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Neurobiological mechanisms of the reinstatement of drug-conditioned place preference
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Neurobiological mechanisms of the reinstatement of drug-conditioned place preference Maria A. Aguilar, Marta Rodríguez-Arias, Jose Miñarro⁎ Unidad de Investigación Psicobiologia de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain
A R T I C LE I N FO
AB S T R A C T
Article history:
Drug addiction is a chronic disorder characterized by a high rate of relapse following
Accepted 13 August 2008
detoxification. There are two main versions of the reinstatement model that are employed
Available online 18 August 2008
to study relapse to drug abuse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference procedure. In the last seven years,
Keywords:
the use of the latter version has become more widespread, and the results obtained
Conditioned place preference
complement those obtained in self-administration studies. It has been observed that the
Reinstatement
conditioned place preference induced by opioids, psychostimulants, nicotine, ethanol and
Drug priming
other drugs of abuse can be extinguished and reinstated by drug priming or exposure to
Stress
stressful events. Herein, the neuroanatomical and neurochemical basis of drug priming-
Drug addiction
and stress-induced reinstatement of morphine and cocaine, together with the molecular correlates of reinstatement behavior, are reviewed. Differences between the conditioned place preference and self-administration studies are also discussed. Evidence suggests that data of reinstatement with the CPP are to be viewed with caution until more extensive analysis of operant procedures has been performed, and that further research will undoubtedly improve our understanding of the neurobiological mechanisms of relapse to drug seeking. © 2008 Elsevier B.V. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . Experimental approaches—methodology. . . . . . . . 2.1. Acquisition . . . . . . . . . . . . . . . . . . . . 2.2. Extinction . . . . . . . . . . . . . . . . . . . . . 2.3. Reinstatement. . . . . . . . . . . . . . . . . . . 2.3.1. Drug priming-induced reinstatement . 2.3.2. Stress-induced reinstatement. . . . . . Neural mechanisms underlying reinstatement of CPP 3.1. Dopamine . . . . . . . . . . . . . . . . . . . . . 3.2. Glutamate . . . . . . . . . . . . . . . . . . . . . 3.3. Endogenous opioids . . . . . . . . . . . . . . .
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⁎ Corresponding author. Fax: +34 96 386 46 68. E-mail address: [email protected] (J. Miñarro). 0165-0173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2008.08.002
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3.4. Corticotrophin-releasing factor . . . . . . 3.5. Noradrenaline . . . . . . . . . . . . . . . 3.6. Cholecystokinin . . . . . . . . . . . . . . 3.7. Other neurotransmitter systems . . . . . 3.8. Other manipulations . . . . . . . . . . . . 4. Stress- versus drug-induced reinstatement . . . 5. Molecular correlates of reinstatement behavior. 6. Differences with self-administration studies . . 7. Relevance of findings to human relapse. . . . . 8. Theoretical landscape . . . . . . . . . . . . . . . 9. Shortcomings of the field . . . . . . . . . . . . . 10. Priorities for future research . . . . . . . . . . . 11. Conclusion . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . Glossary of terminology . . . . . . . . . . . . . . . . .
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Introduction
Drug addiction can be considered a chronic, recurrent brain disease characterized by relapse (Le Moal and Koob, 2007). The high rate of relapse to drug use after detoxification is a major clinical problem and constitutes the primary challenge to the treatment of drug abuse. Intense craving for drugs and relapse to drug-using behavior are observed in abstaining addicts who are confronted with environmental stimuli associated with their drug-taking behavior, the drug itself or stress, even after long periods of abstinence (de Wit, 1996; el-Guebaly and Hodgins, 1998; O'Brien, 1997). The tendency towards relapse in addiction suggests that drugs of abuse produce permanent alterations in the brain (Nestler, 2004). In laboratory animals, it is possible to measure relapse when, following the acquisition and subsequent extinction of a particular behavioral response, the animal reinitiates this response, which is referred to as reinstatement (Carroll and Comer, 1996). There are two main variations of the reinstatement model that are used to study relapse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference (CPP) procedure. In the latter of the two, animals are first trained to acquire a CPP and later undergo a process of extinction of this preference. Reexposure to the drug or to a stressful event induces reinstatement of CPP (for a review, see Shaham et al., 2003; Shalev et al., 2002; Tzschentke, 2007; Weiss, 2005). In addition to reinstatement, other methods can be used in the CPP to measure relapse (re-acquisition and spontaneous recovery). The aim of the present work is to provide an overview of the knowledge obtained to date with the CPP version of the reinstatement model. Most studies have employed morphine and cocaine to evaluate the drug- or stress-induced reinstatement of CPP, although a few have employed other drugs of abuse. We also intend to paint the theoretical landscape of the CPP version of the reinstatement model, identifying areas of dispute, analyzing shortcomings in the field and proposing priorities for future work.
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Experimental approaches—methodology
The CPP paradigm has been widely used to study the conditioned rewarding effects of addictive drugs, since contextual stimuli can acquire secondary appetitive properties (conditioned rewarding effects) when paired with a primary reinforcer, thereby highlighting the liability of abuse (Tzschentke, 2007). In this paradigm, the conditioned rewarding properties of drugs are evaluated by pairing drug effects with initially neutral cues, such as the compartment of an apparatus. The test for CPP can be performed in a drug-free state, enabling an investigation of the appetitive value of drugassociated contextual stimuli while avoiding the confounding influence of consummatory variables. If, after conditioning, the animals spend more time in the compartment associated with the drug, it is assumed that the drug produces CPP.
2.1.
Acquisition
The neutral value of the compartments of the apparatus is evaluated in a pre-conditioning phase in which the time spent in each compartment is recorded and compared with that spent in the same compartment in the test for CPP. When the pre-conditioning test is not performed, the presence of CPP is evaluated by comparing the time spent in the drug- and vehicle-paired compartments (Parker and McDonald, 2000) or comparing vehicle- and drug-conditioned animals (Wang et al. 2000, 2002). The main difference between the studies published until now lies in the protocols followed and the type of drug administration schedule applied during conditioning (see Table 1). There are three types of conditioning: biased, unbiased and balanced. In a biased protocol, the drug is always associated with the same compartment (generally that which was not preferred in a pre-conditioning test), while the other compartment is paired with administration of the vehicle. There can be confusion in the interpretation of CPP expression/ reinstatement when using the biased method. For example, anxiolytic or anxiogenic drugs can alter the time spent in a white or black chamber independently of conditioned drug reward. In an unbiased protocol, there is no clear preference
Table 1 – This table summarizes the methodology used in the reinstatement studies using the CPP paradigm Specie
Age
Sex
Drug
Dose
Pre-C
Type of C
Schedule
Test of Time of Sessions Duration Post-C Type of extinction extinction extinction of C of C session
Year
Parker and McDonald Lu et al.
2000
Rat
Adult
Male Morphine
10
No
Unbiased Alternating 4
30
15
2000
Rat
Adult
Male Morphine
10
15
Unbiased Alternating 3
50
Lu et al. Wang et al.
2001 2000
Rat Rat
Adult Adult
Male Morphine Male Morphine
10 4
15 No
Unbiased Alternating 3 Biased Daily 10
Wang et al. Wang et al.
2001 2002
Rat Rat
Adult Adult
Male Morphine Male Morphine
10 4
15 No
Unbiased Alternating 3 Biased Daily 10
Manzanedo et al. Mueller et al.
2001
Mouse
Adult
Male Morphine
40
2002
Rat
Adult
Male Morphine
10
Ribeiro Do Couto et al. Shi et al.
2003
Mouse
Adult
Male Morphine
40
2004
Rat
Adult
Male Morphine
Leri and Rizos 2005
Rat
Adult
Lu et al.
2005
Rat
Popik et al.
2005
Reinstatement induced by
2, 3, 4
4
Morphine (10)
15
Repeated test None
36
36
50 15
15 10
None None
36 9
36 9
50 15
15 10
None None
29 9
29 9
3 days, Biased Daily 4 15 15 Unbiased Alternating 4
60
15
5, 15, 20
20
45
15
9
9
Morphine (1, 2.5)
60
15
Daily
9
Morphine (5–40)
4
3 days, Unbiased Daily 4 15 15 Unbiased Alternating 4
45
15
Daily
7
Morphine (1–4)
Male Heroin
1
20
4
30
20
5
5
Heroin (1)
Adult
Male Morphine
10
3 days, Unbiased Alternating 4 15
50
15
Repeated test Saline injection Repeated test Repeated test Saline injection Saline injection
Morphine (10) Footshock Morphine (10) Morphine (0.25) Footshock Footshock Morphine (0.25) Footshock Morphine (40)
15
15
Mouse
Adult
Male Morphine
10
20
45
20
3
3
Ribeiro Do Couto et al. Ribeiro Do Couto et al.
2005a Mouse
Adult
Male Morphine
40
4
60
15
Morphine (2.5–20)
Adult
Male Morphine
40
4
60
15
14, 28, 42, 56 Daily
56, 84
2005b Mouse
3 days, Unbiased Daily 15 3 days, Unbiased Daily 15
Saline injection Repeated test Repeated test
Conditioned withdrawal NOT spontaneous withdrawal NOT precipitated withdrawal Morphine (1, 2.5)
9
Ribeiro Do Couto et al. Shoblock et al. Ventura et al.
2005c Mouse
Adult
Male Morphine
40
4
60
15
9
Mouse
Adult
Male Morphine
20
3
30
15
Daily
10
Morphine (20)
2005
Mouse
Adult
Male Morphine
20
20
Unbiased Alternating 4
40
20
9
9
Morphine (5)
Ma et al.
2007
Rat
Adult
Male Morphine
3
15
Unbiased Daily
4
45
15
Repeated test Repeated test Saline injection Repeated test
Daily
2005
3 days, Unbiased Daily 15 15 Unbiased Daily
Cocaine (12.5–50) Amphetamine (1–4) Morphine (10)
7, 15, 31, 63
63
Ribeiro Do Couto et al.
2006
Mouse
Adult
Male Morphine
10, 20, 3 days, Unbiased Daily 40 15
4
30, 60
15
Repeated test
Daily
Morphine (2) Forced swim stress Tail pinch stress Restraint stress Social defeat stress
Unbiased Daily
Unbiased Alternating 1
255
(continued on next page)
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Author/s
256
Table 1 (continued) Year
Specie
Age
Sex
Drug
Wang et al.
2006
Rat
Adult
Male Morphine
10
15
Unbiased Alternating 4
50
15
Zhou and Zhu 2006
Rat
Adult
Male Morphine
10
50
15
Hao et al.
2008
Mouse
Adult
Male Morphine
10
40
15
Mueller and Stewart
2000
Rat
Adult
Male Cocaine
10
3 days, Unbiased Alternating 4 15 2 days, Unbiased Alternating 3 15 15 Unbiased Alternating 4
20
15
Sanchez and Sorg
2001
Rat
Adult
Male Cocaine
Itzhak and Martin
2002
Mouse
Adult
Male Cocaine
Lu et al.
2002
Rat
Adult
Male Cocaine
Szumlinski 2002 et al. Sanchez et al. 2003
Mouse
Adult
Rat
Zavala et al.
2003
Kreibich and Blendy Romieu et al.
Dose
12
Pre-C
15
Type of C
Biased
Schedule
Sessions Duration Post-C Type of Test of Time of of C of C extinction extinction extinction session Saline injection Saline injection None
15
15
Morphine (3)
9
9
Morphine (2.5)
9
9
Morphine (2)
Repeated test Saline injection Repeated test
Daily
12
Cocaine (5)
9
9
Cocaine (5)
Daily
9
Cocaine (5) Conditioned odor Conditioned tone Cocaine (15) Methamphetamine (0.5) Methylphenidate (20) NOT PCP (5) Cocaine (10) Footshock Cocaine (5–25)
Alternating 4
30
15
2 days, Unbiased Alternating 4 20
30
20
Saline injection
9
9
10
15
Unbiased Alternating 4
30
15
22
22
Male Cocaine
15.25
15
Biased
Daily
10
Adult
Male Cocaine
12
30
15
Daily
10
Rat
Adult
Male Cocaine
15
30
15
Weekly
14–56
2004
Mouse
Adult
Male Cocaine
10
2 days, Biased Alternating 4 15 3 days, Biased Alternating 3 15 15 Unbiased Alternating 4
24 h
15
Saline injection Repeated test Repeated test Saline injection Saline injection
9
9
2004
Mouse
Adult
Male Cocaine
30
10
30
10
Saline injection
5
5
Alternating 4
Unbiased Daily
4
15
Reinstatement induced by
Cocaine (5) Immobilization Cocaine (5, 10) Cocaine (10) Forced swim stress Cocaine (15–30) Igmesine (3–10) DHEA (20–40) BTCP (15) Phencyclidine (5) Nicotine (0.5) Morphine (5) Ethanol (1000)
B RA I N R E SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
Author/s
Balda et al.
2006
20
20
Maldonado et al. McGeehan and Olive Carey et al.
Daily
4
30
20
Repeated test
Weekly
Male Cocaine
25.5
4
30
15
2006
Mouse
Adult
Male Cocaine
15
3 days, Unbiased Daily 15 Unbiased Daily
3
20
30
2007
Mouse
Adult
Male Cocaine
10
30
Biased
4
30
30
Repeated test Repeated test Repeated test
Graham et al. 2007
Rat
Adult
Male Cocaine
15
30
Unbiased Alternating 4
30
30
Kelley et al.
2007
Mouse
Adult
Male Cocaine
20
20
Unbiased Alternating 4
30
20
Maldonado et al. Orsini et al.
2007
Mouse
Adult
Male Cocaine
50
30
15
2008
Mouse
Adult
Male Cocaine
5, 20
3 days, Unbiased Daily 4 15 20 Unbiased Alternating 4
40
20
Li et al.
2002
Rats
Adult
Male
30
15
Cruz et al.
2008
Rats
Adolescent
Male Amphetamine
5
30
15
Kuzmin et al. Font et al.
2003
Mouse
Adult
Male Ethanol
800
3 days, Biased Alternating 4 15 3 days, Unbiased Alternating 4 15 10 Unbiased Daily 4
20
10
2008
Mouse
Adult
Male Ethanol
2000
5
Unbiased Alternating 4
5
60
Biala and Budzynska Biala and Budzynska
2006
Rats
Adult
Male Nicotine
0.5
1
Biased
Daily
3
30
15
2008
Rats
Adult
Male Nicotine
0.5
1
Biased
Daily
3
30
15
2007
Mouse
Adolescent Male MDMA
5, 10, 20
3 days 15
Unbiased Alternating 4
30
15
Daza-Losada et al.
D-metamphetamine
1
Mixed
Daily
Weekly
15 21 21 21 Seven–28
Cocaine (5)
Cocaine (3–25)
Weekly
7, 14, 21
Cocaine (15)
Weekly
21
Saline injection Repeated test Repeated test Saline injection Repeated test Saline injection Repeated test Saline injection Repeated test Repeated test
Daily
10
Weekly
28
Cocaine (10) Forced swim stress Cocaine (5–10) SKF81297 (0.1, 1) Cocaine (10)
Weekly
Seven–28
Cocaine (25)
9
9
Cocaine (2.5, 10)
Weekly
42
4
4
Methamphetamine (0.125) Amphetamine (2.5)
Daily
4
Ethanol (400)
5
5
Ethanol (2000)
Daily
3
Daily
3
Repeated test
Weekly
35
Nicotine (0.5) Morphine (10) Nicotine (0.5) WIN55,212-2 (0.5) Ethanol (500) NOT dAmphetamine (2) MDMA (2.5, 5)
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Adolescent Female Male Female Adult
Male Cocaine
2006
Mouse Adolescent Adult Adult Mouse
257
258
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for any compartment before conditioning, and drug and vehicle are administered in randomly assigned compartments. In a balanced protocol, the animals prefer one chamber over the other, but the drug-chamber is purposefully assigned so that no group as a whole has a preference for a particular chamber; in other words, if three mice are conditioned to the drug in the white side, another three are conditioned to the drug in the black side. On the other hand, some studies use a schedule in which drug and vehicle pairings are performed on a daily basis, at intervals of several hours (two-session day schedule), while others perform drug and vehicle pairings on alternate days.
2.2.
Extinction
Extinction is defined as the decrease in the frequency or intensity of learned responses after removal of the unconditioned stimulus (i.e. a drug) that has reinforced the learning (Pavlov, 1927). Extinction provides a measurement of the motivational properties of drugs, which are reflected by the persistence of drug-seeking behavior in the absence of the drug. This is a powerful means of assessing the incentive motivational properties of drug-paired stimuli or non-contingent drug administration in the reinstating response (Pulvirenti, 2003). In the CPP version of the reinstatement model, extinction typically involves exposing rats or mice to the previously drug-paired context while in a drug-free state (Epstein et al., 2006; Shalev et al., 2002). The CPP is considered to be extinguished when there is no significant difference between the time spent in the drug-paired compartment in the extinction session and that spent in the same compartment during pre-conditioning. Generally, a significant difference has been reported between the time spent on the drugpaired side in the extinction session and in the test for CPP. However, some studies considered CPP to be extinct when no significant difference was observed between the time spent in the drug-paired compartment by the drug and vehicle groups (Li et al., 2002), or when animals spent less than 55% of the total time in the drug-paired compartment on two consecutive days (Shoblock et al., 2005). Extinction is usually performed by one of two means (see Table 1): either by administering injections of a vehicle in both the original drug-paired and the original vehicle-paired chambers or by repeating CPP tests until preference is no longer observed. Exposure to vehicle in the previously drugpaired compartment extinguishes the CPP induced by morphine (Leri and Rizos, 2005; Mueller et al., 2002; Popik et al., 2005; Ventura et al., 2005; Wang et al., 2006; Zhou and Zhu, 2006), cocaine (Itzhak and Martin, 2002; Kreibich and Blendy, 2004; Lu et al., 2002; Mueller and Stewart, 2000; Romieu et al., 2004; Zavala et al., 2003) and ethanol (Font et al., 2008). Similarly, after repeated daily or weekly testing, morphine(Ma et al., 2007; Manzanedo et al., 2001; Parker and McDonald, 2000; Ribeiro Do Couto et al., 2003, 2006; Shi et al., 2004; Shoblock et al. 2005), cocaine- (Carey et al., 2007; Kelley et al., 2007; Maldonado et al., 2006, 2007; McGeehan and Olive, 2006; Mueller and Stewart, 2000; Sanchez and Sorg, 2001; Sanchez et al., 2003; Szumlinski et al; 2002), methamphetamine- (Li et al., 2002) ethanol- (Kuzmin et al., 2003), nicotine- (Biala and Budzynska, 2006, 2008) and MDMA-CPP (Daza-Losada et al.,
2007) are extinguished. Moreover, in several early studies, tests for reinstatement of CPP were performed when, after drug-free periods, rats no longer demonstrated morphine CPP (Lu et al., 2000, 2001a,b; Wang et al., 2000, 2002).
2.3.
Reinstatement
In the literature regarding learning, reinstatement refers to the recovery of a learned response when a subject is noncontingently exposed to an unconditioned stimulus after extinction. However, in reinstatement studies, this recovery of a learned response, which represents a return to drug seeking, occurs when rats or mice are exposed to drugs, drug cues or stressors following extinction (Shaham et al., 2003, Epstein et al., 2006). In the CPP version of the reinstatement model, an extinguished CPP is robustly reinstated by noncontingent administration of a priming dose of the drug, and, at least in the case of morphine and cocaine, by exposure to stressful stimuli.
2.3.1.
Drug priming-induced reinstatement
Reinstatement of response through a priming injection of a drug is acknowledged to be a reliable model for studying the mechanisms involved in drug craving and relapse (De Vries et al., 1998; Shalev et al., 2002). In the CPP version of the reinstatement model, an extinguished CPP is recovered after a priming injection of the conditioning drug or, in some cases, of a different drug to that administered during conditioning. To consider that drug priming has induced the reinstatement of the CPP, there should be a significant difference between reinstatement values and those of pre-conditioning or extinction. On the other hand, a lack of significant differences between the values of reinstatement and the test for CPP is necessary for a complete reinstatement to be considered. Both reinstatement induced by the training drug and crossreinstatement induced by other drugs can be demonstrated in the CPP version of the reinstatement model. The information provided in this section is summarized in Table 1. Numerous studies have reported that morphine-induced CPP in rats (Lu et al., 2000, 2001a,b, 2005; Ma et al., 2007; Mueller et al., 2002; Parker and McDonald, 2000; Shi et al., 2004; Wang et al., 2000, 2002, 2006) and in mice (Manzanedo et al., 2001; Popik et al., 2005; Ribeiro Do Couto et al., 2003, 2005a,b,c, 2006; Shoblock et al., 2005; Ventura et al., 2005) is reinstated by a priming injection of morphine. The CPP induced in rats by heroin is reinstated by the same drug (Leri and Rizos, 2005). Similarly, cocaine-induced CPP is reinstated in rats (Graham et al., 2007; Mueller and Stewart, 2000; Sanchez and Sorg, 2001, Sanchez et al., 2003; Zavala et al., 2003) and in mice (Itzhak and Martin, 2002; Kreibich and Blendy, 2004; Maldonado et al., 2006, 2007; McGeehan and Olive, 2006; Szumlinski et al., 2002; Romieu et al., 2004) by a priming injection of cocaine. Reinstatement of CPP has also been demonstrated in rats with amphetamine (Cruz et al., 2008; Li et al., 2002) and nicotine (Biala and Budzynska, 2006, 2008), and in mice with ethanol (Kuzmin et al., 2003; Font et al., 2008) and MDMA (Daza-Losada et al., 2007). Moreover, a cross-reinstatement has been observed between opioids, psychostimulants and other drugs of abuse. A priming injection of a psychostimulant, such as amphetamine
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or cocaine, reinstates morphine CPP in rats and mice (Ribeiro Do Couto et al., 2005b; Wang et al., 2000). Similarly, in mice, a previously extinguished cocaine-induced CPP has been shown to be reinstated by a priming injection of methamphetamine, methylphenidate, BTCP (a selective DA uptake inhibitor), morphine, nicotine and ethanol (Itzhak and Martin, 2002; Romieu et al., 2004). Phencyclidine does not induce reinstatement of cocaine-CPP (Itzhak and Martin, 2002), or produces only a partial effect (Romieu et al., 2004). Morphine, WIN55,212-2 and ethanol also reinstate the CPP induced by nicotine (Biala and Budzynska, 2006, 2008).
2.3.2.
Stress-induced reinstatement
Exposure to stress may be a determining factor in vulnerability to drug abuse. Stress is known to increase the rewarding effects of drugs (Will et al., 1998; Der-Avakian et al., 2005), and its role in relapse is well established (Sinha, 2001; Lu et al., 2003). In experimental animals, reinstatement of a previously extinguished CPP has been evaluated following exposure to different stressful events. Intermittent footshock exposure delays the extinction of morphine CPP (Lu et al., 2000), reactivates morphine-CPP following drug-free periods (Lu et al., 2000; Wang et al., 2000, 2002; Wang et al., 2001) and reinstates morphine-CPP after extinction (Der-Avakian et al., 2001; Wang et al., 2001, 2006). Immobilization (Ribeiro Do Couto et al., 2006), continuous tail-pinch (Ribeiro Do Couto et al., 2006), single forced swim (Ma et al., 2007), conditioned withdrawal from the drug in morphine-dependent animals (Lu et al., 2005) and defeat in social interaction with a conspecific (Ribeiro Do Couto et al., 2006) all reinstate morphine-CPP. Similarly, cocaine-CPP is reinstated by intermittent footshock (Lu et al., 2002), restraint stress (Sanchez et al., 2003), single forced swim (Kreibich and Blendy, 2004) and conditioned fear stimuli such as a tone or an odor previously associated with footshock (Sanchez and Sorg, 2001).
3. Neural mechanisms underlying reinstatement of CPP Several neurotransmitter systems and brain areas have been implicated in drug- and stress-induced reinstatement of CPP. The effects of different manipulations on drug primingand stress-induced reinstatement of CPP are summarized in Table 2.
3.1.
