Serotonin has been implicated in impulsive behaviours such as temporal discounting. While animal studies and theoretical approaches suggest that reduced tonic serotonin levels increase temporal discounting rates and vice versa, evidence from human studies is scarce and inconclusive. Furthermore, an important modulator of serotonin signalling, a genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR), has not been investigated for temporal discounting so far.
Objective:
First, the purpose of this study was to test for a significant association between 5-HTTLPR and temporal discounting. Second, we wished to investigate the effect of high/low tonic serotonin levels on intertemporal choice and blood oxygen-level-dependent response, controlling for 5-HTTLPR.
Methods:
We tested the association of 5-HTTLPR with temporal discounting rates using an intertemporal choice task in 611 individuals. We then manipulated tonic serotonin levels with acute tryptophan interventions (depletion, loading, balanced) in a subsample of 45 short (S)-allele and 45 long (L)/L-allele carriers in a randomised double-blind crossover design using functional magnetic resonance imaging and an intertemporal choice task.
Results:
Overall, we did not find any effect of serotonin and 5-HTTLPR on temporal discounting rates or the brain networks associated with valuation and cognitive control.
Conclusion:
Our findings indicate that serotonin may not be directly involved in choices including delays on longer timescales such as days, weeks or months. We speculate that serotonin plays a stronger role in dynamic intertemporal choice tasks where the delays are on a timescale of seconds and hence are therefore directly experienced during the experiment.
BallardKKnutsonB (2009) Dissociable neural representations of future reward magnitude and delay during temporal discounting. Neuroimage45: 143–150.
2.
BickelWKOdumALMaddenGJ (1999) Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology146: 447–454.
3.
BiskupCSSanchezCLArrantA, et al. (2012) Effects of acute tryptophan depletion on brain serotonin function and concentrations of dopamine and norepinephrine in C57BL/6J and BALB/cJ mice. PLoS One7: e35916.
4.
BizotJLe BihanCPuechAJ, et al. (1999) Serotonin and tolerance to delay of reward in rats. Psychopharmacology (Berl)146: 400–412.
5.
BizotJCThiebotMHLe BihanC, et al. (1988) Effects of imipramine-like drugs and serotonin uptake blockers on delay of reward in rats. Possible implication in the behavioral mechanism of action of antidepressants. J Pharmacol Exp Ther246: 1144–1151.
6.
BlairKSFingerEMarshAA, et al. (2008) The role of 5-HTTLPR in choosing the lesser of two evils, the better of two goods: Examining the impact of 5-HTTLPR genotype and tryptophan depletion in object choice. Psychopharmacology (Berl)196: 29–38.
7.
BooijLvan der DoesAJHaffmansPM, et al. (2005) Acute tryptophan depletion as a model of depressive relapse: Behavioural specificity and ethical considerations. Br J Psychiatry187: 148–154.
8.
BoureauYLDayanP (2011) Opponency revisited: Competition and cooperation between dopamine and serotonin. Neuropsychopharmacology36: 74–97.
9.
BradleySLDodelzonKSandhuHK, et al. (2005) Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. Am J Med Genet B Neuropsychiatr Genet136B: 58–61.
10.
BrainardDH (1997) The psychophysics toolbox. Spat Vis10: 433–436.
11.
CoolsRBlackwellAClarkL, et al. (2005) Tryptophan depletion disrupts the motivational guidance of goal-directed behavior as a function of trait impulsivity. Neuropsychopharmacology30: 1362–1373.
12.
CoolsRNakamuraKDawND (2011) Serotonin and dopamine: Unifying affective, activational, and decision functions. Neuropsychopharmacology36: 98–113.
13.
CreanJRichardsJBde WitH (2002) Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism. Behav Brain Res136: 349–357.
14.
CrisanLGPanaSVulturarR, et al. (2009) Genetic contributions of the serotonin transporter to social learning of fear and economic decision making. Soc Cogn Affect Neurosci4: 399–408.
15.
CrockettMJClarkLLiebermanMD, et al. (2010) Impulsive choice and altruistic punishment are correlated and increase in tandem with serotonin depletion. Emotion10: 855–862.
16.
DemotoYOkadaGOkamotoY, et al. (2012) Neural and personality correlates of individual differences related to the effects of acute tryptophan depletion on future reward evaluation. Neuropsychobiology65: 55–64.
17.
DenkFWaltonMEJenningsKA, et al. (2005) Differential involvement of serotonin and dopamine systems in cost-benefit decisions about delay or effort. Psychopharmacology (Berl)179: 587–596.
18.
