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The Journal of Neuroscience, December 3, 2008, 28(49):13248-13257; doi:10.1523/JNEUROSCI.3027-08.2008

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Behavioral/Systems/Cognitive
Central Amygdala Extracellular Signal-Regulated Kinase Signaling Pathway Is Critical to Incubation of Opiate Craving

Yan-Qin Li,^1 * Fang-Qiong Li,^1 * Xiao-Yi Wang,¹ Ping Wu,¹ Mei Zhao,¹ Chun-Mei Xu,¹ Yavin Shaham,² and Lin Lu¹

¹National Institute on Drug Dependence, Peking University, Beijing 100083, China, and ²Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224

Correspondence should be addressed to Prof. Lin Lu, National Institute on Drug Dependence, Peking University, 38, Xue Yuan Road, Beijing 100083, China. Email: linlu{at}bjmu.edu.cn

Cue-induced drug-seeking in rodents progressively increases after withdrawal from operant self-administration of cocaine, heroin, methamphetamine, and alcohol, a phenomenon termed "incubation of drug craving." Here, we used the opiate drug morphine and explored whether incubation of drug craving also occurs in a pavlovian conditioned place preference (CPP) procedure in which rats learn to associate drug effects with a distinct environmental context. We also explored the role of amygdala extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in this incubation. We found that the expression of morphine CPP progressively increases over the first 14 d after the last drug exposure in rats receiving four pairings of low-dose (1 or 3 mg/kg) but not high-dose (10 mg/kg) morphine with a distinct environment. The progressive increase in low-dose (3 mg/kg) morphine CPP was associated with increased ERK phosphorylation (a measure of ERK activity) and CREB (a downstream target of ERK) phosphorylation in central but not basolateral amygdala. Furthermore, inhibition of central but not basolateral amygdala ERK and CREB phosphorylation by U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] decreased the enhanced (incubated) drug CPP after 14 d of withdrawal from morphine. Finally, stimulation of central amygdala ERK and CREB phosphorylation by NMDA enhanced drug CPP after 1 d of withdrawal from morphine, an effect reversed by U0126. These findings indicate that the rat's response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 d of withdrawal from low but not high morphine doses. Additionally, this "incubation of morphine craving" is mediated by acute activation of central amygdala ERK pathway.

Key words: amygdala; morphine; conditioned place preference; incubation; ERK; CREB; relapse

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Received June 30, 2008; revised Sept. 25, 2008; accepted Oct. 17, 2008.

Correspondence should be addressed to Prof. Lin Lu, National Institute on Drug Dependence, Peking University, 38, Xue Yuan Road, Beijing 100083, China. Email: linlu{at}bjmu.edu.cn

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