Dopamine
The role of dopamine (DA) in drug priming-induced reinstatement of opiate CPP is controversial, since reinstatement of morphine CPP is not affected by DA antagonists and is blocked by lesion of mesolimbic DA structures. In a study performed in our laboratory, we observed that neither DA antagonists (SCH 23390, raclopride, haloperidol, D1, D2, D1 + D2 DA antagonists respectively) nor the DA release inhibitor (CGS 10746B) reinstated the CPP induced by morphine in mice when administered alone. Moreover, these drugs failed to block the reinstatement of CPP induced by morphine. These results suggest that the drug-induced reinstatement of morphine CPP is largely independent of DA neurotransmission (Ribeiro Do
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Couto et al., 2005c). On the other hand, another study investigated the influence of DA D2 receptors on the re-acquisition of a previously extinguished morphine-induced CPP (Lu et al., 2001a). The method used in that study cannot be considered a model of reinstatement, as, when the place preference was extinguished, animals underwent a further training trial with a low dose of morphine, at which point CPP reappeared. Using this model, it was found that acute but not chronic pretreatment with sulpiride significantly attenuated re-acquisition of morphine-induced CPP. The authors suggested that the D2 antagonist contributed to the inhibition of the opioid rewarding process but not to the protracted abstinence syndromes that persisted long after detoxification (Lu et al., 2001a). Mesolimbic DA structures seem to be essential for drug-induced reinstatement of morphine CPP in rats, since an electrolytic lesion of the ventral tegmental area (VTA), the nucleus accumbens (Nac) or its shell has been found to block the reactivation of CPP induced by a morphine prime (Wang et al., 2002). Conversely, the medial prefrontal cortex (mPFC) cannot be involved in reinstatement, since the lesion of this structure fails to prevent priming-induced reinstatement of morphine CPP in mice (Hao et al., 2008). The conflicting results obtained in pharmacological and lesion studies can be explained by variations in the methodology used to evaluate the influence of the DA system in drug-induced reinstatement of CPP. An anatomical lesion produces effects that can differ substantially from those observed when an antagonist drug is administered. An electrolytic lesion of a specific brain structure destroys not only the neuron cell body, but also the pass-by axons of the targeted area, and could, therefore, affect its afferents and efferents, which are mediated by different neurotransmitter systems. Conversely, the administration of a given antagonist interferes with specific neurotransmitters. It is possible that non-dopaminergic projections arriving at the VTA or departing from the Nac are more essential to druginduced reinstatement of CPP than the dopaminergic neurotransmission between these structures. For example, the VTA also sends GABAergic projection neurons to the NAC (Van Bockstaele and Pickel, 1995), and VTA lesions can affect reinstatement by altering these non-DA projections. Moreover, the differences between the results obtained in lesion and dopamine antagonist studies could be due to differences of species (rat versus mouse). The DA system seems to be involved in the drug-induced reinstatement of cocaine CPP. Drugs that stimulate DA transmission, such as the DA uptake inhibitor BTCP (Romieu et al., 2004), and intermediate doses of the DA D1 agonist SKF81297 (Graham et al., 2007) can effectively reinstate cocaine CPP. However, the microinjection of this drug in the mPFC (Sanchez et al., 2003) and the administration of the D2/D3 agonist quinpirole (Graham et al., 2007) do not have the same effect. On the other hand, a microinjection of the DA D1-like antagonist SCH 23390 in the mPFC blocks the reinstatement of cocaine CPP induced by cocaine priming (Sanchez et al., 2003), while DA agonists such as SKF-81297 and quinpirole are unable to block this cocaine-induced reinstatement (Sanchez et al., 2003; Graham et al., 2007). The electrolytic lesion of the shell of the Nac has been seen to block the reinstatement of morphine CPP induced by footshock, although lesions of other DA structures, such as the VTA, and
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Table 2 – This table summarizes the effects of different manipulations on drug priming- and stress-induced reinstatement of CPP Author/s
Year
Lu et al.
2000
CPP induced by Morphine
Reinstatement induced by Morphine (10)
Footshock stress
Lu et al.
2001
Morphine
Morphine (10)
Wang et al.
2001
Morphine
Footshock stress
Lu et al.
2002
Cocaine
Cocaine (10)
Footshock stress
Li et al. Wang et al.
2002 2002
D-metamphetamine Morphine
D-methamphetamine (0.125) Morphine (0.25)
Footshock stress
Kuzmin et al.
2003
Ethanol
Ethanol (400)
Sanchez et al.
2003
Cocaine
Cocaine (5)
Manipulation α-helical CRF CP-154,526 AS-30 α-helical CRF CP-154,526 AS-30 L-365260 MK-329 Clonidine Clonidine DNB lesion VNB lesion Devazepide L365,260 Devazepide Devazepide Devazepide L365,260 L365,260 L365,260 7-nitroindazole ATV lesion Nac lesion Nac core lesion Nac shell lesion ATV lesion Nac lesion Nac core lesion Nac shell lesion CeA lesion Nociceptin Ro 64-6198 Naloxone SKF 81297 SCH 23390
Immobilization stress
SKF 81297 SCH 23390
Zavala et al. Romieu et al.
2003 2004
Cocaine Cocaine
Cocaine (5, 10) Cocaine (15)
Lu et al.
2005
Morphine
Ribeiro Do Couto et al.
2005c
Morphine
Conditioned withdrawal stress Morphine (10)
Shoblock et al. Biala and Budzynska
2005 2006
Morphine Nicotine
Morphine (20) Nicotine (0.5) Morphine (10)
Ma et al.
2007
Morphine
Morphine (2) Forced swim stress
Dose 1, 10 (μg, icv) 1, 10 1, 10 (μg, icv) 1, 10 μg (icv) 1, 10 mg/kg 1, 10 μg (icv) 0.1, 1 0.1, 1 0.1, 1 μg (BNST) 0.1, 1 μg (LC)
0.1, 1 0.1, 1 1, 10 (μl, Nacc) 1, 10 (μl, Amyg) 0.1, 1 0.1, 1 1, 10 μl (Nacc) 1, 10 μl (Amyg) 12.5, 25
5 (nmol) 0.3 1 0.1, 0.3, 1 (μg, mPFC) 0.01, 0.1, 1 (μg, mPFC) 0.1, 0.3, 1 μg (mpFC) 0.01, 0.1, 1 μg (mpFC)
mPFC lesion BD1047 σ1 antisense ODN α-helical CRF
3, 10, 30 20 (μg, icv) 0.1, 1 μg (icv)
SCH 233390 Raclopride Haloperidol CGS 10746B Memantine
0.125, 0.5 0.3, 1.2 0.1, 0.2 1, 10 10, 20, 40
MK-801
0.1, 0.2, 0.3
Ro 64-6198 Nimodipine Flunarizine Nimodipine Flunarizine Ifenprodil Ifenprodil Ifenprodil
1 10, 20 5, 10 10, 20 5, 10 1, 3, 10 2 (μg, Nac, Hipp) 1, 3, 10
Effect on reinstatement Blockade (with None None Blockade (with Blockade None Blockade None Blockade None None Blockade Blockade None Blockade None None Blockade (with Blockade (with Blockade Blockade Blockade Blockade None Blockade None None None Blockade Blockade Blockade Blockade Blockade None
10)
10)
1) 10)
Blockade (with 0.1 and 1) Blockade (with 1) Blockade (with 0.1 and 1) Blockade Blockade (with 30) Blockade Blockade (with 1) None None None None Blockade (with and 40) Blockade (with and 0.3) Blockade Blockade (with Blockade Blockade (with Blockade Blockade (with Blockade None
20 0.2
20) 20) 10)
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Table 2 (continued) Author/s
Year
CPP induced by
Reinstatement induced by
Maldonado et al.
2006
Cocaine
Cocaine (25)
GHB
McGeehan and Olive Wang et al.
2006
Cocaine
Cocaine (15)
Acamprosate
2006
Morphine
Morphine (3)
CP-154,526 CP-154,526 CP-154,526 CP-154,526 CP-154,526 CP-154,526 Arodyn Arodyn AT Quinpirole Memantine CNQX SCN lesion Nimodipine Flunarizine Nimodipine Flunarizine mPFC lesion
Footshock stress
Carey et al.
2007
Cocaine
Font et al. Graham et al. Maldonado et al.
2008 2007 2007
Ethanol Cocaine Cocaine
Cocaine (10) Forced swim stress Ethanol (2000) Cocaine (10) Cocaine (25)
Sleipness et al. Biala and Budzynska
2007 2008
Cocaine Nicotine
Cocaine (5, 10) Ethanol (0.5) WIN55,212-2 (0.5)
Hao et al.
2008
Morphine
Morphine (2)
both the totality of the Nac or merely its core, have been shown to have no effects (Wang et al., 2002). Administration of drugs acting at the DA D1 receptors of the mPFC blocked stressinduced reinstatement of cocaine CPP in rats (Sanchez et al., 2003). Both the DA D1 agonist SKF81297 (1 μg/side) and the DA D1 antagonist SCH 23390 (0.1 and 1 μg/side) were shown to block restraint-induced reinstatement. The authors of the study in question speculated that optimal mPFC D1 receptor activation and DA levels are required to facilitate the activation of output neurons to subcortical structures such as the Nac and to process stress reinstatement cues (Sanchez et al., 2003).
3.2.
Glutamate
This neurotransmitter system seems to play an essential role in the reinstatement of the CPP induced by opiates. We assessed the effects of memantine and MK-801, two Nmethyl-D-aspartate (NMDA) glutamatergic antagonists with different kinetic profiles, on the reinstatement of morphineinduced CPP. Although neither produced reinstatement, both memantine (20 and 40 mg/kg) and MK-801 (0.2 and 0.3 mg/kg) blocked the reinstatement effects of morphine priming. It is unlikely that this effect was due to the motor effects of NMDA antagonists, since the blockade of morphine-induced reinstatement was observed with doses that produced different effects on motor behavior; namely ataxia (unpublished data), no effect, or hyperactivity (Rodríguez-Arias et al., 2002). NMDA antagonists impair memory in a wide variety of tasks and species (Riedel et al., 2003). Thus, the inhibition of reinstatement may be due to the interference of NMDA antagonists with the capacity of morphine to remind the animal of the associations learned during conditioning (Ribeiro Do Couto et al., 2004) and to produce a reinstatement of place preference (Ribeiro Do Couto et al., 2005c). Another study demonstrated that memantine administration during a forced extinction of
Manipulation
Dose
Effect on reinstatement
100, 50, 25, 12.5, 6.25 30, 100
Blockade (with 25)
1 (μg, BNST) 1 (μg, CeA) 1 (μg, Nac) 1 μg (BNST) 1 μg (CeAmyg) 1 μg (Nacc) 0.3 (nmol, icv) 0.3 (nmol, icv) 1000 0.1, 0.3, 1, 3 5, 10 1, 10
None Blockade Blockade Blockade None None None Blockade None None Blockade (with 10) Blockade (with 10) Decrease (with 10) Blockade (with 10) Blockade (with 10) Blockade (with 10) Blockade None
5, 10 5, 10 5, 10 5, 10
Blockade (with 100)
CPP blocked the subsequent drug-induced reinstatement. This protective effect of memantine may be explained by the impairing effects of this drug on re-consolidation processes. Two processes operate simultaneously in extinction: the original association is retrieved and a novel association is formed. In the reactivated state, both associations interact and memantine seems to disrupt the processing of conditioned responses, thereby impairing the re-consolidation of the highly salient drug-related associations. According to the authors of that study, the original association between the effects of morphine and environment were altered in memantine-extinguished mice to the extent that the reinstating effects of morphine priming were blocked (Popik et al., 2005). These results indicate that the activation of NMDA glutamate receptors underlies the drug-induced reinstatement of morphine CPP (Popik et al., 2005; Ribeiro Do Couto et al., 2005c). A recent study, though not employing a reinstatement procedure (extinction did not take place), suggested that glutamate is implicated in the persistent memory associated with addictive drugs. Ketamine, when administered after re-exposure to a morphine-paired context, interferes with the re-consolidation of morphine CPP, suggesting effects of ketamine in the disruption of memory associated with environmental cues and addictive drugs (Zhai et al., 2008). The relation between cocaine and glutamate neurotransmission is clear, since the manipulation of this neurotransmitter system is known to alter many of the effects of cocaine (McFarland and Kalivas, 2001). A recent study in our laboratory evaluated the role of ionotropic glutamate receptors in the reinstatement of cocaine CPP through the administration of NMDA glutamate receptor antagonist memantine (5 or 10 mg/kg) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist CNQX (1 or 10 mg/kg) with a priming dose of 25 mg/kg of cocaine (Maldonado et al., 2007). The results obtained show that the reinstatement of cocaine-
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induced preference by cocaine priming injections are blocked by memantine (10 mg/kg). In other words, animals do not approach the cocaine-related cues when the glutamate neurotransmission at NMDA receptors is blocked, which represents an undermined drug-seeking behavior. Additionally, neither of the two antagonists reinstated the preference. The inhibition of drug-induced reinstatement of cocaine-induced CPP could be due to the interference of memantine with the capacity of cocaine to remind the animal of the associations learned during conditioning and, thus, produce a reinstatement of CPP. Another recent study has confirmed the role of NMDA glutamate receptors in the reinstatement of cocaine-CPP by employing the NMDA receptor antagonist MK-801. The administration of MK-801 prior to a CPP retrieval test, performed a week after the test for CPP, was shown to cause a long-term suppression of the CPP response and block the reinstatement induced by a priming dose of cocaine three weeks after conditioning. These effects can be attributed to the disrupting effects of MK-801 on memory re-consolidation (Kelley et al., 2007). Acamprosate (calcium acetylhomotaurinate) is a modulator of ionotropic and metabotropic glutamate receptor function, and reduces extracellular levels of glutamate when the organism is in a hyperglutamatergic state. Recently, it has been demonstrated that this drug reduces cocaine-induced reinstatement of a previously extinguished cocaine CPP in mice (McGeehan and Olive, 2006). Finally, a recently published study has demonstrated the involvement of AMPA receptors in the Nac in the reinstatement of amphetamine-induced CPP in adolescent rats (Cruz et al., 2008).
3.3.
Endogenous opioids
No changes are detected in the mRNA levels of preproenkephalin (PPE) and preprodynorphin (PPD) in the Nac of rats after morphine-induced reinstatement of CPP (Shi et al., 2004). Conversely, the opioid receptor-like (ORL-1) receptor (also referred to as NOP1 or OP4), which is activated by the endogenous peptide nociceptin/orphanin FQ, seems to play a role in the reinstatement of morphine CPP (Shoblock et al., 2005). The ORL-1 agonist Ro 64-6198 blocks morphine-induced reinstatement, an effect that may be related with the less obvious morphine-induced increase in DA release in Nac, although it is not clear whether the ORL-1 agonist attenuates the rewarding properties of morphine or impairs associative learning (Shoblock et al., 2005). Drug-induced reinstatement of ethanol CPP is inhibited by the non-selective opioid antagonist naloxone, nociceptin, and the ORL 1 agonist Ro 64-6198. This suggests that the opioid system is involved in the reinstatement of ethanol CPP (Kuzmin et al., 2003). However, the inhibition of brain catalase activity (which metabolizes ethanol to acetaldehyde) does not modify reinstatement of ethanol CPP (Font et al., 2008). A recent study has demonstrated the role of the endogenous kappa-opioid system in stress-induced reinstatement of cocaine CPP. Exposure to stress activated the kappa-opioid receptor through release of endogenous dynorphin peptides, and the novel peptide kappa-opioid receptor antagonist arodyn produced a long-lasting antagonism of the antinociception induced by the opioid agonist U50,488. Moreover, arodyn suppressed the reinstatement of cocaine CPP induced by submitting the mice to two sessions of forced swim stress, which suggests
that kappa-opioid receptor antagonists are of therapeutic value in the treatment of relapse to cocaine abuse (Carey et al., 2007).
3.4.
Corticotrophin-releasing factor
Several studies have demonstrated the role of corticotrophinreleasing factor (CRF) receptors in the reinstatement of morphine CPP. Pre-treatment with the non-selective CRF antagonist α-helical CRF (10 μg, i.c.v.) attenuates morphineinduced reinstatement of CPP, while pre-treatment with lower doses (1 μg) or with CRF1 (CP-154,526) or CRF2 (AS-30) antagonists fails to exert the same influence (Lu et al., 2000). Recently, a role for these CRF1 receptors in the amygdala and Nac has also been demonstrated, since CP-154,526 injections into both structures attenuated priming-induced reinstatement of morphine CPP (Wang et al., 2006). The footshock-stress-induced reactivation of morphine CPP is undermined by non-selective and selective corticotrophinreleasing factor type 1 (CRF1) antagonists such as α-helical CRF and CP 154,526, but is unaffected by pre-treatment with AS-30, a CRFR2 antagonist (Lu et al., 2000). Similarly, the reinstatement of morphine CPP induced by conditioned drug withdrawal is blocked by α-helical CRF (Lu et al., 2005). A recent study has demonstrated the role of CRF1 receptors in the bed nucleus of the stria terminalis (BNST) in footshock-induced reinstatement of extinguished morphine CPP. CP-154,526 injections attenuated footshock-stress-induced reinstatement of morphine CPP when administered to the BNST, but not when administered to the amygdala or Nac. Considering the abovementioned findings with drug priming, the roles of CRF1 receptors in the BNST, amygdala, and Nac would appear to differ depending on whether reinstatement of drug CPP is induced by footshockstress or morphine-priming (Wang et al., 2006).
3.5.
Noradrenaline
Drug-priming-induced reinstatement of morphine CPP is also affected by the noradrenaline (NA) in the PFC. Selective prefrontal cortical NA depletion was shown to block the reinstating effects of morphine priming in mice. Moreover, morphine enhanced NA outflow in the mPFC, an effect that is critical to the effects of morphine on mesoaccumbens DA (increase in DA outflow in the Nac). These results suggest an important role for the mesocorticolimbic catecholaminergic circuit, in which prefrontal noradrenergic and accumbens DA transmission are synergistically coupled in order to control morphine CPP and reinstatement (Ventura et al., 2005). The footshock-stress-induced reactivation of morphine CPP is attenuated by clonidine infusion (0.1 and 1 μg, 0.5 μl) into the BNST 30 min before a single footshock stress (Wang et al., 2001). Moreover, a lesion of the ventral noradrenergic bundle caused by 6-OHDA (3 μg), which decreases NA levels in the BNST and hypothalamus, blocks the reinstating effects of stress exposure (Wang et al., 2001). In contrast, microinjection of clonidine into the locus coeruleus and the 6-OHDA (3 μg)-induced lesion of the dorsal noradrenergic bundle, which decreases NA levels in the frontal cortex and hippocampus, do not affect the reinstatement of morphine CPP induced by footshock (Wang et al., 2001). These findings suggest that NA from the locus coeruleus, critical to opiate withdrawal, is not essential for stress-induced
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
reinstatement to morphine CPP. An electrolytic lesion of the central nucleus of the amygdala, which sends CRF-containing fibers to the BNST, has also been shown to block the reinstating effects of stress exposure (Wang et al., 2002).
3.6.
Cholecystokinin
The involvement of the cholecystokinin (CCK) system in the drug-induced reinstatement of morphine CPP has been demonstrated by Lu et al. (2001b). The CCK-B antagonist L-365260 (0.1 and 1 mg/kg) blocked the reactivation of morphine CPP induced by a single injection of morphine. However, the CCK-A receptor antagonist MK-329 did not affect reinstatement, which suggests that the CCK system interacts with opioid rewarding processes, mainly through CCK-B receptors. Moreover, the authors of this study proposed that the blocking effects of the CCK-B antagonist were a result of its anxiolytic effects and/or the modulation of the DA system by CCK (Lu et al., 2001b). The involvement of the CCK system in the reinstatement of psychostimulants has also been demonstrated. Pre-treatment with the CCK-A receptor antagonist devazepide (0.1 and 1 mg/ kg) significantly attenuates the reinstatement of CPP induced by a priming injection of cocaine, while pre-treatment with the CCK-B receptor antagonist L365,260 (0.1 and 1 mg/kg) has no effect. The blockade of cocaine-induced reinstatement is also observed when devazepide (1 and 10 μg) is administered into the Nacc but not when it is administered into the amygdala (Lu et al., 2002). Pre-treatment with the CCK-B antagonist L365,260 (0.1 and 1 mg/kg) blocked the stress-induced reinstatement of cocaine CPP when administered at the highest of two doses, while the CCK-A antagonist devazepide (0.1 and 1 mg/kg) had no effects at any dose. Moreover, the infusion of L365,260 into the Nac (10 μg) or amygdala (1 and 10 μg) blocked stress-induced reinstatement (Lu et al., 2002). The authors of the study in question hypothesized that the role of the CCK-B receptor antagonist in the undermining of stress-induced reinstatement of cocaine dependence was a result of its anxiolytic effects (Lu et al., 2002).
3.7.
Other neurotransmitter systems
Gamma-hydroxybutyric acid (GHB) is a metabolite of GABA, and is naturally present in the brain (Maitre, 1997). GHB belongs to the group of substances referred to as ‘club drugs’, and is consumed for its euphoric, sedative and anabolic effects (Nicholson and Balster, 2001). A previous study found that systemic injections of GHB led to decreased cocaine CPP and self-administration (Fattore et al., 2000). The impact of GHB on the rewarding actions of cocaine and the reinstatement of cocaine CPP after extinction has been evaluated in male mice (Maldonado et al., 2006). CPP was detected in animals treated with the drug during the acquisition or expression of cocaine-induced preference, but was not reinstated by a priming injection of cocaine. This was the contrary to that observed in control animals. GHB may diminish the potency of conditioning when administered during the acquisition phase, possibly due to a delayed action on DA neurotransmission. Protracted memory impairments may account for the absence of relapse in the groups receiving GHB during expression. In animals conditioned only with cocaine, an intermediate dose of GHB blocked cocaine-induced
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reinstatement. The priming dose of cocaine may remind the animal of the hedonic properties of the drug and the significance of the cues previously paired with the drug (Mueller and Stewart, 2000), or perhaps induces a state-dependent learning. GHB could block these processes by altering the subjective perception of the hedonic effect of cocaine. In this way, animals fail to recognize it as the conditioning drug. However, in monkeys, it has been observed that GHB does not effectively antagonize the cocaine discriminative stimulus (Beardsley et al., 1996), which challenges the notion that GHB interferes with the subjective effects of cocaine. In the brain, nitric oxide (NO) is produced primarily by the conversion of L-arginine via neuronal NO synthase (nNOS) in response to the stimulation of NMDA receptors, and facilitates DA release (Lonart and Johnson 1994; Pogun et al. 1994; Hong et al. 2005). The reinstatement of amphetamine-CPP is attenuated by the NOS inhibitor 7-nitroindazole, which demonstrates the involvement of NO in drug-induced reinstatement of a CPP induced by psychostimulants (Li et al., 2002). A recent study has demonstrated that, during adolescence, the nNOS gene is essential for the development of the neural plasticity that enables the reinstatement of cocaine CPP, suggesting that the NO pathway is of critical relevance in the development of the persistent reinstatement behavior that so often begins in adolescence and continues into adulthood (Balda et al., 2006). In the study in question, nNOS KO male and female mice, though acquiring CPP in a similar way to WT mice, presented a more rapid extinction of this CPP (which disappeared one week after conditioning), while re-exposure to cocaine did not produce reinstatement. Similar results were observed in male but not in female adult nNOS KO mice. These findings suggest that, in males, independently of age, the nNOS gene is essential for the long-term neural plasticity that underlies susceptibility to the incentive value of cocaine reward. However, in adult females, neural adaptations seem to be nNOS-independent, suggesting that the role of the nNOS gene is age-dependent. The sigma1 (σ1) receptor is an intracellular neuronal protein associated with membranes. Selective σ1 receptor ligands considerably modulate intracellular Ca2+ mobilizations and extracellular Ca2+ influx. Although the endogenous ligand of this receptor has not yet been identified, the σ1 receptor seems to be one of the main targets of certain neuroactive steroids. Pregnenolone and deydroepiandrosterone (DHEA) act as effective receptor agonists, while progesterone is a potent antagonist. Activation of this particular receptor has been linked to several aspects of cocaine addiction and to druginduced reinstatement of cocaine CPP (Romieu et al., 2004). When the σ1 receptor is inactivated by the σ1 antagonist BD1047 or by the decrease in the expression of the σ1 receptor following in vivo administration of an antisense oligodeoxynucleotide (which targets the σ1 gene), the reinstatement induced by a priming injection of cocaine is completely blocked. Moreover, igmesine, a selective σ1 receptor agonist, and DHEA both induce CPP reinstatement (Romieu et al., 2004). The reinstatement of nicotine CPP induced by nicotine, morphine, WIN55,212-2 and ethanol is blocked by the calcium channel blockers nimodipine and flunarizine, which act at Ltype voltage-gated calcium channels (Biala and Budzynska, 2006, 2008). These results support the hypothesis that calcium ions and calcium channels play an important role in
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modulating the re-acquisition of drug-seeking behavior following extinction, and that a common neuronal pathway (mesolimbic DA system) and similar calcium-dependent neuroadaptations are involved in the reinstatement of nicotine CPP provoked by priming injections of different drugs (Biala and Budzynska, 2006, 2008).
3.8.
abuse. In addition, the neural circuit involved in priming- and stress-induced reinstatement is represented in Figs. 1 and 2, respectively.
4.
