Negative Urgency Mediates the Relation Between Genetically Influenced Serotonin Functioning and Alcohol Problems

Abstract

Serotonin (5-HT) functioning is associated with alcohol problems. However, the mechanisms underlying this association remain unclear. In the current study the authors tested whether five separate dimensions of impulsivity (UPPS-P) mediated the relation between a polygenic score indexing 5-HT functioning and alcohol problems and whether any of these paths were moderated by age. Results showed that a 5-HT polygenic score predicted alcohol problems indirectly through negative urgency, but not any other facet of impulsivity. The 5-HT polygenic score also directly predicted alcohol problems. No age moderation was found. Findings suggest that negative urgency might be one important mechanism underlying the relation between genetically influenced 5-HT functioning and alcohol problems. However, genetically influenced 5-HT functioning likely influences alcohol problems through additional mechanisms. More broadly, results suggest that the previously observed transdiagnostic nature of 5-HT functioning on diverse types of psychopathology might be, in part, explained by its effect on negative urgency.

Keywords

serotonin polygenic risk score alcohol problems negative urgency impulsivity

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References

Aiken

West

(1991). Multiple regression: Testing and interpreting interactions. Newbury Park, CA: Sage.

Balldin

Berggren

Engel

Eriksson

Hård

Söderpalm

(1994). Effect of citalopram on alcohol intake in heavy drinkers. Alcoholism: Clinical and Experimental Research, 18, 1133–1136.

Ballenger

J. C.

Goodwin

F. K.

Major

L. F.

Brown

G. L.

(1979). Alcohol and central serotonin metabolism in man. Archives of General Psychiatry, 36, 224–227.

Banki

C. M.

(1981). Factors influencing monoamine metabolites and tryptophan in patients with alcohol dependence. Journal of Neural Transmission, 50, 89–101.

Bergen

S. E.

Gardner

C. O.

Kendler

K. S.

(2007). Age-related changes in heritability of behavioral phenotypes over adolescence and young adulthood: A meta-analysis. Twin Research and Human Genetics, 10, 423–433.

Brown

S. A.

McGue

Maggs

Schulenberg

Hingson

Swartzwelder

. . . Winters

K. C.

(2008). A developmental perspective on alcohol and youths 16 to 20 years of age. Pediatrics, 121, S290–S310.

Canli

Lesch

K. P.

(2007). Long story short: The serotonin transporter in emotion regulation and social cognition. Nature Neuroscience, 10, 1103–1109.

Carver

C. S.

Johnson

S. L.

Joormann

(2008). Serotonergic function, two-mode models of self-regulation, and vulnerability to depression: What depression has in common with impulsive aggression. Psychological Bulletin, 134, 912–943.

Carver

C. S.

Johnson

S. L.

Joormann

Kim

Nam

J. Y.

(2011). Serotonin transporter polymorphism interacts with childhood adversity to predict aspects of impulsivity. Psychological Science, 22, 589–595.

10.

Chassin

Barrera

Jr. Bech

Kossak-Fuller

(1992). Recruiting a community sample of adolescent children of alcoholics: A comparison of three subject sources. Journal of Studies on Alcohol, 53, 316–319.

11.

Coccaro

E. F.

(1989). Central serotonin and impulsive aggression. British Journal of Psychiatry, 155, 52–62.

12.

Cohen

(1977). Statistical power analysis for the behavioral sciences (Rev. ed.). New York, NY: Academic Press.

13.

Cohen

(1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Erlbaum.

14.

Cools

Roberts

A. C.

Robbins

T. W.

(2008). Serotoninergic regulation of emotional and behavioural control processes. Trends in Cognitive Sciences, 12, 31–40.

15.

Cooper

M. L.

Frone

M. R.

Russell

Mudar

(1995). Drinking to regulate positive and negative emotions: A motivational model of alcohol use. Journal of Personality and Social Psychology, 69, 990–1005.

16.

Coskunpinar

Dir

A. L.

Cyders

M. A.

(2013). Multidimensionality in impulsivity and alcohol use: A meta-analysis using the UPPS model of impulsivity. Alcoholism: Clinical and Experimental Research, 37, 1441–1450.

