Lori France-Larsen
PSY201
(Herman & Balogh)

Polymorphisms of the serotonin transporter and receptor genes: susceptibility to substance abuse

(SUD) Substance use disorders 1) (AD) Alcohol Dependency A. European ancestry study
a.17 studies including 3489 alcoholics and 2325 controls B. Frequency of S allele at 5-HTTLPR significantly associated C. Early childhood trauma clarify relationship between 5-HTTLPR and AD 2) Japanese ancestry study D. Positive association between G allele of rs6311 with inactive ALDH2 compared with control subjects E. Investigating rs6311 on individuals with AD compared with (OD) opiod dependence were enriched with G allele when they carried 5-HTTLPR L allele F. SNP rs6311 not observed to moderate response to alcohol 3) American Indian ancestry G. Examined roll of HTR1B rs6296 vulnerability to AD with (ASPD) antisocial personality disorder a. Frequency of rs6296 C allele elevated b. HTR1B rs6216 significant linkage to AD

4) Taiwanese Han – AD and controls H. rs130058(A-161T) T allele significantly higher in AD cases I. demonstrated in vitro higher than A allele 5) Chinese Han J. T allele of rs130058 associated with AD K. Additional SNP’s in HTR1B related to AD L. Functional HTR1B SNP(rs13212041) described and reported larger portion of variation in self reported anger and hostility compared with HTR1B SNP’s 6) Animal studies and human clinical laboratory paradigms M. 5-HT3 antagonistic potential clinical utility for treating AD c. Efficacy varies widely N. Ondansetron AD treatment homozygous for 5-HTTLPR L allele had fewer drinks and higher abstinence d. Improved drinking outcomes in AD subjects carrying L/L genotype VS L/L genotype recurring sertraline (SSRI) Selective Seratonin reuptake inhibitor O. Twelve week double blind randomized e. Sertraline for AD and genotype for 5-HTTLPR 1. Late onset AD had better outcomes and fewer heavy drinking days 7)

II. Other drug of abuse P. SLC6A4 Polymorphisms related to f. (ND) Nicotine dependence g. (CD) Cocaine dependence h. (OD) Opiod dependence i. association between SLC6A4(5-HTTLPR and STin2) and OD or CD are mixed more research required Q. AD European derived Brazilians j. Influence of 5-HTR2A gene variation 2. HTR2A rs6313 A allele associated with cigarette smoking 3. HTR2A rs6313 unrelated to smoking R. African American cocaine CD patience k. did not observe 5-HTTLPR moderating effects l. influence of 5-HTTLPR on outcome of NRT – no association between genotype and abstinence m. 5-HT gene variants (5HTTLPR rs1799913, rs6295) S. Israeli college students n. carrying two copies of G allele at rs6216 observed to have higher levels of ND T. Japanese ancestry o. Methamphetamine dependence 4. No association between HTR1B SNP’s (rs130058, rs1228814 and rs1228814) and methamphetamine dependence was abserved
III. HTR1B and substance use disorder A. Human HTR1B gene a. Several variants investigated as related to SUD’s i. rs6296 (G861C, Val3Val) synonymous SNP in exon 1 best studied gene variant ii. function of variant unknown
IV. HTR2A and substance use disorders A. Mammals – targets for substance abuse a. 5-HT2A receptor – ubiquitous b. G protein coupled receptor, distributed in central nervous system c. 5-HT2A receptors modulate dopamine neurotransmission B. Genetic research focus – linkage disequilibrium d. SNP rs6311 (A-1438G) e. SNP rs6313 (T102C) in exon 1 of HTR2A and codes the 34th amino acid as serine C. Alternative promoters for HTR2A f. Effect promoter activity g. Alter expression of H2R2A in brain

V. HTR2C and substance use disorders
A. Caucasian
a. Cocaine
i. 5-HT2C receptors modulate discriminative stimulus effects ii.rs6318 (Cys23Ser) encodes missense mutation at codon 23 of Cys-to-Ser b. Violent offenders iii. Ser substitution association with 3-methoxy-4hydroxyphenylglycol, a metabolite of norepinephrine degredations in AD iv. No association with rs6318 and AD or abuse v. No association with four HTR2C promoter SNP’s and AD
VI. HTR3 and substance use disorder A. 5-HT3 receptor only ligand-gated ion channel in 5-HT receptor family a. Plays reward role by modulating dopamine release in mesolimbic pathway b. 1350 variant study in 130 candidate genes i. Past history of severe HD ii. Healthy controls – no drug use history iii. OD association of C allele of rs3758987 in HTR3B 1. These may impact gene expression B. Multi-Site study c. A allele of intronic HTR3B SNP rs3782025 associated with AD and ASPD d. HTR3B missense polymorphism rs1176744 (Tyr129Ser) predictied AD and related to AD and SD together e. Ser129 variant of rs1176744 iv. Expands maximum response to 5-HT v. Lowers desensitization and deactivation kenetics vi. Increases mean channel open time vii. Strong linkage disequalibrium with rs3782025
VII. 5-HT genetics and substance use disorder treatment
A. Not currently part of approved and empirically based addiction treatment algorithm
B. Potential Clinical use a. Improved characterization optimizing addiction medications b. enhance characterization variant with other gene stems for more accurate diagnosis c. predict executive cognitive functioning d. externalize traits of relapse proneness e. earlier identification and intervention
VIII. Conclusion – Based on this literature review A. 5-HT system is modulated by all of major classes of drugs of abuse B. 5-HTtLPR S allele appears to exhibit strongers association with SUD specifically AD a. Best studied 5-HT polymorphism C. Foundational link between 5-HT genetics and SUD’s D. Next step translating SUD and 5-HT into true clinical application b. Benefit whole genome sequencing c. Analyze majority of 5-HT genetic variation into a single project d. Increase sample size of study e. Examine samples from genetically distinct ethnic ancestries