Other manipulations
Stress- versus drug-induced reinstatement
Stress- and drug-induced reinstatement appear to be mediated by different neural pathways. For example, the role of specific CCK receptors differs between drug- and stressinduced reinstatement of cocaine CPP. The antagonism of CCK-A receptors blocks cocaine-but not stress-induced reinstatement, while that of CCK-B receptors blocks stress-induced reinstatement but does not affect the priming effects of cocaine (Lu et al., 2002). A differential effect of the D1 agonist SKF 81297 has also been observed in stress- versus cocaineinduced reinstatement, as it reduces the former but does not affect the latter (Sanchez et al., 2003). The mPFC→VTA→NAS circuit may be critical to stress-induced reinstatement, while the direct mPFC→NAS pathway appears to be essential for cocaine-induced reinstatement (Sanchez et al., 2003). As discussed in more detail in the following section, it has been demonstrated that stress-induced reinstatement is accompanied by a pattern of phosphorylated cAMP response elementbinding protein (pCREB) activation in discrete brain regions that differs from that observed following cocaine-induced reinstatement. For example, on the day of reinstatement, only exposure to stress produces greater increases of pCREB levels in both the amygdala (also induced by cocaine during conditioning) and the Nac. Furthermore, mice deficient in alpha and delta isoforms of CREB show deficits in stress-but not cocaine-induced reinstatement, which indicates that its role in stress-induced behavioral responses to drugs of abuse is specific (Kreibich and Blendy, 2004). It has also been demonstrated that the roles of CRF1 receptors in the BNST, amygdala and Nac in footshock-stressversus morphine-priming-induced reinstatement of morphine CPP are dissociable. Footshock-stress-induced reinstatement of morphine CPP was attenuated when the selective CRF1 receptor antagonist CP-154,526 was injected into the BNST, but not when it was injected into the amygdala or Nac. In contrast, CP-154,526 injections into the amygdala or
Reinstatement of morphine CPP is reversed by single (Wang et al., 2003) or repeated (Shi et al., 2004) peripheral electrical stimulation, a procedure based on acupuncture, by which animals receive an electrical stimulation via two stainless steel needles inserted into their hind legs. The effects of peripheral electrical stimulation seem to be mediated by the endogenous opioid system. The blocking effect against reinstatement of single (2 Hz) peripheral electrical stimulation is reversed by naloxone, which indicates the involvement of endogenous opioid peptides (Wang et al., 2003). Repeated peripheral electrical stimulation (2 Hz) increases PPE mRNA expression in the Nac, thereby stimulating the biosynthesis and release of enkephalin, which interacts with μ and δ-opioid receptors, thus ameliorating craving and eliminating the reinstatement of morphine-CPP. Conversely, repeated peripheral electrical stimulation (100 Hz) increases the expression of PPD mRNAs in the Nac and the biosynthesis of dynorphin, which may interact with kappa-opioid receptors located in dopaminergic nerve terminals and block the release of DA, thereby preventing reinstatement (Shi et al., 2004). The lesion of the prelimbic subregion of mPFC, at the end of the DA mesocorticolimbic pathway, attenuates the reinstatement of cocaine-CPP, which confirms mPFC's involvement in cocaine-priming-induced reinstatement (Zavala et al., 2003). Moreover, lesions of the suprachiasmatic nucleus affect cocaine-induced reinstatement of cocaine CPP, as, in lesioned animals, a more pronounced reinstatement is observed with a low dose of cocaine and a diminished reinstatement after a high dose of the same drug when compared with sham animals (Sleipness et al., 2007). Box 1 summarizes the similarities and differences in the neurotransmitter systems involved in priming- and stressinduced reinstatement of the different classes of drugs of
Reinstatement induced by Drug priming
DA agonists DA antagonists NMDA GLU antagonists ORL-1 agonists Opioid antagonists CRF antagonists NA antagonists CCK antagonists GHB NOS inhibitors σ receptor antagonists CA blockers
Stress
Morphine
Cocaine
Ethanol
Amphetamine
Nicotine
– = ↓ ↓ – ↓ (Amyg, NAc) – ↓ (CCK-B) – – – –
= (mPFC, D1, D2) ↓ (mPFC, D1) ↓ – – – – ↓ (CCK-A) ↓ ↓ ↓ –
– – – ↓ ↓ – – – – – – –
– – – – – – – – – – – –
– – – – – – – – – – – ↓
Morphine – – = (NR2B) – – ↓ (BNST) ↓ – – – – –
Cocaine ↓ ↓ – – ↓ – – ↓ – – –
(mPFC, D1) (mPFC, D1)
(κ)
(CCK-B)
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Fig. 1 – Neural circuits involved in priming-induced reinstatement. The role of several brain structures in priming-induced reinstatement of morphine and cocaine CPP has been studied by inflicting lesions or through intracranial administration of different compounds. ✓ The lesion of the structure affects drug-induced reinstatement. X The lesion of the structure does not The administration of compounds related with the neurotransmitter system or receptor affect drug-induced reinstatement. The administration of compounds related to the neurotransmitter cited in brackets blocks drug-induced reinstatement. system or receptor cited in brackets does not affect drug-induced reinstatement. mPFC: medial prefrontal cortex; NSC: nucleus suprachiasmatic; NAcc: nucleus accumbens; BNST: bed nucleus of the stria terminalis; VTA: ventral tegmental area; AMYG: amygdala. Continuous lines indicate the neural circuit involved in drug priming-induced reinstatement of morphine CPP. Broken lines indicate the neural circuit involved in drug priming-induced reinstatement of cocaine CPP.
Nac, but not into the BNST, diminished morphine-priminginduced reinstatement of morphine CPP (Wang et al., 2006). Similarly, it has been observed that the NR2B-containing NMDA receptor is required for morphine – but not stress – induced reinstatement, since the administration of the NR2B selective antagonist ifenprodil undermined the reinstatement induced by a priming morphine injection, but not that induced by stress (Ma et al., 2007). These results, and those of studies employing using the self-administration paradigm, imply that two different neural pathways are responsible for stress- versus cocaine-induced reinstatement (see Figs. 1 and 2).
5. Molecular correlates of reinstatement behavior With the aim of evaluating the role of the CREB protein, a gene transcription factor, in drug- and stress-induced reinstatement of cocaine CPP, CREB mutant mice were tested for reinstatement after cocaine administration or forced swim exposure. Similarly, levels of pCREB in the Nac, VTA, amygdala and BNST were examined in wild-type mice after reinstatement induced by cocaine or stress (Kreibich and Blendy, 2004). Cocaine priming induced reinstatement of cocaine CPP in CREB mutant and wild-type mice, and increased the levels of pCREB in the VTA of the latter type. Conversely, stress-induced reinstatement of cocaine CPP was not achieved in CREB mutant mice, and pCREB levels in the amygdala in wild-type mice rose after
stress-induced reinstatement. These results indicate that stress- and drug-induced reinstatement produce different molecular changes in determined brain regions. Alterations in CREB levels in the limbic system (Nac and amygdala) appear to be related with stress-induced reinstatement, and the dysregulation of intracellular signaling in the amygdala may interfere with stress-induced reinstatement processes in CREBdeficient mice. The authors of that report suggested that, in wild-type mice, CREB acts presynaptically on CRE elements present in the promoter of the CRF gene (Hatalski and Baram, 1997), thereby increasing CRF production and release, which leads to the precipitation of stress-induced reinstatement. Since CRF1 is coupled with the cAMP pathway and CREB, deficits in CREB may uncouple CRF1 receptors, leading to an attenuation of signaling after stimulation (Kreibich and Blendy, 2004). However, it is important to be cautious when interpreting results obtained with knockout mice, since the behavioral changes observed when a gene is deleted may be due to unknown compensatory changes in other genes. The involvement of CREB in drug-induced reinstatement of morphine CPP has also been evaluated in rats in a study in which CREB levels on the day of reinstatement were found to have increased in the hippocampus and Nac and dropped significantly in the PFC, implying that drug-primed reinstatement involves the activation of CREB in several brain areas (Zhou and Zhu, 2006). Another study of the molecular correlates of reinstatement behavior focused on changes in the levels of glutamate NMDA (NR1, NR2A and NR2B) and AMPA (GluR1) receptor
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Fig. 2 – Neural circuits involved in stress-induced reinstatement. The role of several brain structures in stress-induced reinstatement of morphine and cocaine CPP has been studied by inflicting lesions or through intracranial administration of different compounds. ✓ The lesion of the structure affects stress-induced reinstatement. X The lesion of the structure does not affect stress-induced reinstatement. The administration of compounds related with the neurotransmitter system or receptor The administration of compounds related to the neurotransmitter cited in brackets blocks stress-induced reinstatement. system or receptor cited in brackets does not affect stress-induced reinstatement. mPFC: medial prefrontal cortex; NAcc: nucleus accumbens; BNST: bed nucleus of the stria terminalis; VTA: ventral tegmental area; LC: locus coeruleus; AMYG: amygdala; AMYG CeN: central nucleus of the amygdala. Continuous lines indicate the neural circuit involved in stress-induced reinstatement of morphine CPP. Broken lines indicate the neural circuit involved in stress-induced reinstatement of cocaine CPP.
subunits in brain regions associated with reward and drug craving, such as the Nac, hippocampus, PFC and amygdala (Ma et al., 2007; Cruz et al., 2008). NRB2 levels increased following drug or stress-induced reinstatement of morphine CPP: in the Nac and hippocampus in morphine-induced reinstatement and in the Nac and amygdala in forced swiminduced reinstatement (Ma et al., 2007). Moreover, to determine whether the active involvement of NR2B-containing NMDA receptors is necessary for reinstatement, rats received systemic injections of an antagonist that is highly selective for the NR2B subunit (ifenprodil, 1, 3 or 10 mg/kg) once the morphine CPP had been extinguished. Ifenprodil dose-dependently inhibited the reinstating effect of morphine priming but did not influence stress-induced reinstatement, suggesting that the neural mechanisms mediating drug-induced reinstatement are NMDA receptor-dependent and dissociable from the molecular/neurochemical substrates mediating stress-induced reinstatement. Furthermore, the microinjection of ifenprodil into the Nac and the CA1 region of the dorsal hippocampus inhibited the reinstating effect of morphine priming. These results indicate that the NR2B-containing NMDA receptors in the Nac and dorsal hippocampus play a significant role in mediating the reinstatement of morphine CPP (Ma et al., 2007). On the other hand, drug-induced reinstatement of amphetamine-CPP immediately after extinction (in adolescence) or 30 days later (in adulthood)
was accompanied by decreased levels of the GluR1 receptor subunit in the Nac, while the levels of the NR1 subunit were unaltered. These results suggest that the reinstatement of amphetamine-induced CPP is long-lasting and related to a decreased expression of AMPA receptors in the Nac (Cruz et al., 2008).
6.
Differences with self-administration studies
The animal model most commonly used to study relapse to drug seeking is the extinction-reinstatement model of intravenous self-administration. In this procedure, laboratory animals are trained to perform a task by which they selfadminister a drug, such as pressing a lever. After extinction of the behavior, the ability of different stimuli to reinstate the response is determined. Re-exposure to the drug, to environmental cues previously associated with the drug, or to a stressful event induces the reinstatement of self-administration (for reviews, see Shaham et al., 2003; Shalev et al., 2002; Weiss, 2005). Recently, several laboratories have begun to use the place-conditioning procedure to study relapse to drug abuse (Tzschentke, 2007). In the CPP version of the reinstatement model, animals are first trained to acquire a CPP and later undergo a process of extinction of this preference. As detailed in preceding sections, both drug priming and stress
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induce the reinstatement of CPP. However, the reinstatement of the conditioned rewarding properties of the drug-paired environment induced by cues previously associated with the drug has not been evaluated.
Although most of the results obtained using the CPP model of reinstatement confirm those of self-administration studies (see Table 3), some discrepancies have emerged (see Table 4). These inconsistencies may be due to either a difference in
Table 3 Similarities observed in Drug-induced reinstatement of opioid seeking
Drug-induced reinstatement of psychostimulant seeking
Drug-induced reinstatement of other drugs of abuse
Cross-reinstatement
Stressors that induce/do not induce reinstatement of morphine seeking
Stressors that induce reinstatement of cocaine seeking Role of glutamatergic system in drug-induced cocaine seeking Role of opioid system in drug-induced reinstatement of ethanol seeking Role of CRF in stress-induced reinstatement of morphine seeking Role of noradrenergic system in stress-induced reinstatement of morphine seeking Role of DA system in stress-induced reinstatement of cocaine seeking Role of opioid system in stress-induced reinstatement of cocaine seeking Involvement of PFC in drug-induced reinstatement of cocaine seeking
Conditioned place preference (CPP) Morphine priming reinstates morphine CPP (Parker and McDonald, 2000; Lu et al., 2000; Wang et al., 2000; Heroin priming reinstates heroin CPP (Leri and Rizos, 2005) Cocaine priming reinstates cocaine CPP (Mueller and Stewart, 2000; Sanchez and Sorg, 2001) Amphetamine priming reinstates amphetamine CPP (Li et al., 2002; Cruz et al., 2008) Ethanol priming reinstates ethanol CPP (Kuzmin et al., 2003; Font et al., 2008) Nicotine priming reinstates nicotine CPP (Biala and Budzynska, 2006) MDMA priming reinstates MDMA-CPP (Daza-Losada et al., 2007) Amphetamine priming reinstates morphine CPP (Wang et al., 2000) Cocaine priming reinstates morphine CPP (Ribeiro Do Couto et al., 2005b) Ethanol priming reinstates nicotine CPP (Biala and Budzynska, 2008) Methamphetamine reinstates cocaine CPP (Itzhak and Martin, 2002) Methylphenidate reinstates cocaine CPP (Itzhak and Martin, 2002) BTCP reinstates cocaine CPP (Romieu et al., 2004) Morphine reinstates cocaine CPP (Romieu et al., 2004) Footshock reinstates morphine CPP (Lu et al., 2000) Precipitated drug withdrawal does not reinstate morphine CPP (Lu et al., 2005) Footshock reinstates cocaine CPP (Lu et al., 2002) Acamprosate blocks reinstatement of cocaine CPP (McGeehan and Olive, 2006) Naloxone blocks reinstatement of ethanol CPP (Kuzmin et al., 2003) CP-154,526 blocks reinstatement of morphine CPP (Lu et al., 2000) Clonidine in the BNST (but not in the LC) blocks reinstatement of morphine CPP (Wang et al., 2001) SCH 23390 (in PFC) blocks reinstatement of cocaine CPP (Sanchez et al., 2003) Arodyn blocks reinstatement of cocaine CPP (Carey et al., 2007). Lesion of the prelimbic mPFC attenuates reinstatement of cocaine CPP (Zavala et al., 2003)
Self-administration (SA) Heroin priming reinstates heroin SA (de Wit and Stewart, 1983)
Cocaine priming reinstates cocaine SA (de Wit and Stewart, 1981) Amphetamine priming reinstates amphetamine SA (Ranaldi et al., 1999) Ethanol priming reinstates ethanol SA (Lê et al., 1998) Nicotine priming reinstates nicotine SA (Chiamulera et al., 1996) MDMA priming reinstates MDMA SA (Banks et al., 2008) Amphetamine priming reinstates heroin SA (de Wit and Stewart, 1983) Cocaine priming reinstates heroin SA (De Vries et al., 1998) Nicotine priming reinstates ethanol SA (Lê et al., 2003) Amphetamine reinstates cocaine SA (Schenk and Partridge, 1999) Methylphenidate reinstates cocaine SA (Schenk and Partridge, 1999) BTCP reinstates cocaine SA (Martin-Fardon et al., 2005) Morphine reinstates cocaine SA (de Wit and Stewart, 1981) Footshock reinstates heroin SA (Shaham et al., 1996) Precipitated drug withdrawal does not reinstate SA of heroin (Shaham et al., 1996) Footshock reinstates cocaine SA (Erb et al., 1996) Acamprosate blocks reinstatement of cocaine SA (Bowers et al., 2007) Naltrexone blocks reinstatement of ethanol SA (Lê et al., 1999) CP-154,526 blocks reinstatement of heroin SA (Shaham et al., 1998) Clonidine icv (but not in the LC) blocks reinstatement of heroin SA (Shaham et al., 2000a,b) SCH in prelimbic or orbitofrontal cortex blocks reinstatement of cocaine SA (Capriles et al., 2003) JDTic blocks reinstatement of cocaine SA (Beardsley et al., 2005) Inactivation of the prelimbic mPFC cortex blocks reinstatement of cocaine SA (Capriles et al., 2003).
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Table 4 Differences observed in
Conditioned place preference (CPP)
Cross-reinstatement
Nicotine reinstates cocaine CPP (Romieu et al., 2004) Ethanol reinstates cocaine CPP (Romieu et al., 2004) Morphine reinstates cocaine CPP (Romieu et al., 2004); Restraint reinstates morphine CPP (Ribeiro Do Couto et al., 2006) Food deprivation does not induce reinstatement of morphine CPP (Ma et al., 2007) Spontaneous withdrawal does not induce reinstatement of morphine CPP (Lu et al., 2005) Conditioned fear stress (odor or tone previously paired with footshock) reinstates cocaine CPP (Sanchez and Sorg, 2001) Blockade of CRF1 receptors in the CeA or Nac attenuates reinstatement of morphine CPP (Wang et al., 2006) DA antagonists has no effects on reinstatement of morphine CPP (Ribeiro Do Couto et al., 2005c)
Stressors that induce reinstatement of opioid seeking
Stressors that induce reinstatement of cocaine seeking Role of CRF in priming-induced reinstatement of opioid seeking Role of DA in priming-induced reinstatement of opioid seeking
Role of DA in priming-induced reinstatement of cocaine seeking
Role of glutamate in priminginduced reinstatement of cocaine seeking
D1 agonist SKF 81297 reinstates cocaine CPP (Graham et al., 2007) D2 agonist quinpirole does not block reinstatement of cocaine CPP (Graham et al., 2007) The NMDA receptor antagonist memantine blocks reinstatement of cocaine CPP (Maldonado et al., 2007)
methodology – for example, the animals (species, strain, age and sex) and drugs (doses) employed – or the different response requirements used to assess reinstatement (leverpressing behavior versus movement to a chamber previously paired with the drug). Moreover, it should be considered that CPP and self-administration paradigms evaluate different aspects of reward and, thus, different characteristics of relapse and addictive behavior. Self-administration involves an operant conditioning, models drug-taking behavior and evaluates the primary rewarding properties of drugs, while CPP involves a Pavlovian conditioning, models cue-elicited drug-taking behavior and assesses the incentive value of drug-associated cues for maintaining addictive behavior. The reinstatement of self-administration after extinction implies the restoration of a concrete operant response, while the reinstatement of CPP consists of the reappearance of the approach behavior to a drug-associated context. The data provided by the two models regarding the involvement of different neurotransmitter receptors, such as CRF, DA or glutamate, in drug-induced reinstatement of morphine and cocaine seeking is a subject of discrepancy. The effects of CRF1 receptor blockade on drug-priming-induced reinstatement of morphine vary according to whether studies employ the CPP or self-administration model. When the former was employed, the blockade of these receptors in the central amygdala or Nac attenuated drug-priming-induced reinstatement (Wang et al.,
Self-administration (SA) Nicotine does not reinstate cocaine SA (Schenk and Partridge, 1999) Ethanol does not reinstate cocaine SA (de Wit and Stewart, 1981) Morphine does not reinstate cocaine SA (Schenk and Partridge, 1999) Restraint does not induce reinstatement of heroin SA (Shalev et al., 2000) Food deprivation reinstates heroin SA (Shalev et al., 2000) Spontaneous withdrawal reinstates heroin SA (Shaham et al., 1996) Neither a conditioned fear stress nor a predatory odor reinstate cocaine SA (Shaham et al., 2000a,b) icv α-helical CRF has minimal effects on reinstatement of heroin seeking (Shaham et al., 1997) DA antagonists undermine reinstatement of morphine SA (Ettenberg et al., 1996; Shaham and Stewart, 1996; McFarland and Ettenberg, 1997) D1 agonist SKF 81297 does not reinstate cocaine SA and attenuates cocaine-induced reinstatement (Khroyan et al., 2000) D2 agonist quinpirole produces reinstatement of cocaine SA (Khroyan et al., 2000) Memantine has no effect on reinstatement of cocaine SA (Bespalov et al., 2000)
2006), while in the latter paradigm, the ventricular injections of αhelical CRF had minimal effects on heroin-priming-induced reinstatement of heroin seeking (Shaham et al., 1997). On the other hand, with the CPP paradigm, DA antagonists exerted no effects on morphine-induced reinstatement of a previously extinguished morphine CPP (Ribeiro Do Couto et al., 2005c), while selective D1 (SCH 23390), D2 (raclopride) and non-selective (flupenthixol, haloperidol) DA receptor antagonists undermined reinstatement in the self-administration model (Ettenberg et al., 1996; Shaham and Stewart, 1996; McFarland and Ettenberg, 1997). More recently, the influence of D2 receptors in relapse to heroinseeking behavior has been reported given that the activation of these receptors with quinpirole led to a reinstatement of response during early but not late phases of withdrawal (De Vries et al., 2002). When reinstatement of cocaine is evaluated using the selfadministration or CPP model, the effects of the DA agonists also vary. The ability of the D1 agonist SKF 81297 to reinstate cocaine CPP (Graham et al., 2007) contrasts with its failure to reinstate cocaine-seeking behavior and its attenuation of cocaine- and cue-induced reinstatement in self-administering animals (Self et al., 1996; Alleweireldt et al., 2002). Interestingly, administration of a D1-receptor agonist or antagonist dose-dependently attenuates cocaine-seeking behavior elicited by cocaine priming (Khroyan et al., 2000; Self et al., 1996) or by stimuli previously paired with cocaine (Alleweireldt et
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al., 2002; Ciccocioppo et al., 2001). Moreover, the administration of D1-like agonists into the Nac reinstates cocaine seeking (Bachtell et al., 2005; Schmidt et al., 2006). The D2/D3 agonist quinpirole induces a strong aversion to the cocaine-paired side but has no effect on cocaine-induced reinstatement of CPP (Graham et al., 2007), which contrasts with its ability to reinstate cocaine self-administration (Self et al., 1996; Edwards et al., 2007). These results imply that the role of D1 and D2/D3 receptors in the reinstatement of cocaine-seeking behavior differs depending on whether instrumental or classical procedures are used. Graham et al. (2007) have put forward an explanation based on the way in which DA signals are temporally linked to behavior in both procedures. In cocaine self-administration, DA signals are temporally linked in a response-contingent manner to instrumental behavior. In this way, a lasting D1 receptor activation would mask rather than mimic these discrete reward-related signals (cocaine priming or drug cues) and undermine their capacity to control instrumental behavior. In the CPP paradigm, discrete timing of dopaminergic signals during induction of contextual conditioning is not necessary; therefore, D1 receptor activation during reinstatement may mimic rather than mask the cocaine stimulus experienced during induction of the CPP. On the other hand, D2/D3 activation could reinforce the control exerted by conditioned stimuli over instrumental behavior in the self-administration paradigm (leading to reinstatement), while undermining the control exerted by cocaine-conditioned contextual stimuli in the CPP paradigm (leading to a failure to induce reinstatement). Similarly, the effects of NMDA antagonists on reinstatement of cocaine differ according to the paradigm used. In a self-administration procedure, administration of memantine prior to a priming injection of cocaine eliminated the difference between reinforced and non-reinforced lever response rates; an effect that was due rather to a stronger response to the non-reinforced lever than to a diminished response to the reinforced-lever. In the same study, memantine failed to block the selective increase in the reinforced-lever response induced by exposure to cocaine-related stimuli (Bespalov et al., 2000). Moreover, the NMDA receptor antagonist CGP 39551 has no effect on cue-induced cocaine self-administration (Bäckstrom and Hyytiä, 2006). However, when the CPP paradigm is employed, memantine blocks the reinstatement of cocaine CPP (Maldonado et al., 2007). As discussed previously, the disparity of results obtained with place-conditioning and self-administration models of relapse could be related to methodological aspects. Another discrepancy between CPP and self-administration reinstatement models is the effects of different types of stress on reinstatement. One study using the latter paradigm found that footshock and restraint stress had no effect on the reinstatement of heroin seeking in rats (Shalev et al., 2000). The authors stated that these stressors were ineffective because they were experienced outside the self-administration environment, and suggested that the effects of stress on reinstatement in heroin-trained rats is context- and time-dependent (Shalev et al., 2000). Conversely, a clear reinstatement of morphine-induced CPP was produced in the CPP paradigm, in which restraint and tail-pinch were administered in a different environment to that of place-conditioning, and which
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included two temporal intervals between the stress and the test (0 and 15 min) (Ribeiro Do Couto et al., 2006). Similarly, in self-administration studies, a conditioned fear stress or predatory odor did not reinstate drug self-administration (Shaham et al., 2000a), while a conditioned fear stress (odor or tone previously paired with footshock) produced the reinstatement of cocaine CPP (Sanchez and Sorg, 2001). A possible explanation for these differences is that, in the selfadministration paradigm, the freezing response interferes with operant response (conditioned suppression) to a greater extent than it does with movement in the CPP chambers. Alternatively, the two types of behavior measured (CPP versus self-administration) represent different aspects of behavioral response, and are, therefore, influenced by conditioned fear stimuli in different ways. Finally, in another report, spontaneous withdrawal reinstated heroin seeking in the selfadministration model (Shaham et al., 1996), but failed to reinstate morphine CPP (Lu et al., 2005). In humans, stimuli previously associated with stressful events can precipitate relapse. Other differences between both models include the effects of low doses of drugs, contingency of drug and type of extinction employed. A clear difference between self-administration and CPP reinstatement is observed when low doses of rewarding drugs are used. While it is difficult to reinstate CPP with a prime following conditioning with low doses (Orsini et al., 2008), one study has reported that reinstatement was more pronounced after self-administration sessions with lower unit doses (which resulted in lower total intake in terms of mg/kg, but a higher number of lever presses) than after those that employed higher unit doses (Keiflin et al., 2008). Moreover, in self-administration, the drug is contingent, whereas in CPP conditioning, the drug is non-contingent. Several studies have demonstrated different long-term effects on contingent versus non-contingent drug administration (Jacobs et al., 2005), which may be responsible for differences seen later on during reinstatement. Finally, self-administration sometimes involves a within session extinction/reinstatement (Maccioni et al., 2008), while extinction takes place over several days in the case of CPP. Thus, in both paradigms, differences in drug administration prior to extinction (non-contingent for CPP, and goaldirected with a work requirement for self-administration), are bound to produce clear differences in the dose-dependent effects of a rewarding drug with respect to vulnerability to reinstatement. The time course of vulnerability to reinstatement seems to differ in the CPP and self-administration versions of the reinstatement model. In CPP studies, reinstatement is generally affected by the time elapsed since the previous conditioning session or drug administration. In the selfadministration model, the magnitude of the reinstatement response induced by drug priming, footshock stress or discrete cues does not decrease over time, as cue reactivity rises gradually over a period of weeks or months (incubation effect). However, a recent study has reported that the CPP induced by a low dose of cocaine can only be reinstated after long withdrawal periods, and not immediately after extinction (Orsini et al., 2008), suggesting that the incubation effect may be also characteristic of CPP reinstatement.