17.

Crean

Richards

J. B.

de Wit

(2002). Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism. Behavioural Brain Research, 136, 349–357.

18.

Cuthbert

B. N.

Insel

T. R.

(2013). Toward the future of psychiatric diagnosis: The seven pillars of RDoC. BMC Medicine, 11, 126.

19.

Cyders

M. A.

Dzemidzic

Eiler

W. J.

Coskunpinar

Karyadi

K. A.

Kareken

D. A.

(2014). Negative urgency and ventromedial prefrontal cortex responses to alcohol cues: fMRI evidence of emotion-based impulsivity. Alcoholism: Clinical and Experimental Research, 38, 409–417.

20.

Cyders

M. A.

Dzemidzic

Eiler

W. J.

Coskunpinar

Karyadi

K. A.

Kareken

D. A.

(2015). Negative urgency mediates the relationship between amygdala and orbitofrontal cortex activation to negative emotional stimuli and general risk-taking. Cerebral Cortex, 25, 4094–4102.

21.

Cyders

M. A.

Smith

G. T.

(2008). Emotion-based dispositions to rash action: Positive and negative urgency. Psychological Bulletin, 134, 807–828.

22.

Cyders

M. A.

Smith

G. T.

Spillane

N. S.

Fischer

Annus

A. M.

Peterson

(2007). Integration of impulsivity and positive mood to predict risky behavior: Development and validation of a measure of positive urgency. Psychological Assessment, 19, 107–118. doi:10.1037/1040–3590.19.1.107.

23.

Depue

R. A.

Spoont

M. R.

(1986). A behavioral dimension of constraint. Annals of the New York Academy of Sciences, 487, 47–62.

24.

Endicott

Andreasen

Spitzer

R. L.

(1975). Family history diagnostic criteria. New York, NY: New York Biometrics Research, New York Psychiatric Institute.

25.

Ernouf

Compagnon

Lothion

Narcisse

Benard

J. Y.

Daoust

(1993). Platelets 3H 5-HT uptake in descendants from alcoholic patients: A potential risk factor for alcohol dependence? Life Sciences, 52, 989–995.

26.

Evans

D. M.

Brion

M. J. A.

Paternoster

Kemp

J. P.

McMahon

Munafò

, . . . TAG Consortium. (2013). Mining the human phenome using allelic scores that index biological intermediates. PLOS Genetics, 9, e1003919.

27.

Farren

C. K.

Ziedonis

Clare

A. W.

Hammeedi

F. A.

Dinan

T. G.

(1995). D-fenfluramine-induced prolactin responses in postwithdrawal alcoholics and controls. Alcoholism: Clinical and Experimental Research, 19, 1578–1582.

28.

Feinn

Nellissery

Kranzler

H. R.

(2005). Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 133, 79–84.

29.

Fritz

M. S.

MacKinnon

D. P.

(2007). Required sample size to detect the mediated effect. Psychological Science, 18, 233–239.

30.

Gongwer

M. A.

Murphy

J. M.

McBride

W. J.

Lumeng

T. K.

(1989). Regional brain contents of serotonin, dopamine and their metabolites in the selectively bred high-and low-alcohol drinking lines of rats. Alcohol, 6, 317–320.

31.

Hamshere

M. L.

Langley

Martin

Agha

S. S.

Stergiakouli

Anney

R. J.

. . . Thapar

(2013). High loading of polygenic risk for ADHD in children with comorbid aggression. American Journal of Psychiatry, 170, 909–916.

32.

Hariri

A. R.

Holmes

(2006). Genetics of emotional regulation: The role of the serotonin transporter in neural function. Trends in Cognitive Sciences, 10, 182–191.

33.

Heinz

Mann

Weinberger

D. R.

Goldman

(2001). Serotonergic dysfunction, negative mood states, and response to alcohol. Alcoholism: Clinical and Experimental Research, 25, 487–495.

34.

Higley

J. D.

King

S. T.

Hasert

M. F.

Champoux

Suomi

S. J.

Linnoila

(1996). Stability of interindividual differences in serotonin function and its relationship to severe aggression and competent social behavior in rhesus macaque females. Neuropsychopharmacology, 14, 67–76.

