Drug reward memory:implication from drug-induced conditioned place preference model

Jian-feng LIU,Jun-xu LI

（Department of Pharmacology and Toxicology,Jacobs School of Medicine and Biomedical Sciences,the State University of New York at Buffalo,Buffalo,NY 14214,USA）

Drug reward memory:implication from drug-induced conditioned place preference model

Jian-feng LIU,Jun-xu LI

（Department of Pharmacology and Toxicology,Jacobs School of Medicine and Biomedical Sciences,the State University of New York at Buffalo,Buffalo,NY 14214,USA）

Drug addiction is a chronic，relapsing brain disorder，which develops，in part，because of aberrant learning and memory.Accumulative studies during recent decades demonstrated that addictive drug hijacks the normal memory circuit in the brain to form a long-lasting drug reward memory，which determines relapse to addictive drug.In this review，we will describe what has been learned about drug reward memory，especially focused on one of the associative drug reward memory models，druginduced conditioned place preference.Drug reward memory is a dynamic process，which consists of several stages，including acquisition，consolidation，maintenance，retrieval，reconsolidation and extinction. Interventions with pharmacological in these memory processes will differentially regulate drug reward memory.Furthermore，the recently developed novel pure behavioral procedure according to the hypothesis of memory processes，e.g.post-retrieval extinction，could erase drug reward memory，which shows more advantages than the pharmacological medications that used in memory studies.Finally，we discussed two major methodological issues in drug reward memory，procedure and timing，which should be carefully considered when designing the related studies and interpreting the results from related studies.So far，it is not sure whether it is feasible to develop a pharmacological medication that only erases drug reward memory without impairing normal memories，we propose that inhibition of drug reward memory would be a good strategy to limit the risk of relapse to addictive drug.Although current findings on drug reward memory benefits little for treatment of drug addiction，the ongoing studies on drug reward memory will provide a promising strategy for reducing the risk of relapse to addictive drug.

drug addiction;drug reward memory;consolidation;reconsolidation;maintenance; extinction

Memory is one of the most fundamental mental processes，which determines the behav⁃ioral response and adaptation of organism to the complex environment.The common definition of memory is the storage of things learned from an organism′s experience and/or the process of reproducing or recalling what has been learned，or simply memory is a behavioral change caused by an experience［1］.Better memory capacity usu⁃ally predicts better behavioral strategy dealing with daily life and stressful events.However，when facing with salientstimulus，such as addictive drug-induced experience，these behav⁃ioral changes can also form related memories，which may contribute to the pathology of related disorders.

Drug addiction is a chronic，relapsing brain disorder that is characterized as a compulsionto take the substance with a narrowing of the behavioralrepertoiretowardexcessivedrugintake，and a loss of control in limiting intake（American Psychiatric Association 1994）.Accumulative studies from recent decades elicit the hypothesis that drug addiction develops，in part，because of aberrant learning and memory［2-3］.It is proposed that addictive drug hijacked the normal memory circuits in the brain to form a long-lasting drug reward memory［4］.A large literature has demon⁃strated that different types of memory contribute to different aspects of specific behaviors，and the underlying mechanisms of memory vary with the memory type.The well-studied drug reward memories in drug addiction include both associative memory and non-associative memory. Specifically，in this review we will focus on one of the associative drug memory models，druginduced conditioned place preference（CPP）.CPP is the most well-studied classical conditioning model in addiction，which involves pairing an addictive drug with a specific environment［5-7］. After associated with addictive drug， the drug-paired environment acquires incentive motivational value，which drives the subject to show a conditioned preference for the drug-paired environment.

Classic conditioning memory is a dynamic process，which consists of several stages，including acquisition，consolidation，maintenance，retrieval，reconsolidation and extinction(see Box 1).We will describe what has been learned about drug reward memory according to the memory processes.Considering that it is hard to prevent the acquisition ofdrug memory in the real word，and the acquisition is more likely aprocessoccurred before memory，which is termed as learning，we will not discuss the acqui⁃sition of drug reward memory in this review.

Box 1 Glossary

1 CONSOLIDATION OF DRUG REWARD MEMORY

The concept of memory consolidation has been proposed over one century.The mechanisms underlying memory including the neuroanatomical pathways， synaptic events and molecular mechanisms have been studied several decades since then，by using behavioral models of different kinds of memories，e.g.spatial memory and emotional memory，and some leading electro⁃physiological models of synaptic plasticity，e.g.long-term potentiation(LTP)［8-10］.The memory consolidation hypothesis posits that memory is labile after acquisition，which requires a progres⁃sive post-acquisition stabilization to form a stable long-term memory(LTM).It is proposed that memory consolidation could be divided into cellular consolidation(or named synaptic consolidation) and system consolidation.