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7.
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Relevance of findings to human relapse
The main challenge in the management and treatment of drug addiction is the development of a pharmacotherapy that diminishes craving and, consequently, vulnerability to relapse. The results obtained in studies using the CPP and self-administration versions of the reinstatement model endorse the idea that the neuronal and neurotransmission events that mediate reinstatement differ and are not necessarily associated with those that mediate drug reinforcement (Shalev et al., 2002). Several types of anticraving medication are available nowadays, including naltrexone for alcoholism, bupropion for nicotine, and methadone or buprenorphine for heroin (van dern Brink and van Ree, 2003). However, the efficacy of these treatments is limited and there is a need to develop new compounds with increased therapeutic action and reduced side-effects. Since the CPP version of the reinstatement model is relatively new, only a few compounds have been tested to date, which makes it difficult to assess its validity as a method with which to screen for drugs with therapeutic potential in humans. To confirm the validity of the CPP reinstatement model as a screening method, it is necessary to demonstrate that drugs that are clinically effective are also effective in the model, and that those that are not effective in the clinic are not effective in the model. To date, of all of the drugs approved by the FDA for treating abuse, only naloxone and acamprosate have been tested in the CPP reinstatement model (Kuzmin et al., 2003; McGeehan and Olive, 2006). Moreover, it is difficult to assess the validity of the model by extrapolating the data obtained with the self-administration model, due to the clear differences between the two (as mentioned previously). Several pharmacological agents block the reinstatement of CPP induced by different drugs of abuse and stress. The NMDA glutamate antagonist memantine is a promising candidate for the treatment of drug craving, since it blocks drug-induced reinstatement of morphine- and cocaine-induced CPP (Maldonado et al., 2007; Popik et al., 2005; Ribeiro Do Couto et al., 2005b). It is a fast, voltage-dependent NMDA receptor antagonist and blocks the NMDA receptor when there is a sustained release of low concentrations of glutamate, thus attenuating NMDA receptor function. Clinically, it is used to treat Alzheimer's disease. However, memantine has several sideeffects that limit its utility, such as dizziness, headache and constipation. Another agent, acamprosate, which modulates glutamate receptor function and is used to reduce alcohol craving and relapse, blocks cocaine-induced reinstatement (McGeehan and Olive, 2006), which highlights its potential for preventing relapse to cocaine abuse. In humans, GHB has proven to be effective as a therapeutic tool for combating craving and the symptoms of withdrawal from alcohol and opiates (Addolorato et al., 1998; Gallimberti et al., 1989, 1994). Results obtained with the CPP version of the reinstatement model suggest that GHB undermines cocaine CPP (Maldonado et al., 2006), which is of relevance to the treatment of poly-drug cocaine abusers. However, the narrow margin of effective doses may be an obstacle to its utility as a tool for treating cocaine addicts. The efficacy of CRF antagonists in the treatment and prevention of drug- and stress-induced relapse is by the fact
that these compounds block reinstatement of CPP induced by exposure to morphine (Lu et al., 2002; Wang et al., 2006) and stress (Lu et al., 2000, 2005). Similarly, the utility of CCK antagonists in treating drug- and stress-induced relapse must be studied, since CCK-B antagonists block morphine- and stressinduced reinstatement of morphine CPP (Lu et al., 2001b; Lu et al., 2002) while CCK-A antagonists block cocaine-induced reinstatement of cocaine CPP (Lu et al., 2002). Reinstatement of ethanol CPP is inhibited by naloxone, nociceptin and an ORL1 agonist (Kuzmin et al., 2003), which also blocks reinstatement of morphine CPP (Shoblock et al., 2005). Similarly, stress-induced reinstatement is blocked by the κ opioid antagonist arodyn (Carey et al., 2007). These results highlight naloxone, drugs targeted to the ORL1 receptor and opioid κ antagonists as potential therapeutic agents against drug-seeking behavior and relapse. Finally, given that the reinstatement of nicotine CPP induced by nicotine, morphine, WIN55,212-2 and ethanol is blocked by the calcium channel blockers nimodipine and flunarizine (Biala and Budzynska, 2006, 2008), the potential of these latter agents for treating drug-induced relapse should be studied.
8.
Theoretical landscape
The CPP is a procedure commonly used to study the conditioned rewarding effects of drugs of abuse. There is considerable concordance between drugs with abuse liability and those that produce CPP; a fact that is difficult to explain from a theoretical standpoint. In the CPP paradigm, the primary motivational properties of a drug serve as an unconditioned stimulus that is repeatedly paired with a previously neutral set of environmental stimuli (cues). In the course of conditioning, these stimuli acquire secondary motivational properties, so that they produce approach behaviour when the animal is subsequently exposed to them (Tzschentke, 2007). The CPP paradigm is based on classical conditioning principles, although it does raise some conceptual problems. For example, it is not yet clear what constitutes the unconditioned response induced by the drug. The conditioned response (longer time spent in the drug-paired environment) is due to the association of the affective reaction induced by the drug and the distinctive environment in which the animal always experiences this affective reaction. With repeated pairings, this previously neutral environment acquires a positive valence or salience, inducing an approach behavior in the animal and leading it to spend more time in close contact with these drug-associated cues. On the other hand, and although the CPP cannot be explained within an operant framework (since there is not a discrete response that is reinforced), the more marked approach response to the drug-paired compartment may represent a component of operant learning. In fact, during tests for CPP expression or reinstatement, the operant response of entering the drug-paired chamber could be strengthened by the availability of secondary reinforcers (the conditioned reward of the chamber). What is actually learned during place preference conditioning is a question that continues to demand a response. What constitutes the essential aspect under study with the CPP version of the reinstatement model is another important
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aspect to be determined. The CPP presents extinction when animals are repeatedly exposed to conditioned stimuli in absence of unconditioned stimuli. Which of these stimuli are altered when the stimulus-stimulus association is extinguished is a relevant question that is difficult to answer. The change in the behavior of the animal (progressive decrease in the time spent in the drug-paired compartment) may be due to changes in its motivational state or in the ability of the stimulus to direct its behavior, or both. The phenomenon of reinstatement of learned behavior following extinction was first described by Pavlov in his classic conditioning studies with dogs (Pavlov, 1927). The recovery of CPP after extinction is a classical conditioning model of reinstatement in which approach behavior to a drug-associated context is reinstated, which provides an occasion for drug-taking behavior (Bardo and Bevins, 2000). It is well known that environmental cues associated with drug experience play a critical role in maintaining drug-taking behavior and in relapse after extinction. The reinstating effects of drug priming can be attributed to the hedonic properties of the drug, which produce an incentive motivational state in the animals that promotes drug craving and leads them to seek environmental stimuli associated with the drug. Moreover, the drug priming may recall the extinguished CPP. After the extinction of CPP, the reinstatement of this behavior following a priming injection of the drug could be explained as a “restoration” of the significance or attractiveness of the drug-paired environmental stimuli, which leads the animal to approach those cues and remain in their presence. Indeed, this approach behavior could reflect a reinstatement of craving that leads the animal to seek once more the environmental stimuli it associates with the presence of the drug. According to Mueller and Stewart (2000), the priming injection “reminds” the animal of the significance of the cues previously paired with the drug. Drug-primed reinstatement of CPP is considered to reflect the renewed incentive value of the environmental stimuli via the incentive motivational effects of the drug priming (Mueller and Stewart, 2000). It has been suggested that drug priming induces reinstatement and cross-reinstatement of CPP through the activation of the mesocorticolimbic DA system, thereby influencing incentive motivation and appetitive goal-directed behavior (Wang et al., 2000). However, it has been observed that drug-induced reinstatement of CPP is largely independent of DA neurotransmission, at least with respect to opiate CPP (Ribeiro Do Couto et al., 2005c). Several mechanisms have been proposed to explain the reinstating effect of stress (Shalev et al., 2002), such as the activation of the mesocorticolimbic DA system (Shaham and Stewart, 1995), interference with neuronal inhibitory processes like the medial septum (which inhibits response when reinforcers are not available) (Highfield et al., 2000) and the induction of a withdrawal-like state (aversive feelings that lead animals to recall the motive for approaching the formerly drugpaired chamber) (Whitehead, 1974; Wang et al., 2000). Results obtained with the self-administration paradigm challenge this idea; only spontaneous and not antagonist-precipitated withdrawal reinstates heroin seeking, while footshock stress reinstates drug seeking in animals receiving a maintenance dose of heroin (Shaham and Stewart, 1995; Shaham et al., 1996). Conversely, morphine CPP is reinstated by conditioned withdrawal, which may be a stress-driven effect (Lu et al., 2005).
9.
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Shortcomings of the field
One of the shortcomings of the CPP procedure is the lack of dose–response effects that it produces. Generating a dose– response curve is a standard procedure in the field of behavioral pharmacology; however, this seems to be the exception rather than the rule in the case of the CPP. In this way, it is difficult to employ the CPP to compare the efficacy or potency of different drugs or draw conclusions regarding sensitization. It has been proposed that intermittent exposure to a drug of abuse increases behavioral and neurochemical effects (sensitization), which can lead to relapse (De Vries et al., 2002). Extinguished CPP may be reinstated by doses of the drug lower than that used to produce CPP acquisition, which suggests that a sensitization process contributes to reinstatement through drug priming. Moreover, in some studies, the time spent in the drug-paired compartment after a priming injection of cocaine or morphine was significantly higher than that during the test for CPP (Ribeiro Do Couto et al., 2003, 2005c; Szumlinski et al., 2002), which could be explained as a result of sensitization to the rewarding effects of these drugs. In one study performed in our laboratory (Ribeiro Do Couto et al., 2005a) we evaluated changes in the efficacy of drug priming in inducing reinstatement, and observed some sensitization when extinction/reinstatement took place at 6 week intervals. Reinstatement occurred in animals after the administration of progressively decreasing doses of morphine, even at a dose that was ineffective in animals without previous experience of reinstatement. These results suggest that, when drug-induced reinstatement is repeated, there is sensitization to the reinstating effects of morphine. The fact that the drug is administered by the researcher, and that total exposure is generally low, are factors that limit the relevance of the CPP version of the reinstatement model with respect to compulsive and chronic drug use. Furthermore, as this model does not evaluate the primary reinforcing effects of drugs, the results obtained with it should be complemented with others provided by the self-administration paradigm in order to determine the anatomical, neurochemical and behavioral correlates of drug-seeking reinstatement. Moreover, the duration of CPP reinstatement should be studied to distinguish between lapse and relapse, as Leri and Stewart (2002) did with the self-administration paradigm. Another deficiency of the CPP version of the reinstatement model is the lack of studies evaluating the cue/contextinduced reinstatement of the conditioned rewarding properties of a drug-paired environment in this paradigm. As already discussed, the CPP evaluates the power of drug-paired environmental cues to elicit drug-seeking behavior. For this reason, it is impossible to discriminate between the reinstating effect of re-exposure to environmental cues and of drug priming or stress. A possible strategy with which to overcome this difficulty is to design studies in which a discrete environmental cue, for example a red light, is placed in the drugpaired compartment and its influence in inducing reinstatement is subsequently evaluated. We are currently carrying out studies along these lines. A further shortcoming of the CPP version of the reinstatement model is the interpretation of the reinstating effect of
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drug-priming. Some authors have suggested that reinstatement of CPP is due to a state-dependent learning phenomenon attributable to the discriminative stimuli properties of the drugs. The drug is present and therefore acts as a stimulus during conditioning and reinstatement but not during extinction tests. For this reason, if the expression of CPP is statedependent, animals only show CPP in the presence of the drug. According to this hypothesis, exposure to the drug during test reinstatement should produce a selective increase in the response previously associated with the drug due to its discriminative stimuli properties. However, for several reasons, it is unlikely that the discriminative properties of drug priming injections are responsible for the totality of their effect on reinstatement of CPP. Firstly, in the placeconditioning paradigm, the drug is not associated with a specific instrumental response; thus, it is unlikely that drug priming induces the response habitually elicited by the discriminative properties of the drug. In fact, during the test for CPP, animals exhibit a clear CPP, although they do not receive any treatment or injection on this day. Secondly, the neuronal substrates that mediate discriminative effects (Jaeger and van der Kooy, 1996) are different to those involved in drug-induced reinstatement (Shaham et al., 2003; Shalev et al., 2002). Thirdly, the observation that morphine- and cocaine-induced CPP are reinstated by drugs other than that used during conditioning (cross-reinstatement) challenges the results of drug discrimination studies, which report that generalization to a training drug is typically observed within a given class of drug (Stolerman et al., 1995) but not among drugs from different pharmacological families. Finally, reinstatement can be induced by non-drug stimuli; for example, stress exposure. In this way, since the stimuli used in conditioning and reinstatement phases often differ, we believe that drug-induced reinstatement is not a result of a statedependent retrieval deficit. However, state-dependent learning is not to be ruled out as an explanation for reinstatement. The effects of priming, cross-reinstatement and stressors could be due to context-dependent learning during extinction (of the A→B→A/C type); in other words, the animals learn CPP in the presence of one drug (context A), learn extinction in the absence of drug (context B), and are then tested for reinstatement in a context other than that of extinction (context A in the case of a prime and context C in the case of crossreinstatement or stress). Reinstatement could be explained by the fact that the animal does not learn extinction in this state or context, which may explain reinstatement independently of incentive effects. On the other hand, lithium priming reinstates the conditioned place aversion induced by the same compound (Parker and McDonald, 2000) and morphine withdrawal reinstates place aversion that it induces (Li et al., 2007). These results suggest that CPP and conditioned place aversion can be reinstated by re-exposure to the stimulus that has induced conditioning. As discussed previously, it is not clear whether reinstatement is due to a modification of the incentive value of the chamber or of the motivational state of the animal, or to a state-dependent learning. An additional limitation of the CPP paradigm lies in that drugs are administered acutely in reinstatement studies but chronically in clinical trials. For this reason, drugs that effectively block reinstatement of CPP can induce different
therapeutic or collateral effects when administered chronically to prevent relapse in humans.
10.
Priorities for future research
The CPP version of the reinstatement model is a relatively new field of behavioral pharmacology. Studies performed in recent years have provided valuable information on the neurobiological basis of drug- and stress-induced reinstatement, as described in the course of this review. However, it does possess some shortcomings, and extensive work with improved methods and procedures must be performed in future years to expand and hone the collective knowledge regarding the neurobiology of relapse. According to the recently demonstrated involvement of the endocannabinoid system in reinstatement of self-administration (Fattore et al., 2007), the study of the role of this neurotransmitter system in the reinstatement of CPP is a priority. Already, one report has demonstrated that priming with the cannabinoid receptor agonist WIN55,212-2 reinstates nicotine CPP (Biala and Budzynska, 2008). The effects of cannabinoid agonists and antagonists on the reinstatement of the CPP induced by different drugs of abuse should also be evaluated by future studies. Another area of relevance to be addressed by future studies is the influence of pre-natal or adolescent drug exposure on the reinstatement of the CPP induced by different drugs of abuse in adulthood. For example, a recent study in our laboratory revealed an effect of pre-treatment during adolescence with MDMA and cocaine on acquisition and reinstatement of morphine-induced CPP. The results obtained suggest that periadolescent MDMA exposure alters responsiveness to the rewarding properties of morphine (Daza-Losada et al., 2008). Future studies should evaluate whether pre-treatment during critical phases of brain development with “gateway drugs”, such as ethanol, nicotine and cannabinoids, modifies susceptibility to reinstatement in adulthood. The identification of the neural basis of cross-reinstatement is also a priority. It is important to know which drugs induce reinstatement of the CPP induced by opioids, psychostimulants and other drugs of abuse, and to determine which neurotransmitter systems are involved in this phenomenon. Similarly, a model of cue-induced reinstatement of CPP must be developed in future years. It is well established that drugassociated contextual stimuli, which are initially neutral, gain secondary motivational value through their association with the pleasurable experiences induced by drugs, and are, thus, capable of provoking craving and relapse (Meyer, 1988). Future studies should seek to increase the homology of animal models of reinstatement with human relapse. Successive relapses following prolonged drug-free periods characterize the behavior of experienced addicts of heroin and other drugs of abuse. Some studies using the self-administration paradigm have indicated that the amount of drug intake during training influences the effect of drug priming on reinstatement (for a review, see Shalev et al., 2002). In our laboratory we have observed that repeated extinction-reinstatement sessions increase the reinstating effects of morphine (Ribeiro Do Couto et al., 2005a). Reinstatement of morphine CPP in mice
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can be induced up to 30 weeks after conditioning by a priming dose of morphine approximately twenty four times lower than that used for conditioning, and which would not induce reinstatement after a single extinction (Ribeiro Do Couto et al., 2003). The fact that successive drug-induced reinstatements are possible following extinction with very low doses and a considerable time after conditioning confirms drug addiction as a chronic, relapsing and lasting-long disorder. Furthermore, it should be stressed that the interval between conditioning and reinstatement and between different extinction/reinstatement experiences affects the reinstating effects of morphine. When these intervals are enlarged and the animals have no further experience related to the previously learned CPP, a decrease in the priming effect of morphine is observed, probably due to an impairment of its ability to recall the extinguished CPP (Ribeiro Do Couto et al., 2005a). We are presently performing a series of studies of prolonged conditioning (which models addictive behavior more closely), and preliminary results are promising, since animals exposed to drugs over an extended conditioning phase present different addiction criteria to those undergoing shorter (habitual) conditioning. The study of the influence of different procedural and environmental factors on the ability of a drug to induce reinstatement must be a priority of future research in the field.
11.
Conclusion
The data presented in this review confirm that the CPP version of the reinstatement model is a useful tool for investigating the neurobiological mechanisms of drug- and stress-induced reinstatement of the conditioned rewarding properties of the drug-paired environment and vulnerability to relapse. Drug priming with the conditioning drug or with another substance induces reinstatement of the CPP induced by different drugs of abuse. Several neurotransmitter systems are involved in priming- and stress-induced reinstatement (dopamine, glutamate, opioid, CRF, NA, CCK, etc), although both types of reinstatement are mediated, at least partially, by different neural pathways. Different molecular correlates of reinstatement behavior have been detected, such as the activation of CREB and changes in different subunits of glutamate receptors. The CPP version of the reinstatement model may provide supplementary information to that offered by the traditional intravenous self-administration method, since both procedures permit the evaluation of different aspects of drug relapse. With some exceptions, similar results are obtained with both paradigms, suggesting that the neurobiological basis of self-administration and CPP reinstatement generally overlap. The CPP version of the reinstatement model offers a number of advantages, as it is a relatively inexpensive, non-invasive, rapid and uncomplicated procedure. Moreover, the locomotor effects of drugs produce less interference with the animal's behavior in the CPP than in the self-administration model. Indeed, if a drug produces catalepsy or a similarly severe behavioral disruption, the CPP would clearly be influenced. The CPP version of the reinstatement model has a good criterion validity, which refers to the extent to which laboratory-animal behavior induced by experimental manipulation predicts human behavior induced by a similar event
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(Epstein et al., 2006; Geyer and Markou, 1995). Some conditions that have been reported to provoke drug craving and relapse in humans, such as acute re-exposure to the drug (de Wit, 1996) and stress (Sinha, 2001), induce reinstatement of CPP. Unfortunately, the reinstatement model has a poor construct validity, which refers to the similarity between the mechanisms underlying behavior in the model and modeled condition (Epstein et al., 2006; Geyer and Markou, 1995). There is a lack of homology between the human condition and both reinstatement of CPP and self-administration. For example, the drugfree state occurs for different reasons, and there is no parallelism between drug-priming-induced reinstatement (induced by a non-contingent forced priming) and a selfinitiated relapse. However, several self-administration models are now being employed to experiment with non-imposed drug-free states (for example, using shock to decrease lever pressing) as an alternative to the habitual procedure of extinction (Cooper et al., 2007). Such a technique – for example, shocking the floor of the drug-paired chamber – could be easily employed in the CPP paradigm. In addition, the CPP version of the reinstatement model would appear to be a useful tool for screening the clinical efficacy of new compounds that prevent relapse. An in-depth review of the validity of the reinstatement model has recently been provided by Epstein et al. (2006). At the present time, a theoretical understanding of the CPP version of the reinstatement model is incomplete. Furthermore, several shortcomings limit the validity of this paradigm. The overcoming of these deficiencies should be among the priorities of future research in the field, with the aim of increasing the homology of the procedure with human relapse to drug abuse.
Acknowledgments We wish to thank Mr. Brian Normanly for his editing of the manuscript. This work was financed by the following grants: Ministerio de Sanidad y Consumo, Instituto de Salud “Carlos III” (FIS), RETICS, Red de Trastornos Adictivos (RD06/001/0016); Ministerio de Educación y Ciencia, Dirección General de Investigación and FEDER (SEJ2005-00316/PSIC) (Spain) and Generalitat Valenciana, Agencia Valenciana de Salud, Dirección General de Drogodependencias (FEPAD).
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Glossary of terminology CPP paradigm A classical conditioning procedure used to study the conditioned rewarding effects of drugs and other
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stimuli. During conditioning a set of neutral environmental stimuli is paired with the reinforcing effect of a drug. During the test for CPP, the animal, in a drug-free state, is allowed to choose between the drug-paired and the vehicle-paired environment. An increase in preference for the drug-paired context serves as a measure of the conditioned rewarding effects of the drug. Craving Hypothetical construct that is defined as the memory of the pleasant rewarding effects of drug use, superimposed on a negative emotional state (Koob and Le Moal, 2008). Cross-reinstatement Reinstatement of drug seeking, following extinction, by drugs other than that administered during acquisition of behavior (self-administration or CPP). Drug addiction Chronically relapsing disorder characterized by compulsion to seek and take the drug, loss of control in limiting intake and emergence of a negative emotional state when access to the drug is prevented (Koob and Le Moal, 2008). Drug self-administration paradigm An operant procedure in which animals perform a discrete response (typically lever press) in order to receive an injection of a drug. The drug is a positive reinforcer that controls behavior. Extinction Extinction refers to discontinuing the reinforcement of a response (in the operant conditioning) or the appearance of the conditioned stimulus in the absence of the primary reinforcer (in classical conditioning). Reinstatement Reinstatement refers to the recovery of a learned response when a subject is non-contingently exposed to an unconditioned stimulus after extinction. In studies of reinstatement of drug seeking, reinstatement refers to the recovery of drug-seeking behavior after extinction following exposure to drugs (drug-induced reinstatement), drug cues (cue-induced reinstatement) or stressors (stress-induced reinstatement). Relapse Return to drug-taking behavior following drug-free periods. This is one of the core features of addiction and the most difficult clinical problem in addiction treatment. After prolonged abstinence, relapse is often precipitated by acute re-exposure to the drug itself, drug-associated cues or stress. Versions of the extinction/reinstatement model The extinctionreinstatement model is a procedure used to study relapse into drug abuse in laboratory animals. Animals are first trained to acquire a behavior and, subsequently, undergo a process of extinction of this behavior. Afterwards, animals are exposed to different stimuli in order to evaluate their efficacy in inducing reinstatement of the previously acquired and extinguished behavior. There are two main versions of the reinstatement model; one based on the operant selfadministration procedure (the behavior acquired, extinguished and reinstated is typically the pressing of a lever), and the other based on the classical conditioned place preference procedure (the behavior acquired, extinguished and reinstated is CPP).