35.

Higley

J. D.

Suomi

S. J.

Linnoila

(1992). A longitudinal assessment of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys. Biological Psychiatry, 32, 127–145.

36.

Higley

J. D.

Thompson

W. W.

Champoux

Goldman

Hasert

M. F.

Kraemer

G. W.

. . . Linnoila

(1993). Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoaminemetabolites in rhesus monkeys (Macaca mulatta). Archives of General Psychiatry, 50, 615–623.

37.

Hodgkinson

C. A.

Yuan

Shen

P. H.

Heinz

Lobos

E. A.

. . . Goldman

(2008). Addictions biology: Haplotype-based analysis for 130 candidate genes on a single array. Alcohol and Alcoholism, 43, 505–515.

38.

Huggins

K. N.

Mathews

T. A.

Locke

J. L.

Szeliga

K. T.

Friedman

D. P.

Bennett

A. J.

Jones

S. R.

(2012). Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels. Alcohol, 46, 371–376.

39.

Ioannidis

J. P.

Ntzani

E. E.

Trikalinos

T. A.

Contopoulos-Ioannidis

D. G.

(2001). Replication validity of genetic association studies. Nature Genetics, 29, 306–309.

40.

Jacob

G. A.

Butz

Bader

Lieb

Tuscher

Stahl

(2010). Impulsivity in borderline personality disorder: Impairment in self-report measures, but not behavioral inhibition. Psychopathology, 43, 180–188. doi:10.1159/000304174

41.

Keller

M. C.

(2014). Gene × environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution. Biological Psychiatry, 75, 18–24.

42.

Lee

M. A.

Meltzer

H. Y.

(1991). Neuroendocrine responses to serotonergic agents in alcoholics. Biological Psychiatry, 30, 1017–1030.

43.

LeMarquand

D. G.

Benkelfat

Pihl

R. O.

Palmour

R. M.

Young

S. N.

(1999). Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism. American Journal of Psychiatry, 156, 1771–1779.

44.

LeMarquand

Pihl

R. O.

Benkelfat

(1994). Serotonin and alcohol intake, abuse, and dependence: Clinical evidence. Biological Psychiatry, 36, 326–337.

45.

Lesch

K. P.

(2005). Alcohol dependence and gene x environment interaction in emotion regulation: Is serotonin the link? European Journal of Pharmacology, 526, 113–124.

46.

Litten

R. Z.

Ryan

M. L.

Falk

D. E.

Reilly

Fertig

J. B.

Koob

G. F.

(2015). Heterogeneity of alcohol use disorder: Understanding mechanisms to advance personalized treatment. Alcoholism: Clinical and Experimental Research, 39, 579–584.

47.

Luykx

J. J.

Bakker

S. C.

Lentjes

Neeleman

Strengman

Mentink

. . . Ophoff

R. A.

(2014). Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Molecular Psychiatry, 19, 228–234.

48.

Lynam

Smith

G. T.

Cyders

M. A.

Fischer

Whiteside

S. A.

(2007). The UPPS-P: A multidimensional measure of risk for impulsive behavior. Unpublished technical report.

49.

Munafò

M. R.

Hayward

Harmer

(2006). Selective processing of social threat cues following acute tryptophan depletion. Journal of Psychopharmacology, 20, 33–39.

50.

Muthén

B. O.

Muthén

L. K.

(1998–2012). Mplus version 7.2, computer software and manual. Los Angeles, CA: Muthén and Muthén.

51.

Neter

Wasserman

Kutner

(1989). Applied linear regression models. Boston, MA: Irwin.

52.

Netter

Hennig

Roed

I. S.

(1996). Serotonin and dopamine as mediators of sensation seeking behavior. Neuropsychobiology, 34, 155–165.

53.

Neumeister

Konstantinidis

Stastny

Schwarz

M. J.

Vitouch

Willeit

. . . Kasper

(2002). Association between serotonin transporter gene promoter polymorphism (5-HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Archives of General Psychiatry, 59, 613–620.

54.

