Conditioned place preference
Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. 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. 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. 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.
- 1 Conditioning procedure
- 2 Advantages and disadvantages
- 3 Extinction and reinstatement procedures
- 4 Pharmacological effects
- 5 Knockout mice
- 6 See also
- 7 References
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, water, sweet fluid, novel toys, social interaction, drug intoxication, drug withdrawal, foot shock, illness, wheel running or copulation. 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.
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.
Steps to conditioning place preference or aversion
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. This compartment will become associated with the motivational effects of the unconditioned stimulus. 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.
In the preference testing phase the animal is allowed barrier free access to all compartments of the apparatus. 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. 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. Strength of conditioning is inferred by the magnitude of the difference or in the amount of time taken for the response to show extinction.
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. 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 after effects 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
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. 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.
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 presentation of the to-be-conditioned context. The procedure also can be utilized to measure the neural circuits involved in drug reward.
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.
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. 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 effects of drugs independently from potential genuine rewarding effects.
In addition, individuals who will be handling animals must be trained to do this consistently so as to minimize stress to the animal. It has been shown that stressful handling in rodents can weaken conditioning.
There is debate over whether or not the results obtained from drug studies can be generalized to drug reward in humans. It has been claimed that since the animal passively receives the drug, it cannot be compared.
Extinction and reinstatement procedures
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. 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.
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. 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. 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.
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. Drug-primed reinstatement has been tested in CPP primarily with psychostimulants and opiates. 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 Drug-primed reinstatement of cocaine has shown to also be reinstated by administration of similar psychostimulants including methamphetamine and methylphenidate 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.
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 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.
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 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. 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. 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.
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. 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. 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. 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. 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.
Dopaminergic drugs are drugs that primarily act on the neurotransmitter dopamine. They can act on D1-like receptors (D1 and D5) and/or D2-like receptors (D2, D3, and D4), which are all metabotropic receptors. They may also act on the synthesis, release, and enzymes of dopamine.
Amphetamine is a psychomotor stimulant that functions by diffusing through the dopamine transporter into the cell. When entering the cell amphetamine reverses the directionality of the dopamine transporter, which does not allow the reuptake of dopamine, but allows dopamine to exit the presynaptic cell. It also pushes dopamine out of the vesicles in the presynaptic cell and dopamine is released through the reversed dopamine transporter. This overall process increases the amount of dopamine in the synapse by pushing dopamine out the presynaptic cell and blocking the reuptake of the neurotransmitter. At high doses amphetamine has been shown to also inhibit monoamine oxydase A reducing the degradation of dopamine.
Studies show that intravenous injections of amphetamines exhibit a conditioned place preference at a range of 1–3 mg/kg of the drug. Intracranial injections of amphetamine directly in the nucleus accumbens and intracerbroventricular injections induce a conditioned place preference at certain dosages. Studies show that haloperidol (antipsychotic, & D1/D2 receptor antagonist), α-Flupenthixol (D1/D2 receptor antagonist) and diazepam block conditioned place preference.
Lesion studies have been preformed to measure the direct effects of amphetamine on certain brain areas and their involvement in reinforcement. 6-Hydroxydopamine (6-OHDA) lesions were made to the nucleus accumbens and there was a lack of conditioned place preference shown to amphetamine. Lesions to the pendunculopontine tegmental nucleus were performed through bilateral N-methyl-D-aspartate (NDMA) lesions leading to no conditioned place preference.
Apomorphine is a D1-like and D2-like receptor agonist and it is an emetic drug. Apomorphine displays a conditioned place preference when injected subcutaneous within a range of 5–10 mg/kg. When apomorphine was injected subcutaneous in combination with 7-OH-DPAT (D3 receptor agonist) there was an enhancement of conditioned place preference for apomorphine.
Cocaine is psychomotor stimulant that blocks the monoamine transporter and in turn blocks the reuptake of dopamine, noradrenaline, and serotonin. This causes an increase of monoamines in the synapse. High cocaine use can induce "cocaine psychosis" and is often mistaken for paranoid schizophrenia with similar symptoms. Both are associated with an increase in dopamine. Cocaine has a very addictive property to it, with the initial high experienced dropping off very fast as the drug half life is very short as well. Cocaine's high follows the curve of the cocaine being removed from the body, which gives more motivation to binge and more doses are needed to continuously re-experience the initial high. Cocaine's reinforcing property is mainly related to its effect on the mesolimbic system and this system includes the ventral tegmental area's projection to the nucleus accumbens, which has been associated with dopamine's function on reward.