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Neurobiological mechanisms of the reinstatement of drug-conditioned place preference Maria A. Aguilar, Marta Rodríguez-Arias, Jose Miñarro⁎ Unidad de Investigación Psicobiologia de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain
A R T I C LE I N FO
AB S T R A C T
Article history:
Drug addiction is a chronic disorder characterized by a high rate of relapse following
Accepted 13 August 2008
detoxification. There are two main versions of the reinstatement model that are employed
Available online 18 August 2008
to study relapse to drug abuse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference procedure. In the last seven years,
Keywords:
the use of the latter version has become more widespread, and the results obtained
Conditioned place preference
complement those obtained in self-administration studies. It has been observed that the
Reinstatement
conditioned place preference induced by opioids, psychostimulants, nicotine, ethanol and
Drug priming
other drugs of abuse can be extinguished and reinstated by drug priming or exposure to
Stress
stressful events. Herein, the neuroanatomical and neurochemical basis of drug priming-
Drug addiction
and stress-induced reinstatement of morphine and cocaine, together with the molecular correlates of reinstatement behavior, are reviewed. Differences between the conditioned place preference and self-administration studies are also discussed. Evidence suggests that data of reinstatement with the CPP are to be viewed with caution until more extensive analysis of operant procedures has been performed, and that further research will undoubtedly improve our understanding of the neurobiological mechanisms of relapse to drug seeking. © 2008 Elsevier B.V. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . Experimental approaches—methodology. . . . . . . . 2.1. Acquisition . . . . . . . . . . . . . . . . . . . . 2.2. Extinction . . . . . . . . . . . . . . . . . . . . . 2.3. Reinstatement. . . . . . . . . . . . . . . . . . . 2.3.1. Drug priming-induced reinstatement . 2.3.2. Stress-induced reinstatement. . . . . . Neural mechanisms underlying reinstatement of CPP 3.1. Dopamine . . . . . . . . . . . . . . . . . . . . . 3.2. Glutamate . . . . . . . . . . . . . . . . . . . . . 3.3. Endogenous opioids . . . . . . . . . . . . . . .
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⁎ Corresponding author. Fax: +34 96 386 46 68. E-mail address: [email protected] (J. Miñarro). 0165-0173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2008.08.002
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3.4. Corticotrophin-releasing factor . . . . . . 3.5. Noradrenaline . . . . . . . . . . . . . . . 3.6. Cholecystokinin . . . . . . . . . . . . . . 3.7. Other neurotransmitter systems . . . . . 3.8. Other manipulations . . . . . . . . . . . . 4. Stress- versus drug-induced reinstatement . . . 5. Molecular correlates of reinstatement behavior. 6. Differences with self-administration studies . . 7. Relevance of findings to human relapse. . . . . 8. Theoretical landscape . . . . . . . . . . . . . . . 9. Shortcomings of the field . . . . . . . . . . . . . 10. Priorities for future research . . . . . . . . . . . 11. Conclusion . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . Glossary of terminology . . . . . . . . . . . . . . . . .
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Introduction
Drug addiction can be considered a chronic, recurrent brain disease characterized by relapse (Le Moal and Koob, 2007). The high rate of relapse to drug use after detoxification is a major clinical problem and constitutes the primary challenge to the treatment of drug abuse. Intense craving for drugs and relapse to drug-using behavior are observed in abstaining addicts who are confronted with environmental stimuli associated with their drug-taking behavior, the drug itself or stress, even after long periods of abstinence (de Wit, 1996; el-Guebaly and Hodgins, 1998; O'Brien, 1997). The tendency towards relapse in addiction suggests that drugs of abuse produce permanent alterations in the brain (Nestler, 2004). In laboratory animals, it is possible to measure relapse when, following the acquisition and subsequent extinction of a particular behavioral response, the animal reinitiates this response, which is referred to as reinstatement (Carroll and Comer, 1996). There are two main variations of the reinstatement model that are used to study relapse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference (CPP) procedure. In the latter of the two, animals are first trained to acquire a CPP and later undergo a process of extinction of this preference. Reexposure to the drug or to a stressful event induces reinstatement of CPP (for a review, see Shaham et al., 2003; Shalev et al., 2002; Tzschentke, 2007; Weiss, 2005). In addition to reinstatement, other methods can be used in the CPP to measure relapse (re-acquisition and spontaneous recovery). The aim of the present work is to provide an overview of the knowledge obtained to date with the CPP version of the reinstatement model. Most studies have employed morphine and cocaine to evaluate the drug- or stress-induced reinstatement of CPP, although a few have employed other drugs of abuse. We also intend to paint the theoretical landscape of the CPP version of the reinstatement model, identifying areas of dispute, analyzing shortcomings in the field and proposing priorities for future work.
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262 262 263 263 264 264 265 266 270 270 271 272 273 273 273 277
Experimental approaches—methodology
The CPP paradigm has been widely used to study the conditioned rewarding effects of addictive drugs, since contextual stimuli can acquire secondary appetitive properties (conditioned rewarding effects) when paired with a primary reinforcer, thereby highlighting the liability of abuse (Tzschentke, 2007). In this paradigm, the conditioned rewarding properties of drugs are evaluated by pairing drug effects with initially neutral cues, such as the compartment of an apparatus. The test for CPP can be performed in a drug-free state, enabling an investigation of the appetitive value of drugassociated contextual stimuli while avoiding the confounding influence of consummatory variables. If, after conditioning, the animals spend more time in the compartment associated with the drug, it is assumed that the drug produces CPP.
2.1.
Acquisition
The neutral value of the compartments of the apparatus is evaluated in a pre-conditioning phase in which the time spent in each compartment is recorded and compared with that spent in the same compartment in the test for CPP. When the pre-conditioning test is not performed, the presence of CPP is evaluated by comparing the time spent in the drug- and vehicle-paired compartments (Parker and McDonald, 2000) or comparing vehicle- and drug-conditioned animals (Wang et al. 2000, 2002). The main difference between the studies published until now lies in the protocols followed and the type of drug administration schedule applied during conditioning (see Table 1). There are three types of conditioning: biased, unbiased and balanced. In a biased protocol, the drug is always associated with the same compartment (generally that which was not preferred in a pre-conditioning test), while the other compartment is paired with administration of the vehicle. There can be confusion in the interpretation of CPP expression/ reinstatement when using the biased method. For example, anxiolytic or anxiogenic drugs can alter the time spent in a white or black chamber independently of conditioned drug reward. In an unbiased protocol, there is no clear preference
Table 1 – This table summarizes the methodology used in the reinstatement studies using the CPP paradigm Specie
Age
Sex
Drug
Dose
Pre-C
Type of C
Schedule
Test of Time of Sessions Duration Post-C Type of extinction extinction extinction of C of C session
Year
Parker and McDonald Lu et al.
2000
Rat
Adult
Male Morphine
10
No
Unbiased Alternating 4
30
15
2000
Rat
Adult
Male Morphine
10
15
Unbiased Alternating 3
50
Lu et al. Wang et al.
2001 2000
Rat Rat
Adult Adult
Male Morphine Male Morphine
10 4
15 No
Unbiased Alternating 3 Biased Daily 10
Wang et al. Wang et al.
2001 2002
Rat Rat
Adult Adult
Male Morphine Male Morphine
10 4
15 No
Unbiased Alternating 3 Biased Daily 10
Manzanedo et al. Mueller et al.
2001
Mouse
Adult
Male Morphine
40
2002
Rat
Adult
Male Morphine
10
Ribeiro Do Couto et al. Shi et al.
2003
Mouse
Adult
Male Morphine
40
2004
Rat
Adult
Male Morphine
Leri and Rizos 2005
Rat
Adult
Lu et al.
2005
Rat
Popik et al.
2005
Reinstatement induced by
2, 3, 4
4
Morphine (10)
15
Repeated test None
36
36
50 15
15 10
None None
36 9
36 9
50 15
15 10
None None
29 9
29 9
3 days, Biased Daily 4 15 15 Unbiased Alternating 4
60
15
5, 15, 20
20
45
15
9
9
Morphine (1, 2.5)
60
15
Daily
9
Morphine (5–40)
4
3 days, Unbiased Daily 4 15 15 Unbiased Alternating 4
45
15
Daily
7
Morphine (1–4)
Male Heroin
1
20
4
30
20
5
5
Heroin (1)
Adult
Male Morphine
10
3 days, Unbiased Alternating 4 15
50
15
Repeated test Saline injection Repeated test Repeated test Saline injection Saline injection
Morphine (10) Footshock Morphine (10) Morphine (0.25) Footshock Footshock Morphine (0.25) Footshock Morphine (40)
15
15
Mouse
Adult
Male Morphine
10
20
45
20
3
3
Ribeiro Do Couto et al. Ribeiro Do Couto et al.
2005a Mouse
Adult
Male Morphine
40
4
60
15
Morphine (2.5–20)
Adult
Male Morphine
40
4
60
15
14, 28, 42, 56 Daily
56, 84
2005b Mouse
3 days, Unbiased Daily 15 3 days, Unbiased Daily 15
Saline injection Repeated test Repeated test
Conditioned withdrawal NOT spontaneous withdrawal NOT precipitated withdrawal Morphine (1, 2.5)
9
Ribeiro Do Couto et al. Shoblock et al. Ventura et al.
2005c Mouse
Adult
Male Morphine
40
4
60
15
9
Mouse
Adult
Male Morphine
20
3
30
15
Daily
10
Morphine (20)
2005
Mouse
Adult
Male Morphine
20
20
Unbiased Alternating 4
40
20
9
9
Morphine (5)
Ma et al.
2007
Rat
Adult
Male Morphine
3
15
Unbiased Daily
4
45
15
Repeated test Repeated test Saline injection Repeated test
Daily
2005
3 days, Unbiased Daily 15 15 Unbiased Daily
Cocaine (12.5–50) Amphetamine (1–4) Morphine (10)
7, 15, 31, 63
63
Ribeiro Do Couto et al.
2006
Mouse
Adult
Male Morphine
10, 20, 3 days, Unbiased Daily 40 15
4
30, 60
15
Repeated test
Daily
Morphine (2) Forced swim stress Tail pinch stress Restraint stress Social defeat stress
Unbiased Daily
Unbiased Alternating 1
255
(continued on next page)
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
Author/s
256
Table 1 (continued) Year
Specie
Age
Sex
Drug
Wang et al.
2006
Rat
Adult
Male Morphine
10
15
Unbiased Alternating 4
50
15
Zhou and Zhu 2006
Rat
Adult
Male Morphine
10
50
15
Hao et al.
2008
Mouse
Adult
Male Morphine
10
40
15
Mueller and Stewart
2000
Rat
Adult
Male Cocaine
10
3 days, Unbiased Alternating 4 15 2 days, Unbiased Alternating 3 15 15 Unbiased Alternating 4
20
15
Sanchez and Sorg
2001
Rat
Adult
Male Cocaine
Itzhak and Martin
2002
Mouse
Adult
Male Cocaine
Lu et al.
2002
Rat
Adult
Male Cocaine
Szumlinski 2002 et al. Sanchez et al. 2003
Mouse
Adult
Rat
Zavala et al.
2003
Kreibich and Blendy Romieu et al.
Dose
12
Pre-C
15
Type of C
Biased
Schedule
Sessions Duration Post-C Type of Test of Time of of C of C extinction extinction extinction session Saline injection Saline injection None
15
15
Morphine (3)
9
9
Morphine (2.5)
9
9
Morphine (2)
Repeated test Saline injection Repeated test
Daily
12
Cocaine (5)
9
9
Cocaine (5)
Daily
9
Cocaine (5) Conditioned odor Conditioned tone Cocaine (15) Methamphetamine (0.5) Methylphenidate (20) NOT PCP (5) Cocaine (10) Footshock Cocaine (5–25)
Alternating 4
30
15
2 days, Unbiased Alternating 4 20
30
20
Saline injection
9
9
10
15
Unbiased Alternating 4
30
15
22
22
Male Cocaine
15.25
15
Biased
Daily
10
Adult
Male Cocaine
12
30
15
Daily
10
Rat
Adult
Male Cocaine
15
30
15
Weekly
14–56
2004
Mouse
Adult
Male Cocaine
10
2 days, Biased Alternating 4 15 3 days, Biased Alternating 3 15 15 Unbiased Alternating 4
24 h
15
Saline injection Repeated test Repeated test Saline injection Saline injection
9
9
2004
Mouse
Adult
Male Cocaine
30
10
30
10
Saline injection
5
5
Alternating 4
Unbiased Daily
4
15
Reinstatement induced by
Cocaine (5) Immobilization Cocaine (5, 10) Cocaine (10) Forced swim stress Cocaine (15–30) Igmesine (3–10) DHEA (20–40) BTCP (15) Phencyclidine (5) Nicotine (0.5) Morphine (5) Ethanol (1000)
B RA I N R E SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
Author/s
Balda et al.
2006
20
20
Maldonado et al. McGeehan and Olive Carey et al.
Daily
4
30
20
Repeated test
Weekly
Male Cocaine
25.5
4
30
15
2006
Mouse
Adult
Male Cocaine
15
3 days, Unbiased Daily 15 Unbiased Daily
3
20
30
2007
Mouse
Adult
Male Cocaine
10
30
Biased
4
30
30
Repeated test Repeated test Repeated test
Graham et al. 2007
Rat
Adult
Male Cocaine
15
30
Unbiased Alternating 4
30
30
Kelley et al.
2007
Mouse
Adult
Male Cocaine
20
20
Unbiased Alternating 4
30
20
Maldonado et al. Orsini et al.
2007
Mouse
Adult
Male Cocaine
50
30
15
2008
Mouse
Adult
Male Cocaine
5, 20
3 days, Unbiased Daily 4 15 20 Unbiased Alternating 4
40
20
Li et al.
2002
Rats
Adult
Male
30
15
Cruz et al.
2008
Rats
Adolescent
Male Amphetamine
5
30
15
Kuzmin et al. Font et al.
2003
Mouse
Adult
Male Ethanol
800
3 days, Biased Alternating 4 15 3 days, Unbiased Alternating 4 15 10 Unbiased Daily 4
20
10
2008
Mouse
Adult
Male Ethanol
2000
5
Unbiased Alternating 4
5
60
Biala and Budzynska Biala and Budzynska
2006
Rats
Adult
Male Nicotine
0.5
1
Biased
Daily
3
30
15
2008
Rats
Adult
Male Nicotine
0.5
1
Biased
Daily
3
30
15
2007
Mouse
Adolescent Male MDMA
5, 10, 20
3 days 15
Unbiased Alternating 4
30
15
Daza-Losada et al.
D-metamphetamine
1
Mixed
Daily
Weekly
15 21 21 21 Seven–28
Cocaine (5)
Cocaine (3–25)
Weekly
7, 14, 21
Cocaine (15)
Weekly
21
Saline injection Repeated test Repeated test Saline injection Repeated test Saline injection Repeated test Saline injection Repeated test Repeated test
Daily
10
Weekly
28
Cocaine (10) Forced swim stress Cocaine (5–10) SKF81297 (0.1, 1) Cocaine (10)
Weekly
Seven–28
Cocaine (25)
9
9
Cocaine (2.5, 10)
Weekly
42
4
4
Methamphetamine (0.125) Amphetamine (2.5)
Daily
4
Ethanol (400)
5
5
Ethanol (2000)
Daily
3
Daily
3
Repeated test
Weekly
35
Nicotine (0.5) Morphine (10) Nicotine (0.5) WIN55,212-2 (0.5) Ethanol (500) NOT dAmphetamine (2) MDMA (2.5, 5)
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
Adolescent Female Male Female Adult
Male Cocaine
2006
Mouse Adolescent Adult Adult Mouse
257
258
B RA I N R E SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
for any compartment before conditioning, and drug and vehicle are administered in randomly assigned compartments. In a balanced protocol, the animals prefer one chamber over the other, but the drug-chamber is purposefully assigned so that no group as a whole has a preference for a particular chamber; in other words, if three mice are conditioned to the drug in the white side, another three are conditioned to the drug in the black side. On the other hand, some studies use a schedule in which drug and vehicle pairings are performed on a daily basis, at intervals of several hours (two-session day schedule), while others perform drug and vehicle pairings on alternate days.
2.2.
Extinction
Extinction is defined as the decrease in the frequency or intensity of learned responses after removal of the unconditioned stimulus (i.e. a drug) that has reinforced the learning (Pavlov, 1927). Extinction provides a measurement of the motivational properties of drugs, which are reflected by the persistence of drug-seeking behavior in the absence of the drug. This is a powerful means of assessing the incentive motivational properties of drug-paired stimuli or non-contingent drug administration in the reinstating response (Pulvirenti, 2003). In the CPP version of the reinstatement model, extinction typically involves exposing rats or mice to the previously drug-paired context while in a drug-free state (Epstein et al., 2006; Shalev et al., 2002). The CPP is considered to be extinguished when there is no significant difference between the time spent in the drug-paired compartment in the extinction session and that spent in the same compartment during pre-conditioning. Generally, a significant difference has been reported between the time spent on the drugpaired side in the extinction session and in the test for CPP. However, some studies considered CPP to be extinct when no significant difference was observed between the time spent in the drug-paired compartment by the drug and vehicle groups (Li et al., 2002), or when animals spent less than 55% of the total time in the drug-paired compartment on two consecutive days (Shoblock et al., 2005). Extinction is usually performed by one of two means (see Table 1): either by administering injections of a vehicle in both the original drug-paired and the original vehicle-paired chambers or by repeating CPP tests until preference is no longer observed. Exposure to vehicle in the previously drugpaired compartment extinguishes the CPP induced by morphine (Leri and Rizos, 2005; Mueller et al., 2002; Popik et al., 2005; Ventura et al., 2005; Wang et al., 2006; Zhou and Zhu, 2006), cocaine (Itzhak and Martin, 2002; Kreibich and Blendy, 2004; Lu et al., 2002; Mueller and Stewart, 2000; Romieu et al., 2004; Zavala et al., 2003) and ethanol (Font et al., 2008). Similarly, after repeated daily or weekly testing, morphine(Ma et al., 2007; Manzanedo et al., 2001; Parker and McDonald, 2000; Ribeiro Do Couto et al., 2003, 2006; Shi et al., 2004; Shoblock et al. 2005), cocaine- (Carey et al., 2007; Kelley et al., 2007; Maldonado et al., 2006, 2007; McGeehan and Olive, 2006; Mueller and Stewart, 2000; Sanchez and Sorg, 2001; Sanchez et al., 2003; Szumlinski et al; 2002), methamphetamine- (Li et al., 2002) ethanol- (Kuzmin et al., 2003), nicotine- (Biala and Budzynska, 2006, 2008) and MDMA-CPP (Daza-Losada et al.,
2007) are extinguished. Moreover, in several early studies, tests for reinstatement of CPP were performed when, after drug-free periods, rats no longer demonstrated morphine CPP (Lu et al., 2000, 2001a,b; Wang et al., 2000, 2002).
2.3.
Reinstatement
In the literature regarding learning, reinstatement refers to the recovery of a learned response when a subject is noncontingently exposed to an unconditioned stimulus after extinction. However, in reinstatement studies, this recovery of a learned response, which represents a return to drug seeking, occurs when rats or mice are exposed to drugs, drug cues or stressors following extinction (Shaham et al., 2003, Epstein et al., 2006). In the CPP version of the reinstatement model, an extinguished CPP is robustly reinstated by noncontingent administration of a priming dose of the drug, and, at least in the case of morphine and cocaine, by exposure to stressful stimuli.
2.3.1.
Drug priming-induced reinstatement
Reinstatement of response through a priming injection of a drug is acknowledged to be a reliable model for studying the mechanisms involved in drug craving and relapse (De Vries et al., 1998; Shalev et al., 2002). In the CPP version of the reinstatement model, an extinguished CPP is recovered after a priming injection of the conditioning drug or, in some cases, of a different drug to that administered during conditioning. To consider that drug priming has induced the reinstatement of the CPP, there should be a significant difference between reinstatement values and those of pre-conditioning or extinction. On the other hand, a lack of significant differences between the values of reinstatement and the test for CPP is necessary for a complete reinstatement to be considered. Both reinstatement induced by the training drug and crossreinstatement induced by other drugs can be demonstrated in the CPP version of the reinstatement model. The information provided in this section is summarized in Table 1. Numerous studies have reported that morphine-induced CPP in rats (Lu et al., 2000, 2001a,b, 2005; Ma et al., 2007; Mueller et al., 2002; Parker and McDonald, 2000; Shi et al., 2004; Wang et al., 2000, 2002, 2006) and in mice (Manzanedo et al., 2001; Popik et al., 2005; Ribeiro Do Couto et al., 2003, 2005a,b,c, 2006; Shoblock et al., 2005; Ventura et al., 2005) is reinstated by a priming injection of morphine. The CPP induced in rats by heroin is reinstated by the same drug (Leri and Rizos, 2005). Similarly, cocaine-induced CPP is reinstated in rats (Graham et al., 2007; Mueller and Stewart, 2000; Sanchez and Sorg, 2001, Sanchez et al., 2003; Zavala et al., 2003) and in mice (Itzhak and Martin, 2002; Kreibich and Blendy, 2004; Maldonado et al., 2006, 2007; McGeehan and Olive, 2006; Szumlinski et al., 2002; Romieu et al., 2004) by a priming injection of cocaine. Reinstatement of CPP has also been demonstrated in rats with amphetamine (Cruz et al., 2008; Li et al., 2002) and nicotine (Biala and Budzynska, 2006, 2008), and in mice with ethanol (Kuzmin et al., 2003; Font et al., 2008) and MDMA (Daza-Losada et al., 2007). Moreover, a cross-reinstatement has been observed between opioids, psychostimulants and other drugs of abuse. A priming injection of a psychostimulant, such as amphetamine
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
or cocaine, reinstates morphine CPP in rats and mice (Ribeiro Do Couto et al., 2005b; Wang et al., 2000). Similarly, in mice, a previously extinguished cocaine-induced CPP has been shown to be reinstated by a priming injection of methamphetamine, methylphenidate, BTCP (a selective DA uptake inhibitor), morphine, nicotine and ethanol (Itzhak and Martin, 2002; Romieu et al., 2004). Phencyclidine does not induce reinstatement of cocaine-CPP (Itzhak and Martin, 2002), or produces only a partial effect (Romieu et al., 2004). Morphine, WIN55,212-2 and ethanol also reinstate the CPP induced by nicotine (Biala and Budzynska, 2006, 2008).
2.3.2.
Stress-induced reinstatement
Exposure to stress may be a determining factor in vulnerability to drug abuse. Stress is known to increase the rewarding effects of drugs (Will et al., 1998; Der-Avakian et al., 2005), and its role in relapse is well established (Sinha, 2001; Lu et al., 2003). In experimental animals, reinstatement of a previously extinguished CPP has been evaluated following exposure to different stressful events. Intermittent footshock exposure delays the extinction of morphine CPP (Lu et al., 2000), reactivates morphine-CPP following drug-free periods (Lu et al., 2000; Wang et al., 2000, 2002; Wang et al., 2001) and reinstates morphine-CPP after extinction (Der-Avakian et al., 2001; Wang et al., 2001, 2006). Immobilization (Ribeiro Do Couto et al., 2006), continuous tail-pinch (Ribeiro Do Couto et al., 2006), single forced swim (Ma et al., 2007), conditioned withdrawal from the drug in morphine-dependent animals (Lu et al., 2005) and defeat in social interaction with a conspecific (Ribeiro Do Couto et al., 2006) all reinstate morphine-CPP. Similarly, cocaine-CPP is reinstated by intermittent footshock (Lu et al., 2002), restraint stress (Sanchez et al., 2003), single forced swim (Kreibich and Blendy, 2004) and conditioned fear stimuli such as a tone or an odor previously associated with footshock (Sanchez and Sorg, 2001).
3. Neural mechanisms underlying reinstatement of CPP Several neurotransmitter systems and brain areas have been implicated in drug- and stress-induced reinstatement of CPP. The effects of different manipulations on drug primingand stress-induced reinstatement of CPP are summarized in Table 2.
3.1.
