Abstract
Dynorphin peptides and the κ-opioid receptor are important in the rewarding properties of cocaine, heroin, and alcohol. We tested polymorphisms of the prodynorphin gene (PDYN) for association with cocaine dependence and cocaine/alcohol codependence. We genotyped six single nucleotide polymorphisms (SNPs), located in the promoter region, exon 4 coding, and 3′ untranslated region, in 106 Caucasians and 204 African Americans who were cocaine dependent, cocaine/alcohol codependent, or controls. In Caucasians, we found point-wise significant associations of 3′UTR SNPs (rs910080, rs910079, and rs2235749) with cocaine dependence and cocaine/alcohol codependence. These SNPs are in high linkage disequilibrium, comprising a haplotype block. The haplotype CCT was significantly experiment-wise associated with cocaine dependence and with combined cocaine dependence and cocaine/alcohol codependence (false discovery rate, q=0.04 and 0.03, respectively). We investigated allele-specific gene expression of PDYN, using SNP rs910079 as a reporter, in postmortem human brains from eight heterozygous subjects, using SNaPshot assay. There was significantly lower expression for C allele (rs910079), with ratios ranging from 0.48 to 0.78, indicating lower expression of the CCT haplotype of PDYN in both the caudate and nucleus accumbens. Analysis of total PDYN expression in 43 postmortem brains also showed significantly lower levels of preprodynorphin mRNA in subjects having the risk CCT haplotype. This study provides evidence that a 3′UTR PDYN haplotype, implicated in vulnerability to develop cocaine addiction and/or cocaine/alcohol codependence, is related to lower mRNA expression of the PDYN gene in human dorsal and ventral striatum.
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Acknowledgements
We acknowledge K Bell, E Ducat, D Melia, B Ray, L Borg, P McHugh for recruiting, screening, and assessment of study subjects. We thank Daniel Perl (Alzheimer's Disease Research Center, The Mount Sinai Medical Center, New York, NY) for providing postmortem brain tissues. We are grateful to M Randesi for sequencing assistance. This work was supported by grants from the National Institutes of Health: P60-DA05130 (MJK), R01-MH79880 (MJK), R24-MH59724 (SM), AG05138 (D Perl), RR024143 (B Coller), R01- MH44292 (JO), and grants 30730057 and 30700442 from National Science Foundation of China (JO).
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All the authors, except JO, declare that, except for the income received from our primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interests. One author, JO, wishes to declare that he personally receives book royalties from the Johns Hopkins University Press and that his laboratory receives funding from Hoffmann-La Roche Inc.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
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Yuferov, V., Ji, F., Nielsen, D. et al. A Functional Haplotype Implicated in Vulnerability to Develop Cocaine Dependence is Associated with Reduced PDYN Expression in Human Brain. Neuropsychopharmacol 34, 1185–1197 (2009). https://doi.org/10.1038/npp.2008.187
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DOI: https://doi.org/10.1038/npp.2008.187
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