1.1Cellular consolidation of drug reward memory

Cellularconsolidation beginsimmediately after acquisition and completed within hours，which transfers the short-term memory(STM)to LTM.Cellular consolidation involves the formation of new synapse and the restructuring of existing synapse in local brain regions［11］.

The first findings on the mechanism underlying learning and memory comes from the ground breaking works on LTP in theAplysia californicamodel system，which support the hypothesis that neuronal and synaptic plasticity is necessary and sufficient for learning and memory［10］.As LTP is the potentiation of synaptic connectionsat local brain area but not between brain circuits，it is more ready to fix the cellularconsolidation hypothesis of memory.According to the molecular biochemistry studies，the long-lasting LTP can be divided into two distinct phases：″early″and″late″LTP.It is believed that early LTP does not necessarilylead to long-lasting changesin synaptic strength，while the induction of late LTP depends on activation ofseveralsignaling pathway cascades,e.g.mitogen-activation protein kinase(MAPK)，protein kinase A(PKA)and mammalian target of rapamycin(mTOR)and following protein synthesis［12］.

Ongoing evidence demonstrated that condi⁃tioned memory requires PKA and protein kinase C（PKC）activation and protein synthesis in several kinds of behavioral models［13］.Consistent with these results，the pioneering work from Cervo and colleagues［14］showed thatchelerythrine， a selective PKC inhibitor，and H89，a selective PKA inhibitor，administered immediately after conditioning disrupted cocaine-induced conditioned place preferamce(CPP)，suggesting that both PKC and PKA contribute to the consolidation of cocaine reward memory.Microinjection of H89 into the CA1 of the hippocampus also disrupted consolidation ofmorphine-induced CPP［15］.Other protein kinases，e.g.CDK5 and nitric oxide/soluble guanylyl cyclase/cGMP dependentprotein kinase signaling pathway，also play important roles in drug-reward memory［16-19］.Besides inhibitors of protein kinases，antagonisms of several kinds of receptors，e.g. N-methyl-D-aspartic acid(NMDA) receptor，muscarinic M1receptor，β-adrenergic receptor，cannabinoid receptor type 1(CB1)，and estrogen receptor could also disrupt the consolidation of drug reward memory［20-25］.Furthermore，intracerebroventricular anisomycin，a protein synthesis inhibitor，immediately after conditioning prevented consolidation of morphine-induced CPP［26］. Anisomycin treatment two hours after each drugplace pairing also disrupted the cocaine-induced CPP，whereas the same treatment did not affect methamphetamine-induced CPP［27］，indicating that the role of protein synthesis in the drug reward memories depends on the properties of drug itself.

1.2 System consolidation and late consolidation of drug reward memory

System consolidation refers to a more prolonged process that involves transaction ofstored information between several brain areas. The concept of system consolidation is mainly based on the serial studies in non-drug memory models，especially spatial and context memory，e.g.contextual fear memory and water maze memory.The standard model of system consoli⁃dation was proposed as that the information of recent memory is initially encoded in several specialized primary and associative cortical areas，which is integrated in the hippocampus.With time passing，the connections between these cortical areas strengthen，while the connections between the hippocampus and these cortical areas weaken gradually.The final consequence after system consolidation is that the recent memory becomes remote memory，which is independent of the hippocampus.

Further studies suggested that the prefrontal cortex(PFC)might participate in system consoli⁃dation by inhibiting the activity of the hippocampus in the remote memory recall［11，28］.The transcrip⁃tional changes associated with recent cocaine reward memory in the frontalcortex are lessmagnitudethanthoseobservedinthe hippocampus，which suggests an essential role of the hippocampus for recent cocaine reward memory［29］.Recently， Raybuck and Lattal［30］examined the role of the dorsal hippocampus on expression of recent and remote drug memory. γ-aminobutyric acid A(GABAA)receptor agonist muscimol was microinjected into the dorsal hippo⁃campus before recent and remote cocaine reward memory test，one day and four weeks after CPP training，respectively.The results showed that inactivation of the dorsal hippocampus blocked expression of both recent and remote cocaine reward memory，indicating that remote cocaine reward memory is stilldependenton the hippocampus［30］.

