古柯鹼相關記憶是造成古柯鹼求藥行為與戒斷藥物後復求行為發生的主要原因。過去研究發現：d-serine這個NMDA receptor的促效劑可以減少古柯鹼相關記憶的表現。而Sodium benzoate 被用於精神分裂症的研究當中，主要是借重其對於d-amino acid oxidase這類d-serine等右旋胺基酸氧化脢的抑制作用，透過抑制d-amino acid oxidase，可以增加突觸間d-serine的含量，加強NMDA receptor的活化。因此，我們決定探討 sodium benzoate 會對古柯鹼相關記憶歷程產生什麼樣的影響。在本研究中，我們探討兩個不同的記憶歷程是否會受到sodium benzoate的影響。(1)古柯鹼相關記憶的再穩固化(reconsolidation)歷程(2)古柯鹼相關記憶的消褪(extinction)歷程。我們使用cocaine-induced conditioned place preference (cocaine-induced CPP)來當作古柯鹼相關記憶的指標。由這些實驗的結果我們可以得到三個結論，第一: sodium benzoate 會干擾古柯鹼相關記憶的再穩固化，進而去減少後續cocaine-induced CPP的表現。第二: sodium benzoate可能是透過作用在medial prefrontal cortex這個腦區去干擾古柯鹼相關記憶的再穩固化。第三: sodium benzoate對於古柯鹼相關記憶的消褪則有加強的效果，sodium benzoate強化了這個新學習記憶的穩固化，進而暫時抑制了cocaine-induced CPP的表現，但是無法降低在reminding test中 cocaine-induced CPP的表現。Sodium benzoate 在 兩種不同記憶歷程中所造成的不同結果，可能需要後續再分析sodium benzoate引發的下游分子訊號的機制才能夠更進一步釐清其中的原因。

Drug-associated memory has been known to reinstate drug-seeking behavior during abstinence and consequently lead to relapse. D-serine, an endogenous ligand for the glycine site of the NMDA receptor has been documented to interfere cocaine memory expression. Sodium benzoate is reported to inhibit the activity of d-amino acid oxidase, an enzyme catalyzing d-serine, and thus, to enhance d-serine accumulation and increase activation of NMDA receptor indirectly. In this study, we decided to investigate whether sodium benzoate can modulate the drug-associated memory. Two paradigms of drug memory processes were used: (1) reconsolidation-related protocol and (2) new learning(extinction)-related protocol. Cocaine-induced CPP was used to indicate the cocaine memory. Systemic pretreatment with intraperitoneal sodium benzoate at 500 mg/kg (but not 250 mg/kg) before each reconsolidation trail reduced subsequent cocaine-induced CPP magnitude. It was of importance to note that such a sodium benzoate treatment did not produce nontargeting effect in subsequent cocaine-induced CPP. Moreover, such a dosing regimen did not affect locomotor activity in a 30-min free navigation test. Furthermore, intra-mPFC injections of sodium benzoate before each reconsolidation trail perform a directly effect to reduce cocaine seeking behavior. These results, taken together, suggest that sodium benzoate could be beneficial as a potential medicine of choice in reducing cocaine relapse.

See RE. (2002) Neural substrates of conditioned-cued relapse to drug-seeking behavior. Pharmacol Biochem Behav. 71(3):517-29.

Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, Salmeron BJ, Risinger R, Kelley D, Stein EA. (2000) Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry. 157(11):1789-98.

Maren S, Quirk GJ. (2004) Neuronal signalling of fear memory. Nat Rev Neurosci. 5(11):844-52.

Torregrossa MM, Sanchez H, Taylor JR. (2010) D-cycloserine reduces the context specificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens. J Neurosci. 30(31):10526-33.

Davis S, Butcher SP, Morris RG. (1992) The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J Neurosci. 12(1):21-34.

Feltenstein MW, See RE. (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol Learn Mem. 88(4):435-44.

Lee I, Kesner RP. (2002) Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory. Nat Neurosci. 5(2):162-8.

Yang FY, Lee YS, Cherng CG, Cheng LY, Chang WT, Chuang JY, Kao GS, Yu L. (2013) D-cycloserine, sarcosine and D-serine diminish the expression of cocaine-induced conditioned place preference J Psychopharmacol. 27(6):550-8.

Thanos PK, Bermeo C, Wang GJ, Volkow ND. (2011) D-cycloserine facilitates extinction of cocaine self-administration in rats. Synapse. 65(9):938-44.

Curcio L, Podda MV, Leone L, Piacentini R, Mastrodonato A, Cappelletti P, Sacchi S, Pollegioni L, Grassi C, D'Ascenzo M. (2013) Reduced D-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain. 136(Pt 4):1216-30.

Nagata Y. (1992) Involvement of D-amino acid oxidase in elimination of D-serine in mouse brain. Experientia. 48(8):753-5.

Williams RE, Lock EA. (2005) Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat. Toxicology. 207(1):35-48.

Ferraris D, Duvall B, Ko YS, (2008) Thomas AG, Rojas C, Majer P, Hashimoto K, Tsukamoto T. Synthesis and biological evaluation of D-amino acid oxidase inhibitors. J Med Chem. 51(12):3357-9.

Brugger F, Wicki U, Nassenstein-Elton D, Fagg GE, Olpe HR, Pozza MF. (1990) Modulation of the NMDA receptor by D-serine in the cortex and the spinal cord, in vitro. Eur J Pharmacol. 191(1):29-38

Matthew W. Feltenstein, Ronald E. (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol Learn Mem. 88(4):435-44.

Amy L. Milton, Jonathan L. C. Lee, Victoria J. Butler, Richard Gardner, and Barry J. Everitt (2008) Intra-Amygdala and Systemic Antagonism of NMDA Receptors Prevents the Reconsolidation of Drug-Associated Memory and Impairs Subsequently Both Novel and Previously Acquired Drug-Seeking Behaviors.
J Neurosci. 28(33): 8230-8237

Rita Z. Goldstein1 & Nora D. Volkow (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications Nature Reviews Neuroscience 12, 652-669

Hiranita T, Nawata Y, Sakimura K, Anggadiredja K, Yamamoto T (2006) Suppression of methamphetamine-seeking behavior by nicotinic agonists. Proc Natl Acad Sci. 103:8523–8527

Han J, Li Y, Wang D, Wei C, Yang X, Sui N (2010) Effect of 5-aza-2-deoxycytidine microinjecting into hippocampus and prelimbic cortex on acquisition and retrieval of cocaine-induced place preference in C57BL/6 mice. Eur J Pharmacol 642:93–98.

Merlo E, Milton AL, Goozée ZY, Theobald DE, Everitt BJ. (2014) Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence. J Neurosci. Feb 12;34(7):2422-31

Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003) Stability of retrieved memory: inverse correlation with trace dominance. Science 301:1102–1104.

Pedreira ME, Maldonado H (2003) Protein synthesis subserves reconsolidation or extinction depending on reminder duration. Neuron 38:863–869.

Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795.

Davis HP, Squire LR (1984) Protein synthesis and memory: a review. Psychol Bull 96:518–559.

Miserendino MJ, Sananes CB, Melia KR, Davis M (1990) Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345:716–718.

Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 405:722–726.

Vianna MR, Szapiro G, McGaugh JL, Medina JH, Izquierdo I (2001) Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus. Proc Natl Acad Sci U S A 98:12251–12254.

Lee JL, Milton AL, Everitt BJ (2006) Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26:10051–10056.

Lin CH, Chen PK, Chang YC, Chuo LJ, Chen YS, Tsai GE, Lane HY. (2014) Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2014 May 1;75(9):678-85.