Dopamine
The role of dopamine (DA) in drug priming-induced reinstatement of opiate CPP is controversial, since reinstatement of morphine CPP is not affected by DA antagonists and is blocked by lesion of mesolimbic DA structures. In a study performed in our laboratory, we observed that neither DA antagonists (SCH 23390, raclopride, haloperidol, D1, D2, D1 + D2 DA antagonists respectively) nor the DA release inhibitor (CGS 10746B) reinstated the CPP induced by morphine in mice when administered alone. Moreover, these drugs failed to block the reinstatement of CPP induced by morphine. These results suggest that the drug-induced reinstatement of morphine CPP is largely independent of DA neurotransmission (Ribeiro Do
259
Couto et al., 2005c). On the other hand, another study investigated the influence of DA D2 receptors on the re-acquisition of a previously extinguished morphine-induced CPP (Lu et al., 2001a). The method used in that study cannot be considered a model of reinstatement, as, when the place preference was extinguished, animals underwent a further training trial with a low dose of morphine, at which point CPP reappeared. Using this model, it was found that acute but not chronic pretreatment with sulpiride significantly attenuated re-acquisition of morphine-induced CPP. The authors suggested that the D2 antagonist contributed to the inhibition of the opioid rewarding process but not to the protracted abstinence syndromes that persisted long after detoxification (Lu et al., 2001a). Mesolimbic DA structures seem to be essential for drug-induced reinstatement of morphine CPP in rats, since an electrolytic lesion of the ventral tegmental area (VTA), the nucleus accumbens (Nac) or its shell has been found to block the reactivation of CPP induced by a morphine prime (Wang et al., 2002). Conversely, the medial prefrontal cortex (mPFC) cannot be involved in reinstatement, since the lesion of this structure fails to prevent priming-induced reinstatement of morphine CPP in mice (Hao et al., 2008). The conflicting results obtained in pharmacological and lesion studies can be explained by variations in the methodology used to evaluate the influence of the DA system in drug-induced reinstatement of CPP. An anatomical lesion produces effects that can differ substantially from those observed when an antagonist drug is administered. An electrolytic lesion of a specific brain structure destroys not only the neuron cell body, but also the pass-by axons of the targeted area, and could, therefore, affect its afferents and efferents, which are mediated by different neurotransmitter systems. Conversely, the administration of a given antagonist interferes with specific neurotransmitters. It is possible that non-dopaminergic projections arriving at the VTA or departing from the Nac are more essential to druginduced reinstatement of CPP than the dopaminergic neurotransmission between these structures. For example, the VTA also sends GABAergic projection neurons to the NAC (Van Bockstaele and Pickel, 1995), and VTA lesions can affect reinstatement by altering these non-DA projections. Moreover, the differences between the results obtained in lesion and dopamine antagonist studies could be due to differences of species (rat versus mouse). The DA system seems to be involved in the drug-induced reinstatement of cocaine CPP. Drugs that stimulate DA transmission, such as the DA uptake inhibitor BTCP (Romieu et al., 2004), and intermediate doses of the DA D1 agonist SKF81297 (Graham et al., 2007) can effectively reinstate cocaine CPP. However, the microinjection of this drug in the mPFC (Sanchez et al., 2003) and the administration of the D2/D3 agonist quinpirole (Graham et al., 2007) do not have the same effect. On the other hand, a microinjection of the DA D1-like antagonist SCH 23390 in the mPFC blocks the reinstatement of cocaine CPP induced by cocaine priming (Sanchez et al., 2003), while DA agonists such as SKF-81297 and quinpirole are unable to block this cocaine-induced reinstatement (Sanchez et al., 2003; Graham et al., 2007). The electrolytic lesion of the shell of the Nac has been seen to block the reinstatement of morphine CPP induced by footshock, although lesions of other DA structures, such as the VTA, and
260
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Table 2 – This table summarizes the effects of different manipulations on drug priming- and stress-induced reinstatement of CPP Author/s
Year
Lu et al.
2000
CPP induced by Morphine
Reinstatement induced by Morphine (10)
Footshock stress
Lu et al.
2001
Morphine
Morphine (10)
Wang et al.
2001
Morphine
Footshock stress
Lu et al.
2002
Cocaine
Cocaine (10)
Footshock stress
Li et al. Wang et al.
2002 2002
D-metamphetamine Morphine
D-methamphetamine (0.125) Morphine (0.25)
Footshock stress
Kuzmin et al.
2003
Ethanol
Ethanol (400)
Sanchez et al.
2003
Cocaine
Cocaine (5)
Manipulation α-helical CRF CP-154,526 AS-30 α-helical CRF CP-154,526 AS-30 L-365260 MK-329 Clonidine Clonidine DNB lesion VNB lesion Devazepide L365,260 Devazepide Devazepide Devazepide L365,260 L365,260 L365,260 7-nitroindazole ATV lesion Nac lesion Nac core lesion Nac shell lesion ATV lesion Nac lesion Nac core lesion Nac shell lesion CeA lesion Nociceptin Ro 64-6198 Naloxone SKF 81297 SCH 23390
Immobilization stress
SKF 81297 SCH 23390
Zavala et al. Romieu et al.
2003 2004
Cocaine Cocaine
Cocaine (5, 10) Cocaine (15)
Lu et al.
2005
Morphine
Ribeiro Do Couto et al.
2005c
Morphine
Conditioned withdrawal stress Morphine (10)
Shoblock et al. Biala and Budzynska
2005 2006
Morphine Nicotine
Morphine (20) Nicotine (0.5) Morphine (10)
Ma et al.
2007
Morphine
Morphine (2) Forced swim stress
Dose 1, 10 (μg, icv) 1, 10 1, 10 (μg, icv) 1, 10 μg (icv) 1, 10 mg/kg 1, 10 μg (icv) 0.1, 1 0.1, 1 0.1, 1 μg (BNST) 0.1, 1 μg (LC)
0.1, 1 0.1, 1 1, 10 (μl, Nacc) 1, 10 (μl, Amyg) 0.1, 1 0.1, 1 1, 10 μl (Nacc) 1, 10 μl (Amyg) 12.5, 25
5 (nmol) 0.3 1 0.1, 0.3, 1 (μg, mPFC) 0.01, 0.1, 1 (μg, mPFC) 0.1, 0.3, 1 μg (mpFC) 0.01, 0.1, 1 μg (mpFC)
mPFC lesion BD1047 σ1 antisense ODN α-helical CRF
3, 10, 30 20 (μg, icv) 0.1, 1 μg (icv)
SCH 233390 Raclopride Haloperidol CGS 10746B Memantine
0.125, 0.5 0.3, 1.2 0.1, 0.2 1, 10 10, 20, 40
MK-801
0.1, 0.2, 0.3
Ro 64-6198 Nimodipine Flunarizine Nimodipine Flunarizine Ifenprodil Ifenprodil Ifenprodil
1 10, 20 5, 10 10, 20 5, 10 1, 3, 10 2 (μg, Nac, Hipp) 1, 3, 10
Effect on reinstatement Blockade (with None None Blockade (with Blockade None Blockade None Blockade None None Blockade Blockade None Blockade None None Blockade (with Blockade (with Blockade Blockade Blockade Blockade None Blockade None None None Blockade Blockade Blockade Blockade Blockade None
10)
10)
1) 10)
Blockade (with 0.1 and 1) Blockade (with 1) Blockade (with 0.1 and 1) Blockade Blockade (with 30) Blockade Blockade (with 1) None None None None Blockade (with and 40) Blockade (with and 0.3) Blockade Blockade (with Blockade Blockade (with Blockade Blockade (with Blockade None
20 0.2
20) 20) 10)
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Table 2 (continued) Author/s
Year
CPP induced by
Reinstatement induced by
Maldonado et al.
2006
Cocaine
Cocaine (25)
GHB
McGeehan and Olive Wang et al.
2006
Cocaine
Cocaine (15)
Acamprosate
2006
Morphine
Morphine (3)
CP-154,526 CP-154,526 CP-154,526 CP-154,526 CP-154,526 CP-154,526 Arodyn Arodyn AT Quinpirole Memantine CNQX SCN lesion Nimodipine Flunarizine Nimodipine Flunarizine mPFC lesion
Footshock stress
Carey et al.
2007
Cocaine
Font et al. Graham et al. Maldonado et al.
2008 2007 2007
Ethanol Cocaine Cocaine
Cocaine (10) Forced swim stress Ethanol (2000) Cocaine (10) Cocaine (25)
Sleipness et al. Biala and Budzynska
2007 2008
Cocaine Nicotine
Cocaine (5, 10) Ethanol (0.5) WIN55,212-2 (0.5)
Hao et al.
2008
Morphine
Morphine (2)
both the totality of the Nac or merely its core, have been shown to have no effects (Wang et al., 2002). Administration of drugs acting at the DA D1 receptors of the mPFC blocked stressinduced reinstatement of cocaine CPP in rats (Sanchez et al., 2003). Both the DA D1 agonist SKF81297 (1 μg/side) and the DA D1 antagonist SCH 23390 (0.1 and 1 μg/side) were shown to block restraint-induced reinstatement. The authors of the study in question speculated that optimal mPFC D1 receptor activation and DA levels are required to facilitate the activation of output neurons to subcortical structures such as the Nac and to process stress reinstatement cues (Sanchez et al., 2003).
3.2.
Glutamate
This neurotransmitter system seems to play an essential role in the reinstatement of the CPP induced by opiates. We assessed the effects of memantine and MK-801, two Nmethyl-D-aspartate (NMDA) glutamatergic antagonists with different kinetic profiles, on the reinstatement of morphineinduced CPP. Although neither produced reinstatement, both memantine (20 and 40 mg/kg) and MK-801 (0.2 and 0.3 mg/kg) blocked the reinstatement effects of morphine priming. It is unlikely that this effect was due to the motor effects of NMDA antagonists, since the blockade of morphine-induced reinstatement was observed with doses that produced different effects on motor behavior; namely ataxia (unpublished data), no effect, or hyperactivity (Rodríguez-Arias et al., 2002). NMDA antagonists impair memory in a wide variety of tasks and species (Riedel et al., 2003). Thus, the inhibition of reinstatement may be due to the interference of NMDA antagonists with the capacity of morphine to remind the animal of the associations learned during conditioning (Ribeiro Do Couto et al., 2004) and to produce a reinstatement of place preference (Ribeiro Do Couto et al., 2005c). Another study demonstrated that memantine administration during a forced extinction of
Manipulation
Dose
Effect on reinstatement
100, 50, 25, 12.5, 6.25 30, 100
Blockade (with 25)
1 (μg, BNST) 1 (μg, CeA) 1 (μg, Nac) 1 μg (BNST) 1 μg (CeAmyg) 1 μg (Nacc) 0.3 (nmol, icv) 0.3 (nmol, icv) 1000 0.1, 0.3, 1, 3 5, 10 1, 10
None Blockade Blockade Blockade None None None Blockade None None Blockade (with 10) Blockade (with 10) Decrease (with 10) Blockade (with 10) Blockade (with 10) Blockade (with 10) Blockade None
5, 10 5, 10 5, 10 5, 10
Blockade (with 100)
CPP blocked the subsequent drug-induced reinstatement. This protective effect of memantine may be explained by the impairing effects of this drug on re-consolidation processes. Two processes operate simultaneously in extinction: the original association is retrieved and a novel association is formed. In the reactivated state, both associations interact and memantine seems to disrupt the processing of conditioned responses, thereby impairing the re-consolidation of the highly salient drug-related associations. According to the authors of that study, the original association between the effects of morphine and environment were altered in memantine-extinguished mice to the extent that the reinstating effects of morphine priming were blocked (Popik et al., 2005). These results indicate that the activation of NMDA glutamate receptors underlies the drug-induced reinstatement of morphine CPP (Popik et al., 2005; Ribeiro Do Couto et al., 2005c). A recent study, though not employing a reinstatement procedure (extinction did not take place), suggested that glutamate is implicated in the persistent memory associated with addictive drugs. Ketamine, when administered after re-exposure to a morphine-paired context, interferes with the re-consolidation of morphine CPP, suggesting effects of ketamine in the disruption of memory associated with environmental cues and addictive drugs (Zhai et al., 2008). The relation between cocaine and glutamate neurotransmission is clear, since the manipulation of this neurotransmitter system is known to alter many of the effects of cocaine (McFarland and Kalivas, 2001). A recent study in our laboratory evaluated the role of ionotropic glutamate receptors in the reinstatement of cocaine CPP through the administration of NMDA glutamate receptor antagonist memantine (5 or 10 mg/kg) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist CNQX (1 or 10 mg/kg) with a priming dose of 25 mg/kg of cocaine (Maldonado et al., 2007). The results obtained show that the reinstatement of cocaine-
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induced preference by cocaine priming injections are blocked by memantine (10 mg/kg). In other words, animals do not approach the cocaine-related cues when the glutamate neurotransmission at NMDA receptors is blocked, which represents an undermined drug-seeking behavior. Additionally, neither of the two antagonists reinstated the preference. The inhibition of drug-induced reinstatement of cocaine-induced CPP could be due to the interference of memantine with the capacity of cocaine to remind the animal of the associations learned during conditioning and, thus, produce a reinstatement of CPP. Another recent study has confirmed the role of NMDA glutamate receptors in the reinstatement of cocaine-CPP by employing the NMDA receptor antagonist MK-801. The administration of MK-801 prior to a CPP retrieval test, performed a week after the test for CPP, was shown to cause a long-term suppression of the CPP response and block the reinstatement induced by a priming dose of cocaine three weeks after conditioning. These effects can be attributed to the disrupting effects of MK-801 on memory re-consolidation (Kelley et al., 2007). Acamprosate (calcium acetylhomotaurinate) is a modulator of ionotropic and metabotropic glutamate receptor function, and reduces extracellular levels of glutamate when the organism is in a hyperglutamatergic state. Recently, it has been demonstrated that this drug reduces cocaine-induced reinstatement of a previously extinguished cocaine CPP in mice (McGeehan and Olive, 2006). Finally, a recently published study has demonstrated the involvement of AMPA receptors in the Nac in the reinstatement of amphetamine-induced CPP in adolescent rats (Cruz et al., 2008).
3.3.
Endogenous opioids
No changes are detected in the mRNA levels of preproenkephalin (PPE) and preprodynorphin (PPD) in the Nac of rats after morphine-induced reinstatement of CPP (Shi et al., 2004). Conversely, the opioid receptor-like (ORL-1) receptor (also referred to as NOP1 or OP4), which is activated by the endogenous peptide nociceptin/orphanin FQ, seems to play a role in the reinstatement of morphine CPP (Shoblock et al., 2005). The ORL-1 agonist Ro 64-6198 blocks morphine-induced reinstatement, an effect that may be related with the less obvious morphine-induced increase in DA release in Nac, although it is not clear whether the ORL-1 agonist attenuates the rewarding properties of morphine or impairs associative learning (Shoblock et al., 2005). Drug-induced reinstatement of ethanol CPP is inhibited by the non-selective opioid antagonist naloxone, nociceptin, and the ORL 1 agonist Ro 64-6198. This suggests that the opioid system is involved in the reinstatement of ethanol CPP (Kuzmin et al., 2003). However, the inhibition of brain catalase activity (which metabolizes ethanol to acetaldehyde) does not modify reinstatement of ethanol CPP (Font et al., 2008). A recent study has demonstrated the role of the endogenous kappa-opioid system in stress-induced reinstatement of cocaine CPP. Exposure to stress activated the kappa-opioid receptor through release of endogenous dynorphin peptides, and the novel peptide kappa-opioid receptor antagonist arodyn produced a long-lasting antagonism of the antinociception induced by the opioid agonist U50,488. Moreover, arodyn suppressed the reinstatement of cocaine CPP induced by submitting the mice to two sessions of forced swim stress, which suggests
that kappa-opioid receptor antagonists are of therapeutic value in the treatment of relapse to cocaine abuse (Carey et al., 2007).
3.4.
Corticotrophin-releasing factor
Several studies have demonstrated the role of corticotrophinreleasing factor (CRF) receptors in the reinstatement of morphine CPP. Pre-treatment with the non-selective CRF antagonist α-helical CRF (10 μg, i.c.v.) attenuates morphineinduced reinstatement of CPP, while pre-treatment with lower doses (1 μg) or with CRF1 (CP-154,526) or CRF2 (AS-30) antagonists fails to exert the same influence (Lu et al., 2000). Recently, a role for these CRF1 receptors in the amygdala and Nac has also been demonstrated, since CP-154,526 injections into both structures attenuated priming-induced reinstatement of morphine CPP (Wang et al., 2006). The footshock-stress-induced reactivation of morphine CPP is undermined by non-selective and selective corticotrophinreleasing factor type 1 (CRF1) antagonists such as α-helical CRF and CP 154,526, but is unaffected by pre-treatment with AS-30, a CRFR2 antagonist (Lu et al., 2000). Similarly, the reinstatement of morphine CPP induced by conditioned drug withdrawal is blocked by α-helical CRF (Lu et al., 2005). A recent study has demonstrated the role of CRF1 receptors in the bed nucleus of the stria terminalis (BNST) in footshock-induced reinstatement of extinguished morphine CPP. CP-154,526 injections attenuated footshock-stress-induced reinstatement of morphine CPP when administered to the BNST, but not when administered to the amygdala or Nac. Considering the abovementioned findings with drug priming, the roles of CRF1 receptors in the BNST, amygdala, and Nac would appear to differ depending on whether reinstatement of drug CPP is induced by footshockstress or morphine-priming (Wang et al., 2006).
3.5.
Noradrenaline
Drug-priming-induced reinstatement of morphine CPP is also affected by the noradrenaline (NA) in the PFC. Selective prefrontal cortical NA depletion was shown to block the reinstating effects of morphine priming in mice. Moreover, morphine enhanced NA outflow in the mPFC, an effect that is critical to the effects of morphine on mesoaccumbens DA (increase in DA outflow in the Nac). These results suggest an important role for the mesocorticolimbic catecholaminergic circuit, in which prefrontal noradrenergic and accumbens DA transmission are synergistically coupled in order to control morphine CPP and reinstatement (Ventura et al., 2005). The footshock-stress-induced reactivation of morphine CPP is attenuated by clonidine infusion (0.1 and 1 μg, 0.5 μl) into the BNST 30 min before a single footshock stress (Wang et al., 2001). Moreover, a lesion of the ventral noradrenergic bundle caused by 6-OHDA (3 μg), which decreases NA levels in the BNST and hypothalamus, blocks the reinstating effects of stress exposure (Wang et al., 2001). In contrast, microinjection of clonidine into the locus coeruleus and the 6-OHDA (3 μg)-induced lesion of the dorsal noradrenergic bundle, which decreases NA levels in the frontal cortex and hippocampus, do not affect the reinstatement of morphine CPP induced by footshock (Wang et al., 2001). These findings suggest that NA from the locus coeruleus, critical to opiate withdrawal, is not essential for stress-induced
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
reinstatement to morphine CPP. An electrolytic lesion of the central nucleus of the amygdala, which sends CRF-containing fibers to the BNST, has also been shown to block the reinstating effects of stress exposure (Wang et al., 2002).
3.6.
Cholecystokinin
The involvement of the cholecystokinin (CCK) system in the drug-induced reinstatement of morphine CPP has been demonstrated by Lu et al. (2001b). The CCK-B antagonist L-365260 (0.1 and 1 mg/kg) blocked the reactivation of morphine CPP induced by a single injection of morphine. However, the CCK-A receptor antagonist MK-329 did not affect reinstatement, which suggests that the CCK system interacts with opioid rewarding processes, mainly through CCK-B receptors. Moreover, the authors of this study proposed that the blocking effects of the CCK-B antagonist were a result of its anxiolytic effects and/or the modulation of the DA system by CCK (Lu et al., 2001b). The involvement of the CCK system in the reinstatement of psychostimulants has also been demonstrated. Pre-treatment with the CCK-A receptor antagonist devazepide (0.1 and 1 mg/ kg) significantly attenuates the reinstatement of CPP induced by a priming injection of cocaine, while pre-treatment with the CCK-B receptor antagonist L365,260 (0.1 and 1 mg/kg) has no effect. The blockade of cocaine-induced reinstatement is also observed when devazepide (1 and 10 μg) is administered into the Nacc but not when it is administered into the amygdala (Lu et al., 2002). Pre-treatment with the CCK-B antagonist L365,260 (0.1 and 1 mg/kg) blocked the stress-induced reinstatement of cocaine CPP when administered at the highest of two doses, while the CCK-A antagonist devazepide (0.1 and 1 mg/kg) had no effects at any dose. Moreover, the infusion of L365,260 into the Nac (10 μg) or amygdala (1 and 10 μg) blocked stress-induced reinstatement (Lu et al., 2002). The authors of the study in question hypothesized that the role of the CCK-B receptor antagonist in the undermining of stress-induced reinstatement of cocaine dependence was a result of its anxiolytic effects (Lu et al., 2002).
3.7.
Other neurotransmitter systems
Gamma-hydroxybutyric acid (GHB) is a metabolite of GABA, and is naturally present in the brain (Maitre, 1997). GHB belongs to the group of substances referred to as ‘club drugs’, and is consumed for its euphoric, sedative and anabolic effects (Nicholson and Balster, 2001). A previous study found that systemic injections of GHB led to decreased cocaine CPP and self-administration (Fattore et al., 2000). The impact of GHB on the rewarding actions of cocaine and the reinstatement of cocaine CPP after extinction has been evaluated in male mice (Maldonado et al., 2006). CPP was detected in animals treated with the drug during the acquisition or expression of cocaine-induced preference, but was not reinstated by a priming injection of cocaine. This was the contrary to that observed in control animals. GHB may diminish the potency of conditioning when administered during the acquisition phase, possibly due to a delayed action on DA neurotransmission. Protracted memory impairments may account for the absence of relapse in the groups receiving GHB during expression. In animals conditioned only with cocaine, an intermediate dose of GHB blocked cocaine-induced
263
reinstatement. The priming dose of cocaine may remind the animal of the hedonic properties of the drug and the significance of the cues previously paired with the drug (Mueller and Stewart, 2000), or perhaps induces a state-dependent learning. GHB could block these processes by altering the subjective perception of the hedonic effect of cocaine. In this way, animals fail to recognize it as the conditioning drug. However, in monkeys, it has been observed that GHB does not effectively antagonize the cocaine discriminative stimulus (Beardsley et al., 1996), which challenges the notion that GHB interferes with the subjective effects of cocaine. In the brain, nitric oxide (NO) is produced primarily by the conversion of L-arginine via neuronal NO synthase (nNOS) in response to the stimulation of NMDA receptors, and facilitates DA release (Lonart and Johnson 1994; Pogun et al. 1994; Hong et al. 2005). The reinstatement of amphetamine-CPP is attenuated by the NOS inhibitor 7-nitroindazole, which demonstrates the involvement of NO in drug-induced reinstatement of a CPP induced by psychostimulants (Li et al., 2002). A recent study has demonstrated that, during adolescence, the nNOS gene is essential for the development of the neural plasticity that enables the reinstatement of cocaine CPP, suggesting that the NO pathway is of critical relevance in the development of the persistent reinstatement behavior that so often begins in adolescence and continues into adulthood (Balda et al., 2006). In the study in question, nNOS KO male and female mice, though acquiring CPP in a similar way to WT mice, presented a more rapid extinction of this CPP (which disappeared one week after conditioning), while re-exposure to cocaine did not produce reinstatement. Similar results were observed in male but not in female adult nNOS KO mice. These findings suggest that, in males, independently of age, the nNOS gene is essential for the long-term neural plasticity that underlies susceptibility to the incentive value of cocaine reward. However, in adult females, neural adaptations seem to be nNOS-independent, suggesting that the role of the nNOS gene is age-dependent. The sigma1 (σ1) receptor is an intracellular neuronal protein associated with membranes. Selective σ1 receptor ligands considerably modulate intracellular Ca2+ mobilizations and extracellular Ca2+ influx. Although the endogenous ligand of this receptor has not yet been identified, the σ1 receptor seems to be one of the main targets of certain neuroactive steroids. Pregnenolone and deydroepiandrosterone (DHEA) act as effective receptor agonists, while progesterone is a potent antagonist. Activation of this particular receptor has been linked to several aspects of cocaine addiction and to druginduced reinstatement of cocaine CPP (Romieu et al., 2004). When the σ1 receptor is inactivated by the σ1 antagonist BD1047 or by the decrease in the expression of the σ1 receptor following in vivo administration of an antisense oligodeoxynucleotide (which targets the σ1 gene), the reinstatement induced by a priming injection of cocaine is completely blocked. Moreover, igmesine, a selective σ1 receptor agonist, and DHEA both induce CPP reinstatement (Romieu et al., 2004). The reinstatement of nicotine CPP induced by nicotine, morphine, WIN55,212-2 and ethanol is blocked by the calcium channel blockers nimodipine and flunarizine, which act at Ltype voltage-gated calcium channels (Biala and Budzynska, 2006, 2008). These results support the hypothesis that calcium ions and calcium channels play an important role in
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modulating the re-acquisition of drug-seeking behavior following extinction, and that a common neuronal pathway (mesolimbic DA system) and similar calcium-dependent neuroadaptations are involved in the reinstatement of nicotine CPP provoked by priming injections of different drugs (Biala and Budzynska, 2006, 2008).
3.8.
abuse. In addition, the neural circuit involved in priming- and stress-induced reinstatement is represented in Figs. 1 and 2, respectively.
4.
