enhanced conditioned place preference.<ref name="sora2001"/> No conditioned place preference was found in knockout mice lacking serotonin receptor [[5-HT1B receptor|5-HT<sub>1B</sub>]].<ref>Belzung, C., Scearce-Levie, K., Barreau, S., & Hen, R. (2000). Absence of cocaine-induced place conditioning in serotonin 1B receptor knock-out mice. Pharmacology Biochemistry and Behaviour, 66, 221–225.</ref>

===Nicotine===
Genetic knockouts of nicotinic receptor subunit [[CHRNB2|β<sub>2</sub>]]  in mice resulted in a lack of conditioned place preference.<ref>Walters, L., Brown, S., Changeux, J., Martine, B., & Damaj, M.I. (2006). The β2 but not α7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacology, 184, 339-344.</ref> This further compiling information on the importance of the nAChR subunit β<sub>2</sub> in nicotine's reinforcing properties. Studies also show a lack of conditioned place preference in [[Cannabinoid receptor type 1|CB<sub>1</sub> receptor]] knockout mice,<ref>Castane, A., Valjent, E., Ledent, C., Parmentier, M., Maldonado, R., & Valverde, O. (2002). Lack of CB1 cannabinoid receptors modifies nicotine behavioral responses, but not nicotine abstinence. Neuropharmacology, 43, 857-867.</ref> implicating a possible contribution of the [[endocannabinoid system]].

===Ethanol===
Genetic knockouts of the dopamine D<sub>2</sub> receptor<ref>Cunningham, C.L., Howard, M.A., Gill, S.J., Rubinstein, M., Low, M.J., & Grandy, D.K. (2000). Ethanol-conditioned place preference is reduced in dopamine D2 receptor-deficient mice. Pharmacology Biochemistry and Behaviour, 67, 693–699.</ref> and [[Vesicular monoamine transporter 2|vesicular monoamine transport 2]] (VMAT2)<ref>Savelieva, K.V., Caudle, W.M., & Miller, G.W. (2006). Altered ethanol-associated behaviors in vesicular monoamine transporter heterozygote knockout mice. Alcohol, 40, 87–94.</ref> exhibited a lack of conditioned place preference. Mice lacking the [[mu opioid receptor]] exhibited a lack of conditioned place preference.<ref>Hall, F.S., Sora, I., & Uhl, G.R. (2001). Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology, 154, 43–49.</ref> Knockouts of CB<sub>1</sub> cannabinoid receptor demonstrated a lack of conditioned place preference.<ref name="Thanos2005">Thanos, P.K., Dimitrakakis, E.S., Rice, O., Gifford, A., & Volkow, N.D. (2005). Ethanol self-administration and ethanol-conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behavioural Brain Research, 164, 206–213.</ref> Ethanol appears to have a widespread action on the brain through the many different mechanisms of the drug.

==See also==
* [[Classical conditioning]]
* [[Neuropharmacology]]
* [[Operant conditioning]]
* [[Paradigm]]
* [[Psychopharmacology]]
* [[Reinforcement]]
* [[Self-administration]]

==References==
((reflist|30em))

((Memory))
((Learning))

[[Category:Addiction]]
[[Category:Animal testing]]
[[Category:Laboratory techniques]]
[[Category:Learning]]
[[Category:Memory]]
[[Category:Neurotransmitters]]

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