Another interesting study demonstrated that the newly acquired morphine reward memory tested one day after conditioning depends on extracellular signal-regulated kinase1/2(ERK1/2) and Ca2+/calmodulin-dependent protein kinaseⅡ(CaMKⅡ)activity within 3 hours post-conditioning in the basolateral amygdala(BLA)and the CaMKⅡactivity 12 hours post-conditioning in the medial PFC(mPFC)，suggesting that consolidation of morphine reward memory involve a temporal and molecular switch between the BLA(early consolidation phase)to the mPFC(late consoli⁃dation phase)［31］.Late consolidation hypothesis was first proposed from the serial studies by using foot shock-induced inhibitory avoidance (IA).One day-old IA memory is dependent on early consolidation(within 6 h post-conditioning)，while one week-old IA memory is dependent on late consolidation(around 12 h post-conditioning). Protein synthesis and several protein kinases in the dorsal hippocampus participateinlateconsoli⁃dation of IA memory.However，the neuronal firing activity and protein synthesis in the mPFC during late consolidation determines the one day-old morphine reward memory［31］，which is different with the hypothesis that late consolidation determines the one week-but not one day-old memory in the IA memory paradigm.A recent studyshowed thatmodulation ofdopamine D1 receptor activity during the late consolidation phase(12 h post-training)controls the persis⁃tence ofcocaine reward memory［32］.These findings indicate that different brain areas in late consolidation regulate the persistent length of drug reward memory

2MAINTENANCE OF DRUG REWARD MEMORY

Maintenance of LTP would be a proper model for the maintenance of memory.The molecular mechanism underlying LTP has been extensively investigated.Release ofglutamine activates NMDA receptors and Ca2+influx，which then acti⁃vates several signaling pathways，e.g.CaMKⅡ，CaMKⅣ，and MAPK.Activation of these signaling pathways increases phosphorylation of cAMP response element binding(CREB)，which conse⁃quently stimulates gene expression［33］.Recent study showed that CaMKⅡ activity is required for maintaining olfactory discrimination learning-induced enhancementofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic excitation［34］.The role of CaMKⅡin the maintenance of morphine reward memory has been examined.Inhibition of amygdalar CaMKⅡactivity via daily microinjections of CaMKⅡinhibitor KN-62 into the amygdala for one week suppressed maintenance of morphineinduced CPP［35］.However，some methodological issues should be considered carefully in this study.The daily microinjection of CaMKⅡinhibitor for one week could affect some other molecular changes，but not CaMKⅡper se，that really determines the maintenance of morphine-induced CPP.Moreover，activation of signaling pathway cascades eventually results in gene expression and protein synthesis in LTP.As aforemen⁃tioned，protein synthesis is only required within several hours after training of drug reward memory (consolidation phase)，suggesting that synthesis of″maintenance molecular maker″be completed after consolidation or some other mechanism undery the maintenance of drug reward memory.

It is shown that the induction of LTP depends on several protein kinases including CaMKⅡ，while the maintenance of LTP requires an atypical PKC isoform PKMζ［36-37］.By using the selective inhibitor ζ inhibitory peptide(ZIP)，which inhibits PKMζ activity，several studies have demonstrated that PKMζ maintains several different kinds of memories.Microinjection of ZIP into the nucleus accumbens(NAc)core，but not shell，erased morphine-induced CPP［38］，whereas microinjection of ZIP into the NAc shell abolished cocaineinduced CPP［39］.Furthermore，PKMζ in the BLA but not central amygdala(CeA)maintained morphine-induced memory.PKMζ may be only important for the maintenance of associative drug memory but not the maintenance of nonassociative drug memory，since single postinduction of sensitization ZIP treatment did not affectcocaine sensitization［40］.However，two recent studies showed that knockout of PKMζ did not affect hippocampal plasticity，learning and memory.Moreover，the amnesic effect of ZIP was resulted by the non-specific effect of ZIP. Serious considerations and further studies are required to determine the role of PKMζ in drug memory.

As late consolidation and system consolidation controls recent and remote memories，respectively，this means that these two processes indeed control the maintenance of LTM.Then，another issue about the molecular mechanism of drug memory maintenance is how could the molecules that maintain memory integrate with late consolidation and system consolidation.Moreover，an important phenomenon in addiction is the″incubation of craving″that craving，triggered by drug-associated cues，progressively increases with time passing after withdrawal from addictive drug［41-42］.Uncov⁃ering the mechanisms underlying the mainte⁃nance of drug memory may benefit the under⁃standing of the time-dependent process of incu⁃bation of craving.