Other manipulations
Stress- versus drug-induced reinstatement
Stress- and drug-induced reinstatement appear to be mediated by different neural pathways. For example, the role of specific CCK receptors differs between drug- and stressinduced reinstatement of cocaine CPP. The antagonism of CCK-A receptors blocks cocaine-but not stress-induced reinstatement, while that of CCK-B receptors blocks stress-induced reinstatement but does not affect the priming effects of cocaine (Lu et al., 2002). A differential effect of the D1 agonist SKF 81297 has also been observed in stress- versus cocaineinduced reinstatement, as it reduces the former but does not affect the latter (Sanchez et al., 2003). The mPFC→VTA→NAS circuit may be critical to stress-induced reinstatement, while the direct mPFC→NAS pathway appears to be essential for cocaine-induced reinstatement (Sanchez et al., 2003). As discussed in more detail in the following section, it has been demonstrated that stress-induced reinstatement is accompanied by a pattern of phosphorylated cAMP response elementbinding protein (pCREB) activation in discrete brain regions that differs from that observed following cocaine-induced reinstatement. For example, on the day of reinstatement, only exposure to stress produces greater increases of pCREB levels in both the amygdala (also induced by cocaine during conditioning) and the Nac. Furthermore, mice deficient in alpha and delta isoforms of CREB show deficits in stress-but not cocaine-induced reinstatement, which indicates that its role in stress-induced behavioral responses to drugs of abuse is specific (Kreibich and Blendy, 2004). It has also been demonstrated that the roles of CRF1 receptors in the BNST, amygdala and Nac in footshock-stressversus morphine-priming-induced reinstatement of morphine CPP are dissociable. Footshock-stress-induced reinstatement of morphine CPP was attenuated when the selective CRF1 receptor antagonist CP-154,526 was injected into the BNST, but not when it was injected into the amygdala or Nac. In contrast, CP-154,526 injections into the amygdala or
Reinstatement of morphine CPP is reversed by single (Wang et al., 2003) or repeated (Shi et al., 2004) peripheral electrical stimulation, a procedure based on acupuncture, by which animals receive an electrical stimulation via two stainless steel needles inserted into their hind legs. The effects of peripheral electrical stimulation seem to be mediated by the endogenous opioid system. The blocking effect against reinstatement of single (2 Hz) peripheral electrical stimulation is reversed by naloxone, which indicates the involvement of endogenous opioid peptides (Wang et al., 2003). Repeated peripheral electrical stimulation (2 Hz) increases PPE mRNA expression in the Nac, thereby stimulating the biosynthesis and release of enkephalin, which interacts with μ and δ-opioid receptors, thus ameliorating craving and eliminating the reinstatement of morphine-CPP. Conversely, repeated peripheral electrical stimulation (100 Hz) increases the expression of PPD mRNAs in the Nac and the biosynthesis of dynorphin, which may interact with kappa-opioid receptors located in dopaminergic nerve terminals and block the release of DA, thereby preventing reinstatement (Shi et al., 2004). The lesion of the prelimbic subregion of mPFC, at the end of the DA mesocorticolimbic pathway, attenuates the reinstatement of cocaine-CPP, which confirms mPFC's involvement in cocaine-priming-induced reinstatement (Zavala et al., 2003). Moreover, lesions of the suprachiasmatic nucleus affect cocaine-induced reinstatement of cocaine CPP, as, in lesioned animals, a more pronounced reinstatement is observed with a low dose of cocaine and a diminished reinstatement after a high dose of the same drug when compared with sham animals (Sleipness et al., 2007). Box 1 summarizes the similarities and differences in the neurotransmitter systems involved in priming- and stressinduced reinstatement of the different classes of drugs of
Reinstatement induced by Drug priming
DA agonists DA antagonists NMDA GLU antagonists ORL-1 agonists Opioid antagonists CRF antagonists NA antagonists CCK antagonists GHB NOS inhibitors σ receptor antagonists CA blockers
Stress
Morphine
Cocaine
Ethanol
Amphetamine
Nicotine
– = ↓ ↓ – ↓ (Amyg, NAc) – ↓ (CCK-B) – – – –
= (mPFC, D1, D2) ↓ (mPFC, D1) ↓ – – – – ↓ (CCK-A) ↓ ↓ ↓ –
– – – ↓ ↓ – – – – – – –
– – – – – – – – – – – –
– – – – – – – – – – – ↓
Morphine – – = (NR2B) – – ↓ (BNST) ↓ – – – – –
Cocaine ↓ ↓ – – ↓ – – ↓ – – –
(mPFC, D1) (mPFC, D1)
(κ)
(CCK-B)
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 9 ) 2 5 3–2 7 7
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Fig. 1 – Neural circuits involved in priming-induced reinstatement. The role of several brain structures in priming-induced reinstatement of morphine and cocaine CPP has been studied by inflicting lesions or through intracranial administration of different compounds. ✓ The lesion of the structure affects drug-induced reinstatement. X The lesion of the structure does not The administration of compounds related with the neurotransmitter system or receptor affect drug-induced reinstatement. The administration of compounds related to the neurotransmitter cited in brackets blocks drug-induced reinstatement. system or receptor cited in brackets does not affect drug-induced reinstatement. mPFC: medial prefrontal cortex; NSC: nucleus suprachiasmatic; NAcc: nucleus accumbens; BNST: bed nucleus of the stria terminalis; VTA: ventral tegmental area; AMYG: amygdala. Continuous lines indicate the neural circuit involved in drug priming-induced reinstatement of morphine CPP. Broken lines indicate the neural circuit involved in drug priming-induced reinstatement of cocaine CPP.
Nac, but not into the BNST, diminished morphine-priminginduced reinstatement of morphine CPP (Wang et al., 2006). Similarly, it has been observed that the NR2B-containing NMDA receptor is required for morphine – but not stress – induced reinstatement, since the administration of the NR2B selective antagonist ifenprodil undermined the reinstatement induced by a priming morphine injection, but not that induced by stress (Ma et al., 2007). These results, and those of studies employing using the self-administration paradigm, imply that two different neural pathways are responsible for stress- versus cocaine-induced reinstatement (see Figs. 1 and 2).
5. Molecular correlates of reinstatement behavior With the aim of evaluating the role of the CREB protein, a gene transcription factor, in drug- and stress-induced reinstatement of cocaine CPP, CREB mutant mice were tested for reinstatement after cocaine administration or forced swim exposure. Similarly, levels of pCREB in the Nac, VTA, amygdala and BNST were examined in wild-type mice after reinstatement induced by cocaine or stress (Kreibich and Blendy, 2004). Cocaine priming induced reinstatement of cocaine CPP in CREB mutant and wild-type mice, and increased the levels of pCREB in the VTA of the latter type. Conversely, stress-induced reinstatement of cocaine CPP was not achieved in CREB mutant mice, and pCREB levels in the amygdala in wild-type mice rose after
stress-induced reinstatement. These results indicate that stress- and drug-induced reinstatement produce different molecular changes in determined brain regions. Alterations in CREB levels in the limbic system (Nac and amygdala) appear to be related with stress-induced reinstatement, and the dysregulation of intracellular signaling in the amygdala may interfere with stress-induced reinstatement processes in CREBdeficient mice. The authors of that report suggested that, in wild-type mice, CREB acts presynaptically on CRE elements present in the promoter of the CRF gene (Hatalski and Baram, 1997), thereby increasing CRF production and release, which leads to the precipitation of stress-induced reinstatement. Since CRF1 is coupled with the cAMP pathway and CREB, deficits in CREB may uncouple CRF1 receptors, leading to an attenuation of signaling after stimulation (Kreibich and Blendy, 2004). However, it is important to be cautious when interpreting results obtained with knockout mice, since the behavioral changes observed when a gene is deleted may be due to unknown compensatory changes in other genes. The involvement of CREB in drug-induced reinstatement of morphine CPP has also been evaluated in rats in a study in which CREB levels on the day of reinstatement were found to have increased in the hippocampus and Nac and dropped significantly in the PFC, implying that drug-primed reinstatement involves the activation of CREB in several brain areas (Zhou and Zhu, 2006). Another study of the molecular correlates of reinstatement behavior focused on changes in the levels of glutamate NMDA (NR1, NR2A and NR2B) and AMPA (GluR1) receptor
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Fig. 2 – Neural circuits involved in stress-induced reinstatement. The role of several brain structures in stress-induced reinstatement of morphine and cocaine CPP has been studied by inflicting lesions or through intracranial administration of different compounds. ✓ The lesion of the structure affects stress-induced reinstatement. X The lesion of the structure does not affect stress-induced reinstatement. The administration of compounds related with the neurotransmitter system or receptor The administration of compounds related to the neurotransmitter cited in brackets blocks stress-induced reinstatement. system or receptor cited in brackets does not affect stress-induced reinstatement. mPFC: medial prefrontal cortex; NAcc: nucleus accumbens; BNST: bed nucleus of the stria terminalis; VTA: ventral tegmental area; LC: locus coeruleus; AMYG: amygdala; AMYG CeN: central nucleus of the amygdala. Continuous lines indicate the neural circuit involved in stress-induced reinstatement of morphine CPP. Broken lines indicate the neural circuit involved in stress-induced reinstatement of cocaine CPP.
subunits in brain regions associated with reward and drug craving, such as the Nac, hippocampus, PFC and amygdala (Ma et al., 2007; Cruz et al., 2008). NRB2 levels increased following drug or stress-induced reinstatement of morphine CPP: in the Nac and hippocampus in morphine-induced reinstatement and in the Nac and amygdala in forced swiminduced reinstatement (Ma et al., 2007). Moreover, to determine whether the active involvement of NR2B-containing NMDA receptors is necessary for reinstatement, rats received systemic injections of an antagonist that is highly selective for the NR2B subunit (ifenprodil, 1, 3 or 10 mg/kg) once the morphine CPP had been extinguished. Ifenprodil dose-dependently inhibited the reinstating effect of morphine priming but did not influence stress-induced reinstatement, suggesting that the neural mechanisms mediating drug-induced reinstatement are NMDA receptor-dependent and dissociable from the molecular/neurochemical substrates mediating stress-induced reinstatement. Furthermore, the microinjection of ifenprodil into the Nac and the CA1 region of the dorsal hippocampus inhibited the reinstating effect of morphine priming. These results indicate that the NR2B-containing NMDA receptors in the Nac and dorsal hippocampus play a significant role in mediating the reinstatement of morphine CPP (Ma et al., 2007). On the other hand, drug-induced reinstatement of amphetamine-CPP immediately after extinction (in adolescence) or 30 days later (in adulthood)
was accompanied by decreased levels of the GluR1 receptor subunit in the Nac, while the levels of the NR1 subunit were unaltered. These results suggest that the reinstatement of amphetamine-induced CPP is long-lasting and related to a decreased expression of AMPA receptors in the Nac (Cruz et al., 2008).
6.
Differences with self-administration studies
The animal model most commonly used to study relapse to drug seeking is the extinction-reinstatement model of intravenous self-administration. In this procedure, laboratory animals are trained to perform a task by which they selfadminister a drug, such as pressing a lever. After extinction of the behavior, the ability of different stimuli to reinstate the response is determined. Re-exposure to the drug, to environmental cues previously associated with the drug, or to a stressful event induces the reinstatement of self-administration (for reviews, see Shaham et al., 2003; Shalev et al., 2002; Weiss, 2005). Recently, several laboratories have begun to use the place-conditioning procedure to study relapse to drug abuse (Tzschentke, 2007). In the CPP version of the reinstatement model, animals are first trained to acquire a CPP and later undergo a process of extinction of this preference. As detailed in preceding sections, both drug priming and stress
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induce the reinstatement of CPP. However, the reinstatement of the conditioned rewarding properties of the drug-paired environment induced by cues previously associated with the drug has not been evaluated.
Although most of the results obtained using the CPP model of reinstatement confirm those of self-administration studies (see Table 3), some discrepancies have emerged (see Table 4). These inconsistencies may be due to either a difference in
Table 3 Similarities observed in Drug-induced reinstatement of opioid seeking
Drug-induced reinstatement of psychostimulant seeking
Drug-induced reinstatement of other drugs of abuse
Cross-reinstatement
Stressors that induce/do not induce reinstatement of morphine seeking
Stressors that induce reinstatement of cocaine seeking Role of glutamatergic system in drug-induced cocaine seeking Role of opioid system in drug-induced reinstatement of ethanol seeking Role of CRF in stress-induced reinstatement of morphine seeking Role of noradrenergic system in stress-induced reinstatement of morphine seeking Role of DA system in stress-induced reinstatement of cocaine seeking Role of opioid system in stress-induced reinstatement of cocaine seeking Involvement of PFC in drug-induced reinstatement of cocaine seeking
Conditioned place preference (CPP) Morphine priming reinstates morphine CPP (Parker and McDonald, 2000; Lu et al., 2000; Wang et al., 2000; Heroin priming reinstates heroin CPP (Leri and Rizos, 2005) Cocaine priming reinstates cocaine CPP (Mueller and Stewart, 2000; Sanchez and Sorg, 2001) Amphetamine priming reinstates amphetamine CPP (Li et al., 2002; Cruz et al., 2008) Ethanol priming reinstates ethanol CPP (Kuzmin et al., 2003; Font et al., 2008) Nicotine priming reinstates nicotine CPP (Biala and Budzynska, 2006) MDMA priming reinstates MDMA-CPP (Daza-Losada et al., 2007) Amphetamine priming reinstates morphine CPP (Wang et al., 2000) Cocaine priming reinstates morphine CPP (Ribeiro Do Couto et al., 2005b) Ethanol priming reinstates nicotine CPP (Biala and Budzynska, 2008) Methamphetamine reinstates cocaine CPP (Itzhak and Martin, 2002) Methylphenidate reinstates cocaine CPP (Itzhak and Martin, 2002) BTCP reinstates cocaine CPP (Romieu et al., 2004) Morphine reinstates cocaine CPP (Romieu et al., 2004) Footshock reinstates morphine CPP (Lu et al., 2000) Precipitated drug withdrawal does not reinstate morphine CPP (Lu et al., 2005) Footshock reinstates cocaine CPP (Lu et al., 2002) Acamprosate blocks reinstatement of cocaine CPP (McGeehan and Olive, 2006) Naloxone blocks reinstatement of ethanol CPP (Kuzmin et al., 2003) CP-154,526 blocks reinstatement of morphine CPP (Lu et al., 2000) Clonidine in the BNST (but not in the LC) blocks reinstatement of morphine CPP (Wang et al., 2001) SCH 23390 (in PFC) blocks reinstatement of cocaine CPP (Sanchez et al., 2003) Arodyn blocks reinstatement of cocaine CPP (Carey et al., 2007). Lesion of the prelimbic mPFC attenuates reinstatement of cocaine CPP (Zavala et al., 2003)
Self-administration (SA) Heroin priming reinstates heroin SA (de Wit and Stewart, 1983)
Cocaine priming reinstates cocaine SA (de Wit and Stewart, 1981) Amphetamine priming reinstates amphetamine SA (Ranaldi et al., 1999) Ethanol priming reinstates ethanol SA (Lê et al., 1998) Nicotine priming reinstates nicotine SA (Chiamulera et al., 1996) MDMA priming reinstates MDMA SA (Banks et al., 2008) Amphetamine priming reinstates heroin SA (de Wit and Stewart, 1983) Cocaine priming reinstates heroin SA (De Vries et al., 1998) Nicotine priming reinstates ethanol SA (Lê et al., 2003) Amphetamine reinstates cocaine SA (Schenk and Partridge, 1999) Methylphenidate reinstates cocaine SA (Schenk and Partridge, 1999) BTCP reinstates cocaine SA (Martin-Fardon et al., 2005) Morphine reinstates cocaine SA (de Wit and Stewart, 1981) Footshock reinstates heroin SA (Shaham et al., 1996) Precipitated drug withdrawal does not reinstate SA of heroin (Shaham et al., 1996) Footshock reinstates cocaine SA (Erb et al., 1996) Acamprosate blocks reinstatement of cocaine SA (Bowers et al., 2007) Naltrexone blocks reinstatement of ethanol SA (Lê et al., 1999) CP-154,526 blocks reinstatement of heroin SA (Shaham et al., 1998) Clonidine icv (but not in the LC) blocks reinstatement of heroin SA (Shaham et al., 2000a,b) SCH in prelimbic or orbitofrontal cortex blocks reinstatement of cocaine SA (Capriles et al., 2003) JDTic blocks reinstatement of cocaine SA (Beardsley et al., 2005) Inactivation of the prelimbic mPFC cortex blocks reinstatement of cocaine SA (Capriles et al., 2003).
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Table 4 Differences observed in
Conditioned place preference (CPP)
Cross-reinstatement
Nicotine reinstates cocaine CPP (Romieu et al., 2004) Ethanol reinstates cocaine CPP (Romieu et al., 2004) Morphine reinstates cocaine CPP (Romieu et al., 2004); Restraint reinstates morphine CPP (Ribeiro Do Couto et al., 2006) Food deprivation does not induce reinstatement of morphine CPP (Ma et al., 2007) Spontaneous withdrawal does not induce reinstatement of morphine CPP (Lu et al., 2005) Conditioned fear stress (odor or tone previously paired with footshock) reinstates cocaine CPP (Sanchez and Sorg, 2001) Blockade of CRF1 receptors in the CeA or Nac attenuates reinstatement of morphine CPP (Wang et al., 2006) DA antagonists has no effects on reinstatement of morphine CPP (Ribeiro Do Couto et al., 2005c)
Stressors that induce reinstatement of opioid seeking
Stressors that induce reinstatement of cocaine seeking Role of CRF in priming-induced reinstatement of opioid seeking Role of DA in priming-induced reinstatement of opioid seeking
Role of DA in priming-induced reinstatement of cocaine seeking
Role of glutamate in priminginduced reinstatement of cocaine seeking
D1 agonist SKF 81297 reinstates cocaine CPP (Graham et al., 2007) D2 agonist quinpirole does not block reinstatement of cocaine CPP (Graham et al., 2007) The NMDA receptor antagonist memantine blocks reinstatement of cocaine CPP (Maldonado et al., 2007)
methodology – for example, the animals (species, strain, age and sex) and drugs (doses) employed – or the different response requirements used to assess reinstatement (leverpressing behavior versus movement to a chamber previously paired with the drug). Moreover, it should be considered that CPP and self-administration paradigms evaluate different aspects of reward and, thus, different characteristics of relapse and addictive behavior. Self-administration involves an operant conditioning, models drug-taking behavior and evaluates the primary rewarding properties of drugs, while CPP involves a Pavlovian conditioning, models cue-elicited drug-taking behavior and assesses the incentive value of drug-associated cues for maintaining addictive behavior. The reinstatement of self-administration after extinction implies the restoration of a concrete operant response, while the reinstatement of CPP consists of the reappearance of the approach behavior to a drug-associated context. The data provided by the two models regarding the involvement of different neurotransmitter receptors, such as CRF, DA or glutamate, in drug-induced reinstatement of morphine and cocaine seeking is a subject of discrepancy. The effects of CRF1 receptor blockade on drug-priming-induced reinstatement of morphine vary according to whether studies employ the CPP or self-administration model. When the former was employed, the blockade of these receptors in the central amygdala or Nac attenuated drug-priming-induced reinstatement (Wang et al.,
Self-administration (SA) Nicotine does not reinstate cocaine SA (Schenk and Partridge, 1999) Ethanol does not reinstate cocaine SA (de Wit and Stewart, 1981) Morphine does not reinstate cocaine SA (Schenk and Partridge, 1999) Restraint does not induce reinstatement of heroin SA (Shalev et al., 2000) Food deprivation reinstates heroin SA (Shalev et al., 2000) Spontaneous withdrawal reinstates heroin SA (Shaham et al., 1996) Neither a conditioned fear stress nor a predatory odor reinstate cocaine SA (Shaham et al., 2000a,b) icv α-helical CRF has minimal effects on reinstatement of heroin seeking (Shaham et al., 1997) DA antagonists undermine reinstatement of morphine SA (Ettenberg et al., 1996; Shaham and Stewart, 1996; McFarland and Ettenberg, 1997) D1 agonist SKF 81297 does not reinstate cocaine SA and attenuates cocaine-induced reinstatement (Khroyan et al., 2000) D2 agonist quinpirole produces reinstatement of cocaine SA (Khroyan et al., 2000) Memantine has no effect on reinstatement of cocaine SA (Bespalov et al., 2000)
2006), while in the latter paradigm, the ventricular injections of αhelical CRF had minimal effects on heroin-priming-induced reinstatement of heroin seeking (Shaham et al., 1997). On the other hand, with the CPP paradigm, DA antagonists exerted no effects on morphine-induced reinstatement of a previously extinguished morphine CPP (Ribeiro Do Couto et al., 2005c), while selective D1 (SCH 23390), D2 (raclopride) and non-selective (flupenthixol, haloperidol) DA receptor antagonists undermined reinstatement in the self-administration model (Ettenberg et al., 1996; Shaham and Stewart, 1996; McFarland and Ettenberg, 1997). More recently, the influence of D2 receptors in relapse to heroinseeking behavior has been reported given that the activation of these receptors with quinpirole led to a reinstatement of response during early but not late phases of withdrawal (De Vries et al., 2002). When reinstatement of cocaine is evaluated using the selfadministration or CPP model, the effects of the DA agonists also vary. The ability of the D1 agonist SKF 81297 to reinstate cocaine CPP (Graham et al., 2007) contrasts with its failure to reinstate cocaine-seeking behavior and its attenuation of cocaine- and cue-induced reinstatement in self-administering animals (Self et al., 1996; Alleweireldt et al., 2002). Interestingly, administration of a D1-receptor agonist or antagonist dose-dependently attenuates cocaine-seeking behavior elicited by cocaine priming (Khroyan et al., 2000; Self et al., 1996) or by stimuli previously paired with cocaine (Alleweireldt et
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al., 2002; Ciccocioppo et al., 2001). Moreover, the administration of D1-like agonists into the Nac reinstates cocaine seeking (Bachtell et al., 2005; Schmidt et al., 2006). The D2/D3 agonist quinpirole induces a strong aversion to the cocaine-paired side but has no effect on cocaine-induced reinstatement of CPP (Graham et al., 2007), which contrasts with its ability to reinstate cocaine self-administration (Self et al., 1996; Edwards et al., 2007). These results imply that the role of D1 and D2/D3 receptors in the reinstatement of cocaine-seeking behavior differs depending on whether instrumental or classical procedures are used. Graham et al. (2007) have put forward an explanation based on the way in which DA signals are temporally linked to behavior in both procedures. In cocaine self-administration, DA signals are temporally linked in a response-contingent manner to instrumental behavior. In this way, a lasting D1 receptor activation would mask rather than mimic these discrete reward-related signals (cocaine priming or drug cues) and undermine their capacity to control instrumental behavior. In the CPP paradigm, discrete timing of dopaminergic signals during induction of contextual conditioning is not necessary; therefore, D1 receptor activation during reinstatement may mimic rather than mask the cocaine stimulus experienced during induction of the CPP. On the other hand, D2/D3 activation could reinforce the control exerted by conditioned stimuli over instrumental behavior in the self-administration paradigm (leading to reinstatement), while undermining the control exerted by cocaine-conditioned contextual stimuli in the CPP paradigm (leading to a failure to induce reinstatement). Similarly, the effects of NMDA antagonists on reinstatement of cocaine differ according to the paradigm used. In a self-administration procedure, administration of memantine prior to a priming injection of cocaine eliminated the difference between reinforced and non-reinforced lever response rates; an effect that was due rather to a stronger response to the non-reinforced lever than to a diminished response to the reinforced-lever. In the same study, memantine failed to block the selective increase in the reinforced-lever response induced by exposure to cocaine-related stimuli (Bespalov et al., 2000). Moreover, the NMDA receptor antagonist CGP 39551 has no effect on cue-induced cocaine self-administration (Bäckstrom and Hyytiä, 2006). However, when the CPP paradigm is employed, memantine blocks the reinstatement of cocaine CPP (Maldonado et al., 2007). As discussed previously, the disparity of results obtained with place-conditioning and self-administration models of relapse could be related to methodological aspects. Another discrepancy between CPP and self-administration reinstatement models is the effects of different types of stress on reinstatement. One study using the latter paradigm found that footshock and restraint stress had no effect on the reinstatement of heroin seeking in rats (Shalev et al., 2000). The authors stated that these stressors were ineffective because they were experienced outside the self-administration environment, and suggested that the effects of stress on reinstatement in heroin-trained rats is context- and time-dependent (Shalev et al., 2000). Conversely, a clear reinstatement of morphine-induced CPP was produced in the CPP paradigm, in which restraint and tail-pinch were administered in a different environment to that of place-conditioning, and which
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included two temporal intervals between the stress and the test (0 and 15 min) (Ribeiro Do Couto et al., 2006). Similarly, in self-administration studies, a conditioned fear stress or predatory odor did not reinstate drug self-administration (Shaham et al., 2000a), while a conditioned fear stress (odor or tone previously paired with footshock) produced the reinstatement of cocaine CPP (Sanchez and Sorg, 2001). A possible explanation for these differences is that, in the selfadministration paradigm, the freezing response interferes with operant response (conditioned suppression) to a greater extent than it does with movement in the CPP chambers. Alternatively, the two types of behavior measured (CPP versus self-administration) represent different aspects of behavioral response, and are, therefore, influenced by conditioned fear stimuli in different ways. Finally, in another report, spontaneous withdrawal reinstated heroin seeking in the selfadministration model (Shaham et al., 1996), but failed to reinstate morphine CPP (Lu et al., 2005). In humans, stimuli previously associated with stressful events can precipitate relapse. Other differences between both models include the effects of low doses of drugs, contingency of drug and type of extinction employed. A clear difference between self-administration and CPP reinstatement is observed when low doses of rewarding drugs are used. While it is difficult to reinstate CPP with a prime following conditioning with low doses (Orsini et al., 2008), one study has reported that reinstatement was more pronounced after self-administration sessions with lower unit doses (which resulted in lower total intake in terms of mg/kg, but a higher number of lever presses) than after those that employed higher unit doses (Keiflin et al., 2008). Moreover, in self-administration, the drug is contingent, whereas in CPP conditioning, the drug is non-contingent. Several studies have demonstrated different long-term effects on contingent versus non-contingent drug administration (Jacobs et al., 2005), which may be responsible for differences seen later on during reinstatement. Finally, self-administration sometimes involves a within session extinction/reinstatement (Maccioni et al., 2008), while extinction takes place over several days in the case of CPP. Thus, in both paradigms, differences in drug administration prior to extinction (non-contingent for CPP, and goaldirected with a work requirement for self-administration), are bound to produce clear differences in the dose-dependent effects of a rewarding drug with respect to vulnerability to reinstatement. The time course of vulnerability to reinstatement seems to differ in the CPP and self-administration versions of the reinstatement model. In CPP studies, reinstatement is generally affected by the time elapsed since the previous conditioning session or drug administration. In the selfadministration model, the magnitude of the reinstatement response induced by drug priming, footshock stress or discrete cues does not decrease over time, as cue reactivity rises gradually over a period of weeks or months (incubation effect). However, a recent study has reported that the CPP induced by a low dose of cocaine can only be reinstated after long withdrawal periods, and not immediately after extinction (Orsini et al., 2008), suggesting that the incubation effect may be also characteristic of CPP reinstatement.