Nigg

J. T.

(in press). On the relations among self-regulation, self-control, executive functioning, effortful control, cognitive control, impulsivity, risk-taking, and inhibition for developmental psychopathology. Journal of Child Psychology and Psychiatry.

55.

Purcell

S. M.

Wray

N. R.

Stone

J. L.

Visscher

P. M.

O’Donovan

M. C.

Sullivan

P. F.

. . . Fraser

(2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460, 748–752.

56.

Robins

L. N.

Cottler

L. B.

Bucholz

K. K.

Compton

W. M.

North

C. S.

Rourke

K. M.

(2000). Diagnostic Interview Schedule for the DSM-IV (DIS-IV). St. Louis, MO: Washington University School of Medicine.

57.

Schuckit

M. A.

(1994). Low level of response to alcohol as a predictor of future alcoholism. American Journal of Psychiatry, 151, 184–189.

58.

Smith

G. T.

Cyders

M. A.

(2016). Integrating affect and impulsivity: The role of positive and negative urgency in substance use risk. Drug and Alcohol Dependence, 163, S3–S12.

59.

Smith

G. T.

Guller

Zapolski

T. C.

(2013). A comparison of two models of urgency: Urgency predicts both rash action and depression in youth. Clinical Psychological Science, 1, 266–275.

60.

Soubriè

(1986). Reconciling the role of central serotonin neurons in human and animal behavior. Behavioral and Brain Sciences, 9, 319–335.

61.

Stanley

Traskman-Bendz

Dorovini-Zis

(1985). Correlations between aminergic metabolites simultaneously obtained from human CSF and brain. Life Sciences, 37, 1279–1286.

62.

Stautz

Cooper

(2013). Impulsivity-related personality traits and adolescent alcohol use: A meta-analytic review. Clinical Psychology Review, 33, 574–592.

63.

Substance Abuse and Mental Health Services Administration. (2014). Results from the 2013 National Survey on Drug Use and Health: Summary of national findings (NSDUH Series H-48, HHS Pub. No. SMA 14-4863). Rockville, MD: Author.

64.

Thakore

J. H.

O’Keane

Dinan

T. G.

(1996). d-Fenfluramine-induced prolactin responses in mania: Evidence for serotonergic subsensitivity. American Journal of Psychiatry, 153, 1460–1463.

65.

Tian

Gregersen

P. K.

Seldin

M. F.

(2008). Accounting for ancestry: Population substructure and genome-wide association studies. Human Molecular Genetics, 17, R143–R150.

66.

Van der Linden

D’Acremont

Zermatten

A. N.

Jermann

Lari

Willems

. . . Bechara

(2006). A French adaptation of the UPPS Impulsive Behavior Scale: Confirmatory factor analysis in a sample of undergraduate students. European Journal of Psychological Assessment, 22, 38–42. doi:10.1027/1015–5759.22.1.38

67.

Wang

F. L.

Chassin

Bates

J. E.

Dick

Lansford

J. E.

Pettit

G. S.

Dodge

K. A.

(2017). Serotonin functioning and adolescents’ alcohol use: A genetically informed study examining mechanisms of risk. Development and Psychopathology. Advance online publication. doi:10.1017/S095457941700058X

68.

Wang

F. L.

Chassin

Eisenberg

Spinrad

T. L.

(2015). Effortful control predicts adolescent antisocial-aggressive behaviors and depressive symptoms: Co-occurrence and moderation by impulsivity. Child Development, 86, 1812–1829.

69.

Whiteside

S. P.

Lynam

D. R.

(2001). The five factor model and impulsivity: Using a structural model of personality to understand impulsivity. Personality and Individual Differences, 30, 669–689.

70.

Yates

J. R.

Darna

Gipson

C. D.

Dwoskin

L. P.

Bardo

M. T.

(2015). Dissociable roles of dopamine and serotonin transporter function in a rat model of negative urgency. Behavioural Brain Research, 291, 201–208.

71.

Young-Wolff

K. C.

Enoch

M. A.

Prescott

C. A.

(2011). The influence of gene–environment interactions on alcohol consumption and alcohol use disorders: A comprehensive review. Clinical Psychology Review, 31, 800–816.

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