Conditioned place preference

Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences.[1] 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.[2][3] 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 is injected.[4] This method allows the animal to choose the compartment they get the drug and vehicle in. In comparison, the unbiased method does not allow the animal to choose what compartment they get the drug and vehicle in and instead the researcher chooses the compartments.[4]

Humans have also been shown to develop conditioned place preferences; for example, individuals taking therapeutic doses of amphetamine develop a CPP for where they consumed the drug.[5][6]

Conditioned place preference apparatus
Different floor textures in conditioned place preference

Conditioning procedure

Conditioned place preference protocol

As in Pavlovian conditioning, an initially 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,[7] water,[8] sweet fluid,[9] novel toys,[10] social interaction,[11] drug intoxication, drug withdrawal, foot shock, illness, wheel running[12] or copulation.[13] 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.[14]

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 texture may be used to ensure the animal can discriminate between the compartments.[14]

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.[14] This is done to reduce the effects of novelty and usually consists of one five-minute trial.[14]

Preference testing

In the preference testing phase the animal is allowed barrier free access to all compartments of the apparatus.[15] Time spent in each compartment is measured either by the experimenter or by motion detecting software; often the mean seconds per minute spent in each compartment is calculated.[14] Statistical testing is used to determine whether the time difference is large enough, in comparison to the control group, to conclude that conditioned place preference or aversion has occurred.[14] Strength of conditioning is inferred by the magnitude of the difference or in the amount of time taken for the response to show extinction.[14]

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.[14] In this phase of the procedure the animal is only allowed access to one compartment of the apparatus.[15] This compartment will become associated with the motivational effects of the unconditioned stimulus.[1] The environment will come to elicit approach or avoidance-withdrawal depending on the nature of the unconditioned stimulus. The conditioning procedure usually consists of eight or more five-minute sessions.

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.[14] Alternatively, when the unconditioned stimulus is aversive, rodents will be more likely to escape and avoid the compartment that contains cues associated with it.[14] Timing of presentation of the unconditioned stimulus can determine whether place preference or aversion will be conditioned.[1] 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.[1] However, if the animal is given the drug and then the experimenter implements a sufficient delay so that the animal is experiencing the negative after effects of the drug, conditioned place aversion is more likely to occur.[1] The timing of these events can be manipulated by the experimenter in order to condition place preference or avoidance.[1]

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.[14] In some cases conditioning can occur with two stimulus-context pairings.[16] It allows both rewarding and aversive effects to be tested and it provides unique information about the motivational effects of unconditioned stimuli.[1][14] 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.[17][18]

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.[14] The testing is also sensitive to the effects of low drug doses.[14] 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.[15] This can be done by varying the time of drug administration in relation to presentation of the to-be-conditioned context.[19] The procedure also can be utilized to measure the neural circuits involved in drug reward.[20]

Disadvantages

The conditioned place preference and aversion protocol is 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.[21]

Another limitation of the procedure is the distinction between a biased and an unbiased CPP-apparatus. Some authors indicate the importance to declare in the publication, which type of CPP-box has been used.[22] Thus a pretest is needed to define a possibly existing preference to 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 an 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 antiaversive e€ffects of drugs independently from potential genuine rewarding e€ffects.[23]
In addition, individuals who will be handling animals must be trained to do this consistently so as to minimize stress to the animal.[14] It has been shown that stressful handling in rodents can weaken conditioning.[24]

There is debate over whether or not the results obtained from drug studies can be generalized to drug reward in humans.[15] It has been claimed that since the animal passively receives the drug, it cannot be compared.[25]

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 aversives or appetitive stimulus is greatly reduced, thus diminishing the place preference or aversion.[26] 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.[27]

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 is a topic of debate.[28] Reinstatement is the rapid reacquisition of an extinguished 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 completely eliminate an association, since the association between the UCS and the CS can be rapidly reacquired.[29] In the context of conditioned place preference, after a place preference has been extinguished, the behavior is said to be reintsated 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.[1]