3EXPRESSION OF DRUG REWARD MEMORY

The expression of drug reward memory mimics the relapse of cocaine-seeking behavior. Serial studies have demonstrated that expression of cocaine reward memory requires the activation of AMPA/kainite receptors，NMDA receptors，trace-amine associated receptor 1，M1 receptor，ERK1/2，PKC and PKA［14-15，43-46］.Systemic or intra-BLA injection of protein synthesis inhibitor also inhibited the expression of cocaine-induced CPP［47］.Whereas memory expression is only the recall of memory，intervention of memory expression is proposed to leave thebona fidememory intact.Afterexpression， memory could be retrieved/reactivated.Afterretrieval， memory could enter into two opposite processes，recon⁃solidation and extinction，depending on the length of retrieval，memory strength，memory age，and other factors［48-51］.More attention has been drawn to these two processes after retrieval，because modulations ofreconsolidation and extinction have generated prominent strategiesto erase memory itself［52-53］.

4 RECONSOLIDATION OF DRUG REWARD MEMORY

The memory reconsolidation hypothesis posits that consolidated memory becomes labile again after retrieval，which requires a progressive post-retrieval re-stabilization process to reform a stable LTM.Lots of studies have shown that reconsolidation shares a lot of molecular signaling pathways with consolidation.Moreover，similar to the hypothesized cellular and system consoli⁃dations，memory can also undergo reconsolidation atboth the cellularand system levels［54］，suggesting that consolidation and reconsolidation are similar with each other［55］.Nevertheless，some distinct molecular mechanisms may underlie consolidation and reconsolidation processes［56-57］. It has been demonstrated that brain derives neurotrophic factor(BNDF)mediates consolidation while zif268 mediates reconsolidation of contextual fear memory［58］.The reconsolidation marker zif268 is also critical for the reconsolidation of cocaine reward memory［59］，although zif268 in the BLA and the NAc core mediates different aspects of reconsolidation of drug reward memory［60］.

To be re-stabilized after retrieval，consolidated memory requires to be destabilized first［61］.A recent study demonstrated that ubiqutin-protea⁃some system-dependent protein dgradation in the NAc after retrieval of cocaine-induced CPP played an important role in destabilization of cocaine reward memory［62］.During the labile state afterretrieval，interventions ofseveral important signaling pathways，e.g.MAPK，PKA，CDK5，mTOR，Zif268，eIF2alpha，NFKAPAB，NMDA receptors，β-adrenergic receptor，CB1 receptor，and perineuronal nets would disrupt reconsolidation and persistently prevent return of drug reward memory［16，22，25，45，59，63-67］.Also，inhibition of protein synthesis by anisomycin after retrieval eraseddrugrewardmemoryandprevented cocaine-seeking behavior［62,68-71］，but see［47，72］. However，most pharmacological agents used in reconsolidation studies cannot be used in clinical settings because of the toxicity and/or treatment route，e.g.brain regional microinjection［50］.So far，one agent that can be most potentially used in the clinic is β-receptor antagonist propranolol.4.1Effect of propranolol on drug reward memory in animals

Animal studies on pharmacological manipu⁃lation of β-receptor system by propranolol on reconsolidation of drug reward memory demon⁃strated that the effect of propranolol shows a drug type-dependent manner［73］.Post-retrieval propranolol disrupted cocaine-induced CPP in rats，indicating that propranolol disrupted recon⁃solidation of cocaine reward memory［74-77］.However，the inhibitory effect of propranolol on morphineinduced CPP was reinstated by morphine priming，indicating that post-retrieval propranolol did not eliminate morphine reward memory［77］.Propranolol injection after ethanol-induced CPP retrieval test did not modify subsequent memory retention［78］，but see［79］.Post-retrieval systemic administration of propranolol，but not the peripheralacting antagonist nadolol，blocked the expression of morphine-induced CPP，suggesting that central but not peripheral β-adrenergic system is involved in the reconsolidation of drug memory［77］.The BLA does not seem to participate in the effect of propranololon reconsolidation ofmorphineinduced CPP［80］.Furthermore，boundary conditions on reconsolidation，e.g.the strength and age of memory，modulate the effect of propranolol on morphine reward memory［81］.It is shown that post-retrieval propranolol had no effect on the morphine-induced CPP if the memory had reacti⁃vation history before the treatment，suggesting that novelty of the reactivation procedure is important for propranolol′s effect on drug reward memory［82］.