A conditioned place preference was demonstrated in rats with an intravenous injection of 0.25-0.5 mg/kg of cocaine. Cocaine has demonstrated a conditioned place preference with intracranial injections into the nucleus accumbens shell and olfactory tubercle. This finding further implicating cocaine's reinforcing affects on the nucleus accumbens through the mesolimbic system. Studies show the conditioned place preference of cocaine appears to be blocked by a variety of drugs including mecamylamine, scopolamine, and caffeine. The specific dosages administered established if the conditioned place preference was blocked. Lesion studies have been preformed to measure the effects certain areas have on the conditioned place preference of cocaine. There was a reduction of conditioned place preference with NDMA lesions to the dorsal hippocampus. NDMA lesions to the basolateral amygdala eliminated a conditioned place preference for cocaine as well. The basolateral amygdala has been associated with modulating the consolidation of memories through norepinephrines action on the basolateral amygdala.
Methylphenidate, or as it's more commonly known as Ritalin is a psychomotor stimulant that blocks the dopamine and norepinephrine transporter. By blocking the dopamine and norepinephrine transporter, the reuptake of dopamine and norepinephrine cannot occur. This causes an increase of dopamine and norepinephrine in the synapse. Methylphenidate functions in a similar way to cocaine. Methylphenidate has been primarily used in the treatment of ADHD. It has demonstrated a conditioned place preference at 5 mg/kg through intravenous and intraperitoneal injections. Even though the conditioned place preference of methylphenidate appears to show it has an addictive property, it does not display the same effects in humans. Methylphenidate demonstrates an initial high, but the high drops immediately and methylphenidate has a long half life with no high associated. Taking any further doses will not bring the high back because of the long half life of the drug, unlike cocaine with a shorter half life.
Cholinergic drugs are drugs that primarily act on the neurotransmitter acetylcholine. They can act on the muscarinic receptors (mAChR), which are metabotropic receptors and/or nicotinic receptors (nAChR), which are ionotropic receptors. They may also act on the synthesis, release, and enzymes of acetylcholine.
Nicotine is an agonist at nicotinic acetylcholine receptors. Nictonic receptors are widespread throughout the brain, but the specific reinforcing effects of nicotine has been implicated in acetylcholines projection to the ventral tegmental area. There are nAChRs in the ventral tegmental area, which is one of the main sites of dopamine production and it projects dopamine through the mesolimbic system consisting of projections to the nucleus accumbens. The projection from the ventral tegmental area to the nucleus accumbens has been primarily studied and associated with reward. In this case this projection has been implicated in nicotine's reinforcing properties. Specifically α6 and β2 nAchR subunits are found in the dopaminergic neurons and have been found to mediate nicotine's reinforcing effects on the mesolimbic system.
Nicotine has been shown to produce a conditioned place preference at specific doses, beyond these specific doses no conditioned place preference is displayed. Studies that have examined subcutaneous injections of nicotine in rats and mice have demonstrated a conditioned place preference from a range of 0.2 - 0.6 mg/kg. Studies that have examined intraperitoneal injections in rats and mice have shown a conditioned place preference around 1 mg/kg. The exact dosages that produced a conditioned place preference varied across studies. Intracranial injections of nicotine directly into the ventral tegmental area produced a conditioned place preference, further implicating the effects of nicotine on the mesolimbic system.
Through combinations of drugs with nicotine, there has been evidence that drugs can block the conditioned place preference of nicotine. Nicotine induced conditioned place preference appears to be blocked consistently by naloxone (opioid receptor antagonist) and mecamylamine (nicotinic receptor antagonist), but appears to be dose dependent for both drugs. Mecamylamine blocks the conditioned place preference of nicotine due to being an nAChR antagonist blocking the binding of nicotine.
GABAergic drugs are drugs that primarily act on the neurotransmitter GABA(gamma-aminobutyric acid).They can act on the GABAA receptors, which are ionotropic receptors and/or GABAB receptors, which are metabotropic receptors. They may also act on the synthesis, release, and enzymes of GABA.
Diazepam (Valium) is a benzodiazepine and an agonist at GABAA receptors. Studies of conditioned place preference with diazepam have shown conflicting results with some finding no evidence of conditioning and other studies demonstrating conditioned place preference with intraperitoneal injections around 2.5 to 5 mg/kg of the drug. Evidence debates the conditioned place preference of diazepam.
Muscimol is an agonist at GABAA receptors. Intracranial injections of muscimol into the ventral tegmental area produces a conditioned place preference . α-Flupenthixol, which is a D1/D2 dopamine receptor antagonist has been shown to block the conditioned place preference of intracranial injections of muscimol into ventral tegmental area. Blocking the dopamine receptors with α-Flupenthixol appears to block the reinforcing effects of muscimol.
Ethanol is a psychoactive alcohol. Ethanol is an agonist at GABAA receptors causing a hyperpolarization of the postsynaptic cell. This hyperpolarization causes an inhibitory effect and this explains the sedative properties of alcohol. Ethanol's reinforcing effects have been associated with the ventral tegmental area and its projections to the nucleus accumbens. GABA and opioid receptors are thought to mediate ethanol's effects. Many conditioned place preference studies have been documented under different conditions with most injections of ethanol being interperitonally into rats and mice with most studies finding a conditioned place preference. Intracranial injections of methylnaloxonium (opioid receptor antagonist) or baclofen (GABAB receptor agonist) into the ventral tegmental area reduced the conditioned place preference of ethanol.