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Relevance of findings to human relapse
The main challenge in the management and treatment of drug addiction is the development of a pharmacotherapy that diminishes craving and, consequently, vulnerability to relapse. The results obtained in studies using the CPP and self-administration versions of the reinstatement model endorse the idea that the neuronal and neurotransmission events that mediate reinstatement differ and are not necessarily associated with those that mediate drug reinforcement (Shalev et al., 2002). Several types of anticraving medication are available nowadays, including naltrexone for alcoholism, bupropion for nicotine, and methadone or buprenorphine for heroin (van dern Brink and van Ree, 2003). However, the efficacy of these treatments is limited and there is a need to develop new compounds with increased therapeutic action and reduced side-effects. Since the CPP version of the reinstatement model is relatively new, only a few compounds have been tested to date, which makes it difficult to assess its validity as a method with which to screen for drugs with therapeutic potential in humans. To confirm the validity of the CPP reinstatement model as a screening method, it is necessary to demonstrate that drugs that are clinically effective are also effective in the model, and that those that are not effective in the clinic are not effective in the model. To date, of all of the drugs approved by the FDA for treating abuse, only naloxone and acamprosate have been tested in the CPP reinstatement model (Kuzmin et al., 2003; McGeehan and Olive, 2006). Moreover, it is difficult to assess the validity of the model by extrapolating the data obtained with the self-administration model, due to the clear differences between the two (as mentioned previously). Several pharmacological agents block the reinstatement of CPP induced by different drugs of abuse and stress. The NMDA glutamate antagonist memantine is a promising candidate for the treatment of drug craving, since it blocks drug-induced reinstatement of morphine- and cocaine-induced CPP (Maldonado et al., 2007; Popik et al., 2005; Ribeiro Do Couto et al., 2005b). It is a fast, voltage-dependent NMDA receptor antagonist and blocks the NMDA receptor when there is a sustained release of low concentrations of glutamate, thus attenuating NMDA receptor function. Clinically, it is used to treat Alzheimer's disease. However, memantine has several sideeffects that limit its utility, such as dizziness, headache and constipation. Another agent, acamprosate, which modulates glutamate receptor function and is used to reduce alcohol craving and relapse, blocks cocaine-induced reinstatement (McGeehan and Olive, 2006), which highlights its potential for preventing relapse to cocaine abuse. In humans, GHB has proven to be effective as a therapeutic tool for combating craving and the symptoms of withdrawal from alcohol and opiates (Addolorato et al., 1998; Gallimberti et al., 1989, 1994). Results obtained with the CPP version of the reinstatement model suggest that GHB undermines cocaine CPP (Maldonado et al., 2006), which is of relevance to the treatment of poly-drug cocaine abusers. However, the narrow margin of effective doses may be an obstacle to its utility as a tool for treating cocaine addicts. The efficacy of CRF antagonists in the treatment and prevention of drug- and stress-induced relapse is by the fact
that these compounds block reinstatement of CPP induced by exposure to morphine (Lu et al., 2002; Wang et al., 2006) and stress (Lu et al., 2000, 2005). Similarly, the utility of CCK antagonists in treating drug- and stress-induced relapse must be studied, since CCK-B antagonists block morphine- and stressinduced reinstatement of morphine CPP (Lu et al., 2001b; Lu et al., 2002) while CCK-A antagonists block cocaine-induced reinstatement of cocaine CPP (Lu et al., 2002). Reinstatement of ethanol CPP is inhibited by naloxone, nociceptin and an ORL1 agonist (Kuzmin et al., 2003), which also blocks reinstatement of morphine CPP (Shoblock et al., 2005). Similarly, stress-induced reinstatement is blocked by the κ opioid antagonist arodyn (Carey et al., 2007). These results highlight naloxone, drugs targeted to the ORL1 receptor and opioid κ antagonists as potential therapeutic agents against drug-seeking behavior and relapse. Finally, given that the reinstatement of nicotine CPP induced by nicotine, morphine, WIN55,212-2 and ethanol is blocked by the calcium channel blockers nimodipine and flunarizine (Biala and Budzynska, 2006, 2008), the potential of these latter agents for treating drug-induced relapse should be studied.
8.
Theoretical landscape
The CPP is a procedure commonly used to study the conditioned rewarding effects of drugs of abuse. There is considerable concordance between drugs with abuse liability and those that produce CPP; a fact that is difficult to explain from a theoretical standpoint. In the CPP paradigm, the primary motivational properties of a drug serve as an unconditioned stimulus that is repeatedly paired with a previously neutral set of environmental stimuli (cues). In the course of conditioning, these stimuli acquire secondary motivational properties, so that they produce approach behaviour when the animal is subsequently exposed to them (Tzschentke, 2007). The CPP paradigm is based on classical conditioning principles, although it does raise some conceptual problems. For example, it is not yet clear what constitutes the unconditioned response induced by the drug. The conditioned response (longer time spent in the drug-paired environment) is due to the association of the affective reaction induced by the drug and the distinctive environment in which the animal always experiences this affective reaction. With repeated pairings, this previously neutral environment acquires a positive valence or salience, inducing an approach behavior in the animal and leading it to spend more time in close contact with these drug-associated cues. On the other hand, and although the CPP cannot be explained within an operant framework (since there is not a discrete response that is reinforced), the more marked approach response to the drug-paired compartment may represent a component of operant learning. In fact, during tests for CPP expression or reinstatement, the operant response of entering the drug-paired chamber could be strengthened by the availability of secondary reinforcers (the conditioned reward of the chamber). What is actually learned during place preference conditioning is a question that continues to demand a response. What constitutes the essential aspect under study with the CPP version of the reinstatement model is another important
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aspect to be determined. The CPP presents extinction when animals are repeatedly exposed to conditioned stimuli in absence of unconditioned stimuli. Which of these stimuli are altered when the stimulus-stimulus association is extinguished is a relevant question that is difficult to answer. The change in the behavior of the animal (progressive decrease in the time spent in the drug-paired compartment) may be due to changes in its motivational state or in the ability of the stimulus to direct its behavior, or both. The phenomenon of reinstatement of learned behavior following extinction was first described by Pavlov in his classic conditioning studies with dogs (Pavlov, 1927). The recovery of CPP after extinction is a classical conditioning model of reinstatement in which approach behavior to a drug-associated context is reinstated, which provides an occasion for drug-taking behavior (Bardo and Bevins, 2000). It is well known that environmental cues associated with drug experience play a critical role in maintaining drug-taking behavior and in relapse after extinction. The reinstating effects of drug priming can be attributed to the hedonic properties of the drug, which produce an incentive motivational state in the animals that promotes drug craving and leads them to seek environmental stimuli associated with the drug. Moreover, the drug priming may recall the extinguished CPP. After the extinction of CPP, the reinstatement of this behavior following a priming injection of the drug could be explained as a “restoration” of the significance or attractiveness of the drug-paired environmental stimuli, which leads the animal to approach those cues and remain in their presence. Indeed, this approach behavior could reflect a reinstatement of craving that leads the animal to seek once more the environmental stimuli it associates with the presence of the drug. According to Mueller and Stewart (2000), the priming injection “reminds” the animal of the significance of the cues previously paired with the drug. Drug-primed reinstatement of CPP is considered to reflect the renewed incentive value of the environmental stimuli via the incentive motivational effects of the drug priming (Mueller and Stewart, 2000). It has been suggested that drug priming induces reinstatement and cross-reinstatement of CPP through the activation of the mesocorticolimbic DA system, thereby influencing incentive motivation and appetitive goal-directed behavior (Wang et al., 2000). However, it has been observed that drug-induced reinstatement of CPP is largely independent of DA neurotransmission, at least with respect to opiate CPP (Ribeiro Do Couto et al., 2005c). Several mechanisms have been proposed to explain the reinstating effect of stress (Shalev et al., 2002), such as the activation of the mesocorticolimbic DA system (Shaham and Stewart, 1995), interference with neuronal inhibitory processes like the medial septum (which inhibits response when reinforcers are not available) (Highfield et al., 2000) and the induction of a withdrawal-like state (aversive feelings that lead animals to recall the motive for approaching the formerly drugpaired chamber) (Whitehead, 1974; Wang et al., 2000). Results obtained with the self-administration paradigm challenge this idea; only spontaneous and not antagonist-precipitated withdrawal reinstates heroin seeking, while footshock stress reinstates drug seeking in animals receiving a maintenance dose of heroin (Shaham and Stewart, 1995; Shaham et al., 1996). Conversely, morphine CPP is reinstated by conditioned withdrawal, which may be a stress-driven effect (Lu et al., 2005).
9.
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Shortcomings of the field
One of the shortcomings of the CPP procedure is the lack of dose–response effects that it produces. Generating a dose– response curve is a standard procedure in the field of behavioral pharmacology; however, this seems to be the exception rather than the rule in the case of the CPP. In this way, it is difficult to employ the CPP to compare the efficacy or potency of different drugs or draw conclusions regarding sensitization. It has been proposed that intermittent exposure to a drug of abuse increases behavioral and neurochemical effects (sensitization), which can lead to relapse (De Vries et al., 2002). Extinguished CPP may be reinstated by doses of the drug lower than that used to produce CPP acquisition, which suggests that a sensitization process contributes to reinstatement through drug priming. Moreover, in some studies, the time spent in the drug-paired compartment after a priming injection of cocaine or morphine was significantly higher than that during the test for CPP (Ribeiro Do Couto et al., 2003, 2005c; Szumlinski et al., 2002), which could be explained as a result of sensitization to the rewarding effects of these drugs. In one study performed in our laboratory (Ribeiro Do Couto et al., 2005a) we evaluated changes in the efficacy of drug priming in inducing reinstatement, and observed some sensitization when extinction/reinstatement took place at 6 week intervals. Reinstatement occurred in animals after the administration of progressively decreasing doses of morphine, even at a dose that was ineffective in animals without previous experience of reinstatement. These results suggest that, when drug-induced reinstatement is repeated, there is sensitization to the reinstating effects of morphine. The fact that the drug is administered by the researcher, and that total exposure is generally low, are factors that limit the relevance of the CPP version of the reinstatement model with respect to compulsive and chronic drug use. Furthermore, as this model does not evaluate the primary reinforcing effects of drugs, the results obtained with it should be complemented with others provided by the self-administration paradigm in order to determine the anatomical, neurochemical and behavioral correlates of drug-seeking reinstatement. Moreover, the duration of CPP reinstatement should be studied to distinguish between lapse and relapse, as Leri and Stewart (2002) did with the self-administration paradigm. Another deficiency of the CPP version of the reinstatement model is the lack of studies evaluating the cue/contextinduced reinstatement of the conditioned rewarding properties of a drug-paired environment in this paradigm. As already discussed, the CPP evaluates the power of drug-paired environmental cues to elicit drug-seeking behavior. For this reason, it is impossible to discriminate between the reinstating effect of re-exposure to environmental cues and of drug priming or stress. A possible strategy with which to overcome this difficulty is to design studies in which a discrete environmental cue, for example a red light, is placed in the drugpaired compartment and its influence in inducing reinstatement is subsequently evaluated. We are currently carrying out studies along these lines. A further shortcoming of the CPP version of the reinstatement model is the interpretation of the reinstating effect of
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drug-priming. Some authors have suggested that reinstatement of CPP is due to a state-dependent learning phenomenon attributable to the discriminative stimuli properties of the drugs. The drug is present and therefore acts as a stimulus during conditioning and reinstatement but not during extinction tests. For this reason, if the expression of CPP is statedependent, animals only show CPP in the presence of the drug. According to this hypothesis, exposure to the drug during test reinstatement should produce a selective increase in the response previously associated with the drug due to its discriminative stimuli properties. However, for several reasons, it is unlikely that the discriminative properties of drug priming injections are responsible for the totality of their effect on reinstatement of CPP. Firstly, in the placeconditioning paradigm, the drug is not associated with a specific instrumental response; thus, it is unlikely that drug priming induces the response habitually elicited by the discriminative properties of the drug. In fact, during the test for CPP, animals exhibit a clear CPP, although they do not receive any treatment or injection on this day. Secondly, the neuronal substrates that mediate discriminative effects (Jaeger and van der Kooy, 1996) are different to those involved in drug-induced reinstatement (Shaham et al., 2003; Shalev et al., 2002). Thirdly, the observation that morphine- and cocaine-induced CPP are reinstated by drugs other than that used during conditioning (cross-reinstatement) challenges the results of drug discrimination studies, which report that generalization to a training drug is typically observed within a given class of drug (Stolerman et al., 1995) but not among drugs from different pharmacological families. Finally, reinstatement can be induced by non-drug stimuli; for example, stress exposure. In this way, since the stimuli used in conditioning and reinstatement phases often differ, we believe that drug-induced reinstatement is not a result of a statedependent retrieval deficit. However, state-dependent learning is not to be ruled out as an explanation for reinstatement. The effects of priming, cross-reinstatement and stressors could be due to context-dependent learning during extinction (of the A→B→A/C type); in other words, the animals learn CPP in the presence of one drug (context A), learn extinction in the absence of drug (context B), and are then tested for reinstatement in a context other than that of extinction (context A in the case of a prime and context C in the case of crossreinstatement or stress). Reinstatement could be explained by the fact that the animal does not learn extinction in this state or context, which may explain reinstatement independently of incentive effects. On the other hand, lithium priming reinstates the conditioned place aversion induced by the same compound (Parker and McDonald, 2000) and morphine withdrawal reinstates place aversion that it induces (Li et al., 2007). These results suggest that CPP and conditioned place aversion can be reinstated by re-exposure to the stimulus that has induced conditioning. As discussed previously, it is not clear whether reinstatement is due to a modification of the incentive value of the chamber or of the motivational state of the animal, or to a state-dependent learning. An additional limitation of the CPP paradigm lies in that drugs are administered acutely in reinstatement studies but chronically in clinical trials. For this reason, drugs that effectively block reinstatement of CPP can induce different
therapeutic or collateral effects when administered chronically to prevent relapse in humans.
10.
Priorities for future research
The CPP version of the reinstatement model is a relatively new field of behavioral pharmacology. Studies performed in recent years have provided valuable information on the neurobiological basis of drug- and stress-induced reinstatement, as described in the course of this review. However, it does possess some shortcomings, and extensive work with improved methods and procedures must be performed in future years to expand and hone the collective knowledge regarding the neurobiology of relapse. According to the recently demonstrated involvement of the endocannabinoid system in reinstatement of self-administration (Fattore et al., 2007), the study of the role of this neurotransmitter system in the reinstatement of CPP is a priority. Already, one report has demonstrated that priming with the cannabinoid receptor agonist WIN55,212-2 reinstates nicotine CPP (Biala and Budzynska, 2008). The effects of cannabinoid agonists and antagonists on the reinstatement of the CPP induced by different drugs of abuse should also be evaluated by future studies. Another area of relevance to be addressed by future studies is the influence of pre-natal or adolescent drug exposure on the reinstatement of the CPP induced by different drugs of abuse in adulthood. For example, a recent study in our laboratory revealed an effect of pre-treatment during adolescence with MDMA and cocaine on acquisition and reinstatement of morphine-induced CPP. The results obtained suggest that periadolescent MDMA exposure alters responsiveness to the rewarding properties of morphine (Daza-Losada et al., 2008). Future studies should evaluate whether pre-treatment during critical phases of brain development with “gateway drugs”, such as ethanol, nicotine and cannabinoids, modifies susceptibility to reinstatement in adulthood. The identification of the neural basis of cross-reinstatement is also a priority. It is important to know which drugs induce reinstatement of the CPP induced by opioids, psychostimulants and other drugs of abuse, and to determine which neurotransmitter systems are involved in this phenomenon. Similarly, a model of cue-induced reinstatement of CPP must be developed in future years. It is well established that drugassociated contextual stimuli, which are initially neutral, gain secondary motivational value through their association with the pleasurable experiences induced by drugs, and are, thus, capable of provoking craving and relapse (Meyer, 1988). Future studies should seek to increase the homology of animal models of reinstatement with human relapse. Successive relapses following prolonged drug-free periods characterize the behavior of experienced addicts of heroin and other drugs of abuse. Some studies using the self-administration paradigm have indicated that the amount of drug intake during training influences the effect of drug priming on reinstatement (for a review, see Shalev et al., 2002). In our laboratory we have observed that repeated extinction-reinstatement sessions increase the reinstating effects of morphine (Ribeiro Do Couto et al., 2005a). Reinstatement of morphine CPP in mice
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can be induced up to 30 weeks after conditioning by a priming dose of morphine approximately twenty four times lower than that used for conditioning, and which would not induce reinstatement after a single extinction (Ribeiro Do Couto et al., 2003). The fact that successive drug-induced reinstatements are possible following extinction with very low doses and a considerable time after conditioning confirms drug addiction as a chronic, relapsing and lasting-long disorder. Furthermore, it should be stressed that the interval between conditioning and reinstatement and between different extinction/reinstatement experiences affects the reinstating effects of morphine. When these intervals are enlarged and the animals have no further experience related to the previously learned CPP, a decrease in the priming effect of morphine is observed, probably due to an impairment of its ability to recall the extinguished CPP (Ribeiro Do Couto et al., 2005a). We are presently performing a series of studies of prolonged conditioning (which models addictive behavior more closely), and preliminary results are promising, since animals exposed to drugs over an extended conditioning phase present different addiction criteria to those undergoing shorter (habitual) conditioning. The study of the influence of different procedural and environmental factors on the ability of a drug to induce reinstatement must be a priority of future research in the field.
11.
Conclusion
The data presented in this review confirm that the CPP version of the reinstatement model is a useful tool for investigating the neurobiological mechanisms of drug- and stress-induced reinstatement of the conditioned rewarding properties of the drug-paired environment and vulnerability to relapse. Drug priming with the conditioning drug or with another substance induces reinstatement of the CPP induced by different drugs of abuse. Several neurotransmitter systems are involved in priming- and stress-induced reinstatement (dopamine, glutamate, opioid, CRF, NA, CCK, etc), although both types of reinstatement are mediated, at least partially, by different neural pathways. Different molecular correlates of reinstatement behavior have been detected, such as the activation of CREB and changes in different subunits of glutamate receptors. The CPP version of the reinstatement model may provide supplementary information to that offered by the traditional intravenous self-administration method, since both procedures permit the evaluation of different aspects of drug relapse. With some exceptions, similar results are obtained with both paradigms, suggesting that the neurobiological basis of self-administration and CPP reinstatement generally overlap. The CPP version of the reinstatement model offers a number of advantages, as it is a relatively inexpensive, non-invasive, rapid and uncomplicated procedure. Moreover, the locomotor effects of drugs produce less interference with the animal's behavior in the CPP than in the self-administration model. Indeed, if a drug produces catalepsy or a similarly severe behavioral disruption, the CPP would clearly be influenced. The CPP version of the reinstatement model has a good criterion validity, which refers to the extent to which laboratory-animal behavior induced by experimental manipulation predicts human behavior induced by a similar event
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(Epstein et al., 2006; Geyer and Markou, 1995). Some conditions that have been reported to provoke drug craving and relapse in humans, such as acute re-exposure to the drug (de Wit, 1996) and stress (Sinha, 2001), induce reinstatement of CPP. Unfortunately, the reinstatement model has a poor construct validity, which refers to the similarity between the mechanisms underlying behavior in the model and modeled condition (Epstein et al., 2006; Geyer and Markou, 1995). There is a lack of homology between the human condition and both reinstatement of CPP and self-administration. For example, the drugfree state occurs for different reasons, and there is no parallelism between drug-priming-induced reinstatement (induced by a non-contingent forced priming) and a selfinitiated relapse. However, several self-administration models are now being employed to experiment with non-imposed drug-free states (for example, using shock to decrease lever pressing) as an alternative to the habitual procedure of extinction (Cooper et al., 2007). Such a technique – for example, shocking the floor of the drug-paired chamber – could be easily employed in the CPP paradigm. In addition, the CPP version of the reinstatement model would appear to be a useful tool for screening the clinical efficacy of new compounds that prevent relapse. An in-depth review of the validity of the reinstatement model has recently been provided by Epstein et al. (2006). At the present time, a theoretical understanding of the CPP version of the reinstatement model is incomplete. Furthermore, several shortcomings limit the validity of this paradigm. The overcoming of these deficiencies should be among the priorities of future research in the field, with the aim of increasing the homology of the procedure with human relapse to drug abuse.
Acknowledgments We wish to thank Mr. Brian Normanly for his editing of the manuscript. This work was financed by the following grants: Ministerio de Sanidad y Consumo, Instituto de Salud “Carlos III” (FIS), RETICS, Red de Trastornos Adictivos (RD06/001/0016); Ministerio de Educación y Ciencia, Dirección General de Investigación and FEDER (SEJ2005-00316/PSIC) (Spain) and Generalitat Valenciana, Agencia Valenciana de Salud, Dirección General de Drogodependencias (FEPAD).
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Glossary of terminology CPP paradigm A classical conditioning procedure used to study the conditioned rewarding effects of drugs and other
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stimuli. During conditioning a set of neutral environmental stimuli is paired with the reinforcing effect of a drug. During the test for CPP, the animal, in a drug-free state, is allowed to choose between the drug-paired and the vehicle-paired environment. An increase in preference for the drug-paired context serves as a measure of the conditioned rewarding effects of the drug. Craving Hypothetical construct that is defined as the memory of the pleasant rewarding effects of drug use, superimposed on a negative emotional state (Koob and Le Moal, 2008). Cross-reinstatement Reinstatement of drug seeking, following extinction, by drugs other than that administered during acquisition of behavior (self-administration or CPP). Drug addiction Chronically relapsing disorder characterized by compulsion to seek and take the drug, loss of control in limiting intake and emergence of a negative emotional state when access to the drug is prevented (Koob and Le Moal, 2008). Drug self-administration paradigm An operant procedure in which animals perform a discrete response (typically lever press) in order to receive an injection of a drug. The drug is a positive reinforcer that controls behavior. Extinction Extinction refers to discontinuing the reinforcement of a response (in the operant conditioning) or the appearance of the conditioned stimulus in the absence of the primary reinforcer (in classical conditioning). Reinstatement Reinstatement refers to the recovery of a learned response when a subject is non-contingently exposed to an unconditioned stimulus after extinction. In studies of reinstatement of drug seeking, reinstatement refers to the recovery of drug-seeking behavior after extinction following exposure to drugs (drug-induced reinstatement), drug cues (cue-induced reinstatement) or stressors (stress-induced reinstatement). Relapse Return to drug-taking behavior following drug-free periods. This is one of the core features of addiction and the most difficult clinical problem in addiction treatment. After prolonged abstinence, relapse is often precipitated by acute re-exposure to the drug itself, drug-associated cues or stress. Versions of the extinction/reinstatement model The extinctionreinstatement model is a procedure used to study relapse into drug abuse in laboratory animals. Animals are first trained to acquire a behavior and, subsequently, undergo a process of extinction of this behavior. Afterwards, animals are exposed to different stimuli in order to evaluate their efficacy in inducing reinstatement of the previously acquired and extinguished behavior. There are two main versions of the reinstatement model; one based on the operant selfadministration procedure (the behavior acquired, extinguished and reinstated is typically the pressing of a lever), and the other based on the classical conditioned place preference procedure (the behavior acquired, extinguished and reinstated is CPP).