4.2Effect of propranolol on drug reward memory in human

In abstinent heroin addicts，oral administration of propranolol disrupted the reconsolidation of drug-related positive and negative word list［83］.A double-blind，placebo-controlled study showedthat propranolol administration after cocaine cue exposure attenuated craving and cardiovascular reactivity during the memory test［84］.A single dose of propranolol prior to retrieval of smoking related memories did notaffectphysiologicaland emotional reactivity to smoking cues［85］.A recent randomized-controlled trial showed that ingestion of propranolol capsules before drug-related memory reactivation reduced craving among substancedependent individuals［86］.However，considering the sample size is too small and the sample includes a mix ofdependencies (alcohol，cocaine，opiates/opioids and marijuana)，more comprehensive trials are required to draw the conclusion on the effect of propranolol on drug reward memory and craving.

5EXTINCTIONOFDRUGREWARD MEMORY

Generally，long-term or repeated exposure to conditioned stimulus(CS)induces memory extinction.Successful extinction lowers behavioral conditioned response.The number of sessions required forsuccessfulextinction has been shown positively correlated with the strength of drug reward memory［87］.In the clinic，extinction has successfully suppressed some conditioned behaviors，termed as cue exposure therapy. However，extinguished conditioned response will reemerge in specific conditions，e.g.reinstatement， renewal， and spontaneous recovery，which indicate that extinction only inhibits，but not erases，original conditioned memory.Indeed,itisproposed thatduring extinction a new CS-no unconditioned stimulus (UCS)association memory forms.As with other conditioned memories，extinction memory also has acquisition，consolidation，maintenance，retrieval，and reconsolidation processes.It is anticipated that the facilitation of extinction by modulation ofextinction memoryprovidesa more efficient strategy than exposure therapy alone to interfere with drug reward memory and prevent drug addiction relapse.

5.1 Acquisition of extinction of drug reward memory

The agents that showed facilitative effect on drug memory extinction when given pre-extinction includesAMPAreceptorspotentiator，NMDA receptors glycin site agonist，positive allosteric modulator of metabotropic glutamate receptor 5，dopamine D1but not D2agonist，GABABreceptor agonist，CB1 receptor antagonist，orexin-1 and-2 receptors antagonist，phosphodiesterase9 inhibitor，and histone deacetylase(HDAC)inhibitor［23，88-100］. The facilitative effect of pre-extinction intervention，e.g.shortening the extinction latency，suggests that these agents promote the acquisition of extinction memory.As mentioned above，the conditioned response would return after extinction，as is the case in drug addiction that relapse will still occur after extinction.In the CPP model，drug-induced reinstatement of CPP is widely used to evaluate the persistent inhibitory effect ondrugmemoryafterextinction.Moreover，prevention of reinstatement of CPP is usually taken as one of the criteria of drug memory erasure. Among the above agents，pre-extinction adminis⁃tration of CB1 receptor antagonist AM251 and PDE9 phosphodiesterase inhibitor BAY-73-6691 significantly facilitated extinction and further reduced subsequentreinstatementofdrug reward memory，suggesting that administration of these agents following extinction erase drug memory［88，98］.Another study showed that degra⁃dation of perineuronal nets in the amygdala following extinction could disruptmorphineinduced and cocaine-induced，but not foodinduced CPP，indicating a specific role of amygdalar perineuronal nets in extinction of drug but not natural reward memory［101］.

5.2 Consolidation of extinction of drug reward memory

Post-extinction interventions can be inter⁃preted as the modulations on consolidation of extinction memory.Systemic or intra-amygdala post-extinction trial injections of oxotremorine，a cholinergic muscarinic receptoragonist，and glucose facilitated extinction of amphetamine-induced CPP［102-103］.Post-extinction administration of baclofen，a GABA(B)agonist，dose-depend⁃ently facilitated extinction of morphine-induced CPP［104］.Inhibition of HDAC during extinction consolidation reduced subsequent reinstatement of cocaine-induced CPP［105-107］.Post-extinction administration ofprazosin， an α1-adrenergic receptors antagonist，prevented the formation of extinction LTM memory，indicating that consoli⁃dation of extinction can be bidirectionally regulated［108］.These findings indicate that promotion of consolidation of drug reward memory facilitates extinction memory and reduces subsequent reinstatement，which highlights this potential strategy in the treatment of drug addiction.