Serotonergic drugs refer to drugs that interact with the neurotransmitter serotonin and its respective receptors. Generally, serotonergic drugs influence CPP with drugs that have the highest selectivity for the serotonin transporter producing the most profound CPP. These drugs include sertraline, paroxetine, fluoxetine, etc.
Many recreational and psychoactive drugs have a large impact on the dopamine and serotonin systems in the brain. Lysergic acid (LSD) is one of these drugs and an interesting finding by Meehan and Schechter in 1998 demonstrated that LSD produced CPP in male rats, but not in female rats. Another example of a drug that interferes with the serotonin system is cocaine. Cocaine has been demonstrated to produce CPP, and this could possibly be due to the effect of the drug on the serotonin system.
Also, serotonin receptor antagonists have been researched with CPP influenced by recreational drugs. However, in one study testing MDMA-induced CPP, there was no effect of a serotonin 1 & 2 receptor antagonist metergoline.
Glutamatergic drugs refer to drugs that interact with the glutamate-neurotransmitter system. This particular neurotransmitter system has been demonstrated to be an important part of reinstatement of the opiate-influenced CPP. Glutamatergic antagonists (such as memantine and dizocilpine) blocked the reinstatement of morphine-produced CPP. The effect of glutamatergic antagonists on CPP may be on the disruption of processing of conditioned responses, therefore impairing drug-related associations and their reconsolidation.
Glutamatergic antagonists have also been reported to have an effect on cocaine-induced CPP. Memantine was shown to block CPP produced by cocaine. In this study, animals did not approach cues that were associated with cocaine when NMDA receptors had glutamate transmission blocked. This suggests that glutamatergic antagonists may aid in extinguishing drug-seeking behaviour.
Noradrenergic drugs are drugs that influence the areas of the body and nervous system that utilize noradrenaline (or norepinephrine). Norepinephrine is a catecholamine that has many functions, including a hormone and neurotransmitter function.
Norandrenergic drugs when used in isolation have generally not been associated with the development of CPP. For example, desipramine and imipramine (both tricyclic antidepressants) have been demonstrated to have no influence on CPP. Also, neither phenylephrine (an alpha-1 receptor agonist) nor prazosin (an alpha-1 receptor antagonist) produced any effect on CPP.
However, a 2003 study by Lebedev and their colleagues demonstrated that phenamine (a drug which has a similar action to epinephrine) did in fact produce CPP. Also, norepinephrine has been shown to be involved in opiate-influenced CPP. For example, morphine causes an increased amount of norepinephrine leaving the medial prefrontal cortex which has a direct impact on the amount of dopamine leaving the nucleus accumbens. This suggests that norepinephrine plays an important role in developing and maintaining opiate-induced CPP.
Opiates refer to a classification of drugs that are derived from the opium plant. These drugs bind to opioid receptors in the peripheral and central nervous systems producing analgesic effects. Many opiates have been demonstrated to produce CPP in animals. For example, morphine, heroin, and fentanyl have been shown to produce conditioned place preference.
Although opiates seem to induce CPP, there are a few interactive effects that are of interest to researchers. For example, a study comparing CPP effects of morphine on aggressive versus non-aggressive male mice demonstrated that it was only the non-aggressive mice which showed CPP. Also, it has been demonstrated that rats that are exposed to electric footshock or fear-stress prior to conditioning sessions showed no opiate-induced CPP.
Opioid-antagonists have been demonstrated to have interactive effects with CPP created by other substances. For example, ethanol-influenced CPP was inhibited by opioid antagonists (such as nalaxone) and arodyn (a kappa-opioid receptor antagonist) inhibited the reinstatement of cocaine-produced CPP. Results like these suggest that opioid-receptor antagonists may be useful in treatment of relapse of substances such as cocaine.
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.
Genetic knockouts of the dopamine transporter failed to eliminate the conditioned place preference of cocaine implicating there maybe different mechanisms of cocaine's reinforcing properties. Mice lacking the noradrenaline transporter and serotonin transporter separately or at the same time demonstrated an enhanced conditioned place preference. No conditioned place preference was found in knockout mice lacking serotonin receptor 5-HT1B.
Genetic knockouts of nicotinic receptor subunit β2 in mice resulted in a lack of conditioned place preference. 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, implicating a possible contribution of the endocannabinoid system.
Genetic knockouts of the dopamine D2 receptor and vesicular monoamine transport 2 (VMAT2) exhibited a lack of conditioned place preference. Mice lacking the mu opioid receptor exhibited a lack of conditioned place preference. Knockouts of CB1 cannabinoid receptor demonstrated a lack of conditioned place preference. Ethanol appears to have a widespread action on the brain through the many different mechanisms of the drug.
- Classical conditioning
- Operant conditioning
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