Intronic Polymorphisms Affecting Alternative Splicing of Human Dopamine D2 Receptor Are Associated with Cocaine Abuse

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 36; no. 4; pp. 753 - 762
• Main Authors: Moyer, Robert A, Wang, Danxin, Papp, Audrey C, Smith, Ryan M, Duque, Linda, Mash, Deborah C, Sadee, Wolfgang
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2011; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/726/649; 631/337/1645/1946; 692/699/476/5; Addictive behaviors; Adult; Adult and adolescent clinical studies; Alternative splicing; Alternative Splicing - genetics; Autopsy; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Brain; Brain - metabolism; Brain - pathology; Cocaine; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Cocaine-Related Disorders - pathology; Cortex (prefrontal); Dopamine D2 receptors; Drug abuse; Drug addiction; Exons; Female; Genetic Predisposition to Disease; HEK293 Cells; Humans; Introns; Introns - genetics; Linkage disequilibrium; Male; Medical sciences; Medicine; Medicine & Public Health; Memory; Mental disorders; Middle Aged; mRNA; Neuropharmacology; Neurosciences; Original; original-article; Pharmacology. Drug treatments; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Putamen; Receptors, Dopamine D2 - biosynthesis; Receptors, Dopamine D2 - genetics; Single-nucleotide polymorphism; Young Adult; alternative splicing; D2S; DRD2; cocaine; dopamine; human; Human; Alternative splicing; Drug addiction; Dopamine; CNS stimulant; Psychotropic; Catecholamine; Ester; D2 Dopamine receptor; Neurotransmitter; Cocaine; Drug of abuse; Polymorphism
• DOI: 10.1038/npp.2010.208
• ISSN: 0893-133X; 1740-634X

The dopamine receptor D2 (encoded by DRD2 ) is implicated in susceptibility to mental disorders and cocaine abuse, but mechanisms responsible for this relationship remain uncertain. DRD2 mRNA exists in two main splice isoforms with distinct functions: D2 long (D2L) and D2 short (D2S, lacking exon 6), expressed mainly postsynaptically and presynaptically, respectively. Two intronic single-nucleotide polymorphisms (SNPs rs2283265 (intron 5) and rs1076560 (intron 6)) in high linkage disequilibrium (LD) with each other have been reported to alter D2S/D2L splicing and several behavioral traits in human subjects, such as memory processing. To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls). Robust effects of rs2283265 and rs1076560 on reducing formation of D2S relative to D2L were confirmed. The minor alleles of rs2283265/rs1076560 were considerably more frequent in Caucasians (18%) compared with African Americans (7%). Also, in Caucasians, rs2283265/rs1076560 minor alleles were significantly overrepresented in cocaine abusers compared with controls (rs2283265: 25 to 9%, respectively; p =0.001; OR=3.4 (1.7–7.1)). Several SNPs previously implicated in diverse clinical association studies are in high LD with rs2283265/rs1076560 and could have served as surrogate markers. Our results confirm the role of rs2283265/rs1076560 in D2 alternative splicing and support a strong role in susceptibility to cocaine abuse.