5.3 Maintenance of extinction of drug reward memory

As aforementioned，extinction memory has similar processes as the original conditioned memory.A study examined the role of the potential molecular marker of memory maintenance PKMζ in extinction of drug memory［109］.He，et al［109］showed that inhibition of PKMζ activity by ZIP in the infralimbic cortex，but not prelimbic cortex，within the medial PFC disrupted extinction memory of morphine-induced CPP，indicating that PKMζ in the infralimbic cortex is required for the mainte⁃nance of extinction memory of morphine-induced CPP.Nevertheless，the specificity of ZIP on PKMζ should be considered as the case in the maintenance oforiginalconditioned memory mentioned above.

5.4 Facilitative effect of D-cycloserine and D-serine on extinction of drug reward memory

Growing evidence suggests the combination of D-cycloserine，a NMDA receptor glycin site agonist，with extinction as a potential treatment that be used in the clinic.

D-cycloserine was first found to facilitate extinction of fear memory and prevents the return of fear in rats，suggesting potential clinical benefits for this drug［110］.Botreau，et al［111］first determined the effect of D-cycloserine on extinction of drug memory.They showed that systemic or intra-BLA injection of D-cycloserine immediately after each extinction trial accelerated extinction of cocaine-induced CPP.The facilitative effect of D-cycloserine on extinction of cocaine-induced CPP is long-lasting and resistant to reinstatement［112］. A randomized placebo-controlled trial demon⁃strated that D-cycloserine augments the effect of cue-exposure-based extinction training for alcoholism［113］.However，the effect of D-cycloserine on extinction of drug reward memory is not always consistent.D-Cycloserine has no effect on extinction of morphine-induced CPP，which limits the use in opioid addiction［114］.Furthermore，a study showed that intra-BLA infusions of D-cycloserine potentiated reconsolidation of cocaine reward memory to increase cue-induced relapse in rat drug-seeking behaviors［115］.Therefore， further studies are required to carefully evaluate the benefits of therapeutic effects of D-cycloserine on drug addiction.

As a partial agonist，D-cycloserine may act as a competitive antagonist to inhibit NMDA receptor rather than an activator of NMDA receptor［115］. Recently，the effects of D-serine，a full agonist of NMDA receptor at the glycine site，has been tested in drug reward memory studies.Systemic administration of D-serine also facilitated extinc⁃tion and reduced drug-primed reinstatement of cocaine-induced CPP in rats［116］.A recent study showed that systemic or intra-nucleus accumbens D-serine alone induced extinction of cocaineinduced CPP［117］.Considering that higher dose of D-cycloserine facilitated the reinstatement of cocaine-induced CPP after extinction，it may indicate that higher doses of D-cycloserine may promote relapse［118］.D-serine may be a more effective and much safer therapeutic agent than D-cycloserine to treat drug addiction.

6 POST-RETRIEVAL EXTINCTION PRO⁃CEDURE IN DRUG REWARD MEMORY

So far，most of the amnestic agents were tested only in animal models，which are not ready for use in humans because of the toxicity of the agents and/or administration route.Recently，serial studies demonstrated that post-retrieval extinction procedure，a pure behavioral para⁃digm，disrupted reconsolidation and prevented return of fear and relapse to addictive drug［119-124］，but see［122］.Retrieval of drug reward memory 10 min or 1 h，but not 6 h，before extinction reduced reinstatement，spontaneous recovery and renewal，indicating persistently disrupted morphine-induced CPP in rats［124］.Post-retrieval extinction also attenuated spontaneous recovery and drug-induced reinstatementof cocaine reward memory［125］.Furthermore，retrieval-extinction procedure attenuated cue-induced heroin craving for at least half a year［124］.Because memory undergoes reconsolidation after retrieval，the post-retrieval extinction was usually interpreted as extinction during reconsolidation process disrupted the reconsolidation of original memory［119-124］,but see［126-127］.Reconsolidation onlyhappensto the reactivated conditioned stimulus［128］.The post-retrieval extinction only affects the reactivated memory for the retrieved cue and does not interfere with memories for other cues.However，in the real life，drug addiction cannot be only associated with a single cue.It is certainly desirable to use a pure behavioral procedure to eliminate drug reward memory associated with all related cues.