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. 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.[30] Drug-primed reinstatement has been tested in CPP primarily with psychostimulants and opiates.[1] 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[30] Drug-primed reinstatement of cocaine has shown to also be reinstated by administration of similar psychostimulants including methamphetamine and methylphenidate[31] 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 drugs rewarding effects. This is also the case with morphine. Administration of morphine, heroin and cocaine induce reinstatement or morphine induced CPP.[32]

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[33] 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.[34]

When rats experience stress in the form of foot-shock or noise, changes occur in the norepinephrine system and the hypothalamic-pituitary-adrenal axis. These changes have a high impact on the reinstatement 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 neurotransmitter in the hypothalamic regions of the brain to mediate stress-induced changes in brain activity[35] 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.[35] 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 neurotrasmitter noradrenaline also plays a role in stress induced reinstatement.[36] Blockage of certain noradrenergic receptors inhibit stress-induced reinstatement. Furthermore, disinhibition of areas of the brain which inhibit the release or noradrenaline also nullify 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 treatment of addiction research in humans. Reinstatement studies on stress and drug primes provide evidence for their role in relapse behavior in humans.[28] In addition to conditioned placed preference, animal testing using self-administration procedures have also been used to examine potential causes of relapse in humans. Stress and drug-primes have also shown to contribute to relapse behaviour in humans.[37] 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 their 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.[32] Researchers use the reinstatement procedure to test the ability of certain drugs to 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.[38] 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

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 researches to study the effects of certain genes missing and the implications of missing genes on physiology and behaviour.

Cocaine

Genetic knockouts of the dopamine transporter failed to eliminate the conditioned place preference of cocaine implicating there may be different mechanisms of cocaine's reinforcing properties.[39] Mice lacking the noradrenaline transporter and serotonin transporter separately or at the same time demonstrated an enhanced conditioned place preference.[39] No conditioned place preference was found in knockout mice lacking serotonin receptor 5-HT1B.[40]

Nicotine

Genetic knockouts of nicotinic receptor subunit β2 in mice resulted in a lack of conditioned place preference.[41] This further compiling information of the importance of the nAChR subunit β2 in nicotine's reinforcing properties. Studies also show a lack of conditioned place preference in CB1 receptor knockout mice,[42] implicating a possible contribution of the endocannabinoid system.

Ethanol

Genetic knockouts of the dopamine D2 receptor[43] and vesicular monoamine transport 2 (VMAT2)[44] exhibited a lack of conditioned place preference. Mice lacking the mu opioid receptor exhibited a lack of conditioned place preference.[45] Knockouts of CB1 cannabinoid receptor demonstrated a lack of conditioned place preference.[46] Ethanol appears to have a widespread action on the brain through the many different mechanisms of the drug.

