Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 49, Pages 13248-13257Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3027-08.2008
Keywords
amygdala; morphine; conditioned place preference; incubation; ERK; CREB; relapse
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Funding
- National Basic Research Program of China [2007CB512302, 2009CB522004]
- National High Technology Research and Development Program of China 863 Program [2006AA02Z4D1]
- Natural Science Foundation of China [30670713, 30725016]
- National Institute on Drug Abuse, Intramural Research Program
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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.
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