Recently，a UCS-retrieval extinction proce⁃dure was developed to show an erasure effect on unconditioned stimulus associated memories. Unconditioned stimulus retrieval induces recon⁃solidation and destabilization of all UCS-associated memories［129］.To distinguish with this UCS-retrievalextinction，the above post-retrieval extinction was renamed as CS-retrieval extinction. Extinction ofonly one conditioned stimulus during UCS-triggered reconsolidation disrupted all memories for multiple CSs associated with that US but not with other US，indicating that this UCS-retrieval extinction procedure shows more advantages than CS-retrieval extinction［130］. In a cocaine-seeking model，UCS-retrieval extinction procedure reduced renewal and reinstatement of cocaine-seeking behavior in the presence of cocaine cues that were not extinguished，and decreased spontaneous recovery of cocaineseeking behavior， suggesting UCS-retrieval extinction could be a promising strategy for reducing the risk of relapse to addictive drug［131］.

7 METHODOLOGICAL ISSUES IN DRUG REWARD MEMORY RESEARCH:PRO⁃CEDURE，TIMING AND IMPLICATIONS

Interventions in different memory processes with amnesticagentssurelyengage distinct mechanisms and require distinct interpretations with the results.Before drawing conclusion from the related studies， carefulconsiderations should be addressed with important methodological issues.

7.1 Procedure

7.1.1 For expression and consolidation，influ⁃ence mainly comes from the training procedure

Training procedure would affect the strength of drug reward memory，which includes training dose of drug，number of training trial，partial or continuous reinforcement schedule.The general effects of these factors are list as below:①Higher doses of drug usually form more stable memory than lower dose.②Ascending dosing schedules producestrongermemorythanfixeddosing schedules.③ Increase in number of training trialenhances memory strength.④ Partial reinforcement schedule produce stronger memory than continuous reinforcement schedule.

These factors can be included in experiment designed to study the difference between weak and strong drug memory，and in special needs to satisfy some special memory process，e.g.late consolidation and system consolidation.

7.1.2 For reconsolidation and extinction，influ⁃ence mainly comes from retrieval procedure

In general，short-term retrieval triggers recon⁃solidation，whereas long-term retrieval induces extinction.For the drug-induced CPP，retrieval schedule and retrieval duration are the main factors that regulate the process after memory retrieval.

(1)Four schedules are usually used to trigger reconsolidation:①confining the subject in the drug-paired context once;② a standard test for CPP expression;③an additional conditioning;④a single injection of non-contingent drug used in conditioning.

(2)Two schedules are usually used to induce extinction:① the same procedure as training except for removing the drug or substituting the drug with saline (onfined extinction schedule);②daily test until the preference for drug-paired context is diminished(test schedule).

(3)The strength of original memory affects the subsequent consequence after retrieval.A strong drug reward memory may be resistant or hard to be extinguished，and more number of extinction trials is required to reach the criteria of extinction.

(4)Because extinction trials are discontinued，the first trial of extinction in the CPP model is indeed as the same as some of the strategies that used to trigger the reconsolidation(confined in the drug-paired context or a standard test)，then the effect observed from treatment during the first trial of extinction should be carefully considered.

(5)According to the updating hypothesis of reconsolidation，memory is updated after recon⁃solidation.Then，the drug reward memory with the retrieval history could be different with the original one.However，this issue only receives a little attention in the current studies.

(6)The renewal after extinction cannot be examined in the CPP model，which can be easily tested in drug self-administration，another behav⁃ioral model of drug addiction.

These factors should be considered when designing the reconsolidation and extinction studies and when interpreting the results obtained from these studies.Moreover，extinction memory can also be trained to be weak or strong as the original one to satisfy some special process，e.g.late consolidation of extinction memory.

7.2 Timing

Timing is critical when interpreting the results from memory studies as well as defining the memory processes.

(1)Interventions before conditioning are usually taken as influence on acquisition.

(2)Interventions after conditioning within hours(usually within 6 h after conditioning，but not for the late and system consolidations)are usually taken as influence on consolation.

(3)Interventions before a standard test are usually taken as influence on expression.

(4)Interventions after the aforementioned four schedules that trigger reconsolidation within hours(usually within 6 h after retrieval，but not for the late and system reconsolidations)are usually taken as influence on reconsolidation.

(5)Interventions before the aforementioned two schedules that induce extinction are usually taken as influence on the acquisition of extinction memory.

(6)Interventions after the aforementioned two schedules that induce extinction within hours (usually within 6 h after extinction)are usually taken as influence on the consolidation of extinction memory.