See also

References

  1. 1 2 3 4 5 6 7 8 9 Tzschentke, T.(2007). Measuring reward with the conditioned place preference(CPP) paradigm: update of the last decade. Addiction Biology. 12, 227-462.
  2. ↑ Campbell J., Wood R., Spear L. (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav 68:487–493
  3. ↑ 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.
  4. 1 2 Prus, AJ., James, JR., Rosecrans, AJ.(2009). Methods of Behavioral Analysis in Neuroscience. Augusta, CRC press.
  5. ↑ Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (2011). Castells X, ed. "Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults". Cochrane Database Syst. Rev. (6): CD007813. doi:10.1002/14651858.CD007813.pub2. PMID 21678370. Nevertheless, we deemed blinding to be at unclear risk of bias in all of them because amphetamines have powerful subjective effects that may reveal the assigned treatment (Johanson 1980; Wachtel 1992; Makris 2004; Makris 2007; Childs 2009). ...
    Childs 2009
    Childs E, De Wit H. Amphetamine-induced place preference in humans. Biological Psychiatry
  6. ↑ Childs E, de Wit H (2009). "Amphetamine-induced place preference in humans". Biol. Psychiatry. 65 (10): 900–4. doi:10.1016/j.biopsych.2008.11.016. PMC 2693956Freely accessible. PMID 19111278. 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.
  7. ↑ Spyraki C, Fibiger HC, Phillips AG (1982) Attenuation by haloperidol of place preference conditioning using food reinforcement. Psychopharmacology 77:379–382.
  8. ↑ 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
  9. ↑ Ågmo A, Marroquin E (1997) Role of gustatory and postingestive actions of sweeteners in the generation of positive affect as evaluated by place preference conditioning. Appetite 29:269– 289
  10. ↑ 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
  11. ↑ Calcagnetti DJ, Schechter MD (1992) Place conditioning reveals the rewarding aspect of social interaction in juvenile rats. Physiol Behav 51:667–672
  12. ↑ Antoniadis EA, Ko CH, Ralph MR, McDonald RJ (2000) Circadian rhythms, aging and memory. Behav Brain Res (in press)
  13. ↑ 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.
  14. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Cunningham, C., Gremel, C. & Groblewski, P. (2006). Drug-induced conditioned place preference and aversion in mice. Nature Protocols, 1(4), 1662-1670.
  15. 1 2 3 4 Bardo, M. & Bevins, R. (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology. 153, 31-43.
  16. ↑ 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 (Berl.) 160, 414–424 (2002).
  17. ↑ Hughes RA, Baker MR, Rettig KM (1995) Cocaine-conditioned place preference in young precocial domestic fowl. Exp Clinical Psychopharmacology 3:105–111.
  18. ↑ Meisel, R. & Joppa, M. (1993). Conditioned place preference in female hamsters following aggressive or sexual encounters. Physiology and behaviour, 56(5), 1115-1118.
  19. ↑ 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 (Berl.) 92, 376–381 (1987).
  20. ↑ 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).
  21. ↑ 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 noveltymaintained place preference. Exp Clinical Psychopharmacology 1:101–109.
  22. ↑ Cunningham, C.L., Ferree, N.K. & Howard, M.A. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl.) 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).
  23. ↑ 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
  24. ↑ 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).
  25. ↑ Dworkin, S. & Smith, J. in NIDA Research Monograph (ed. Harris, L.S.) 266–274. (US Department of Health and Human Services, Rockville, MD, 1988).
  26. ↑ Cherry, K. (2012). What is extinction?. Retrieved from http://psychology.about.com/od/eindex/g/extinction.htm
  27. ↑ Bahi, A. (2012) The selective metabatropic glutamate receptor 7 allosteric agonist AMN082 prevents reinstatement of extinguished ethanol induced conditioned place preference in mice. Pharmacology, Biochemistry and Behaviour. 101, 93-100.
  28. 1 2 Katz, JL, Higging, ST(2003). The validity of the reinstatement model of craving and relapse to drug use.Psychopharmacology.168, 21-30.
  29. ↑ Bouton, M.(2007). Learning and Behavior. A contemporary synthesis. Massachusetts: Sinauer Associates, Inc. Publishers.
  30. 1 2 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
  31. ↑ Itzhak, Y.,Martin, J.(2001). Cocaine-induced Conditioned Place Preference in Mice: Induction, Exctinction and Reinstatement by Related Psychostimulants. Neuropsychopharmacology. 26(1), 130-134.
  32. 1 2 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.
  33. ↑ 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.
  34. ↑ Wang, B., Luo, F., Zhang, W., Han, J.(2000). Stress or drug priming induces reinstatment of extinguished conditioned place preference. Neuroreport. 11(1221), 2781-2784.
  35. 1 2 Erb, S., Salmaso, N., Rodaros, d., Stewart, J.(2001). A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 158, 360-365.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ Biala, GG., Staniak, NN., Budzynska, BB.(2010). Effects of varenicline and mecamylamineon the acquisition, expression, and reinstatement of nicotine conditioned place preference by drug priming in rats. Naunyn-Schmied Arch Pharmacol. 381, 361-370.
  39. 1 2 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ Castane, A., Valjent, E., Ledent, C., Parmentier, M., Maldonado, R., & Valverde, O. (2002).Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology, 43, 857-867.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ Thanos, P.K., Dimitrakakis, E.S., Rice, O., Gifford, A., & Volkow, N.D. (2005). Ethanol self-administration and ethanol conditioned place pref-erence are reduced in mice lacking cannabinoid CB1 receptors. Behavioural Brain Research, 164, 206–213.
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