Publication Date:
2008-05-27
Description:
Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574981/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574981/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conrad, Kelly L -- Tseng, Kuei Y -- Uejima, Jamie L -- Reimers, Jeremy M -- Heng, Li-Jun -- Shaham, Yavin -- Marinelli, Michela -- Wolf, Marina E -- DA00453/DA/NIDA NIH HHS/ -- DA015835/DA/NIDA NIH HHS/ -- DA020654/DA/NIDA NIH HHS/ -- DA09621/DA/NIDA NIH HHS/ -- Z01 DA000434-08/Intramural NIH HHS/ -- England -- Nature. 2008 Jul 3;454(7200):118-21. doi: 10.1038/nature06995. Epub 2008 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18500330" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Cocaine
;
Cocaine-Related Disorders/genetics/metabolism/*physiopathology
;
Cues
;
Gene Expression Regulation
;
Male
;
Nucleus Accumbens/*metabolism/physiopathology
;
Rats
;
Rats, Long-Evans
;
Rats, Sprague-Dawley
;
Receptors, AMPA/deficiency/genetics/*metabolism
;
Self Administration
;
Time Factors
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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