(7)Interventions outside these important time points are usually taken as influence on the maintenance of extinction memory.

(8)In the consolidation and reconsolidation studies(both original memory and extinction memory)，a control group of rats received treat⁃ment outside the time window(usually 6 h after conditioning，retrieval，and extinction)should be included.

(9)In the reconsolidations，a control group of rats received the same interventions without memory retrieval should be included.

(10)To evaluate the erasure of memory，spontaneous recovery test and/or reinstatement test should be included.

8 TRANSLATIONAL VALUE FROM DRUG REWARD MEMORY STUDIES：ERASURE，REVISION，OR INHIBITION

So far，current treatments of drug addictionbenefit little from the studies on drug reward memory.Like the treatment in other psychiatric disorders，the treatment strategies for drug addiction require a long-term treatment and are usually not curative，which includes agonists and partial agonists treatment，antagonist treatment，blockade ofeuphoria， anti-craving medications and medications that produce an aversive response［132］. Even the potential vaccination approach，which shows great potential use to prevent craving and relapse to addictive drug，will not cure the addiction.Erasure or revision of drug reward memory might be a potential clinical strategy to permanently cure drug addiction and persistently prevent craving and relapse to addictive drug.

However，drug reward memory shares a lot of mechanisms with normal memories.Even though the specificity of reconsolidation on retrieved memory shines a light on specifically erasing drug reward memory，it is still not sure whether it is feasible to develop a pharmacological medi⁃cation that only erases drug reward memory without impairing normal memories.A recent study on Alzheimer disease demonstrated that the retrieval of memory is weakened,while the memoryper seis still stored in the brain of animal in Alzheimer disease model［133］.Like the case in Alzheimer disease，it is also possible that the aberrant drug reward memoryper seis notstrong butthe retrievalofmemory is enhanced by the reinforcing effect of drugs. Currently，before we could completely under⁃stand the memory system，inhibition of drug reward memory would be also a viable strategy to lower the risk of relapse to addictive drug.

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药物奖赏记忆：从药物诱导的条件性位置偏爱模型中的见解

刘剑锋，李俊旭

（Department of Pharmacology and Toxicology，Jacobs School of Medicine and Biomedical Sciences，the State University of New York at Buffalo，Buffalo，NY 14214，USA）

药物成瘾是一种慢性复发性脑疾病，其发生至少部分原因是由于异常的学习记忆所导致。大量的研究表明，成瘾性药物篡夺了正常记忆的神经环路，从而形成了长期维持的药物记忆，这可能是导致药物成瘾复吸的重要原因。本文综述了关联性药物奖赏记忆的模型之一药物诱导的条件性位置偏爱的相关研究结果，旨在阐述目前对于药物奖赏记忆的认识。药物奖赏记忆是一个动态的过程，包括习得、巩固、维持、唤起、再巩固和消退多个阶段，对这些药物奖赏记忆阶段进行药理学干预可以不同地调控药物奖赏记忆。最近，根据记忆阶段假说所发展的纯行为学模式，例如唤起-消退模式，展现出比药理学手段干预药物奖赏记忆更强的优越性。最后，本综述讨论了在药物奖赏记忆实验设计与相关实验结果解释时需要重点考虑2个方法学问题：模式和时间。目前为止，仍然不确定是否能发展一种药理学治疗方法，仅仅抹除药物奖赏记忆而不影响正常的记忆。我们提出，抑制药物奖赏记忆的方法仍不失一种有效降低复吸风险的手段。虽然目前关于药物奖赏记忆的研究对药物成瘾的治疗贡献并不大，但继续深入的研究将为降低成瘾复吸带来新的治疗方法。

药物成瘾；药物奖赏记忆；巩固；再巩固；维持；消退

李俊旭，E-mail：junxuli@buffalo.edu，Tel：+1（716）-8292482

2016-03-28 接受日期：2016-06-17）

R964

:A

:1000-3002-(2016)06-0674-17

10.3867/j.issn.1000-3002.2016.06.007

Biography:Jian-feng LIU(1987-),male,PhD,research scholar,main reseach field isneural mechanisms of fear momory and drug addiction.E-mail:jliu66@buffalo.edu, Tel:+1(716)200-2315;Jun-xu LI(1977-),male,Associate Professor,main reseach field is behavioral pharmacology of pain and drug addiction.

Jun-xu LI,E-mail:junxuli@buffalo. edu,Tel:+1(716)829-2482

（本文编辑：乔 虹）