Deza-AraujoYINeukamPTMarxenM, et al. (2018) Acute tryptophan loading decreases functional connectivity between the default mode network and emotion-related brain regions. Hum Brain Mapp40: 1844–1855.
19.
DingerkusVLGaberTJHelmboldK, et al. (2012) Acute tryptophan depletion in accordance with body weight: Influx of amino acids across the blood-brain barrier. J Neural Transm (Vienna)119: 1037–1045.
20.
DukalHFrankJLangM, et al. (2015) New-born females show higher stress- and genotype-independent methylation of SLC6A4 than males. Borderline Personal Disord Emot Dysregul2: 8.
21.
FaulknerPMancinelliFLockwoodPL, et al. (2017) Peripheral serotonin 1B receptor transcription predicts the effect of acute tryptophan depletion on risky decision-making. Int J Neuropsychopharmacol20: 58–66.
22.
FaulknerPSelvarajSPineA, et al. (2014) The relationship between reward and punishment processing and the 5-HT1A receptor as shown by PET. Psychopharmacology (Berl)231: 2579–2586.
23.
FignerBKnochDJohnsonEJ, et al. (2010) Lateral prefrontal cortex and self-control in intertemporal choice. Nat Neurosci13: 538–539.
24.
FonsecaMSMurakamiMMainenZF (2015) Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr Biol25: 306–315.
25.
GorgolewskiKBurnsCDMadisonC, et al. (2011) Nipype: A flexible, lightweight and extensible neuroimaging data processing framework in Python. Front Neuroinform5: 13.
26.
HareTAHakimiSRangelA (2014) Activity in dlPFC and its effective connectivity to vmPFC are associated with temporal discounting. Front Neurosci8: 50.
27.
HeilsATeufelAPetriS, et al. (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem66: 2621–2624.
28.
HellwigMGeisslerSMatthesR, et al. (2011) Transport of free and peptide-bound glycated amino acids: Synthesis, transepithelial flux at CACO-2 cell monolayers, and interaction with apical membrane transport proteins. Chem-BioChem12: 1270–1279.
29.
HenleTWalterHKrauseI, et al. (1991) Efficient determination of individual maillard compounds in heat-treated milk products by amino acid analysis. Int Dairy J1: 125–135.
30.
HombergJRLeschKP (2011) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry69: 513–519.
31.
HuXZLipskyRHZhuG, et al. (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet78: 815–826.
32.
JedemaHPGianarosPJGreerPJ, et al. (2010) Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission. Mol Psychiatry15: 512–522, 446.
33.
JeffreysH (1961) Theory of probability. Oxford: Oxford University Press.
LeschKPBengelDHeilsA, et al. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science274: 1527–1531.
36.
McFarquharMMcKieSEmsleyR, et al. (2016) Multivariate and repeated measures (MRM): A new toolbox for dependent and multimodal group-level neuroimaging data. Neuroimage132: 373–389.
37.
MarshAAFingerECBuzasB, et al. (2006) Impaired recognition of fear facial expressions in 5-HTTLPR S-polymorphism carriers following tryptophan depletion. Psychopharmacology (Berl)189: 387–394.
38.
MathewsTAFedeleDECoppelliFM, et al. (2004) Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods140: 169–181.
39.
MazurJE (1987) An adjusting procedure for studying delayed reinforcement. In: CommonsMMazurJENevinJ, et al. (eds) Quantitative Analyses of Behavior: Vol. 5: The Effect of Delay and of Intervening Events on Reinforcement Value. Hillsdale, NJ: Earlbaum, pp. 55–73.
40.
MiyazakiKMiyazakiKWDoyaK (2011) Activation of dorsal raphe serotonin neurons underlies waiting for delayed rewards. J Neurosci31: 469–479.
41.
MobiniSChiangTJAl-RuwaiteaAS, et al. (2000a) Effect of central 5-hydroxytryptamine depletion on inter-temporal choice: A quantitative analysis. Psychopharmacology (Berl)149: 313–318.
42.
MobiniSChiangTJHoMY, et al. (2000b) Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology152: 390–397.
43.
NeukamPTKroemerNBDeza AraujoYI, et al. (2018) Risk-seeking for losses is associated with 5-HTTLPR, but not with transient changes in 5-HT levels. Psychopharmacology (Berl)235: 2151–2165.
44.
PelliDG (1997) The videotoolbox software for visual psychophysics: Transforming numbers into movies. Spat Vis10: 437–442.
45.
PetersJBüchelC (2011) The neural mechanisms of inter-temporal decision-making: Understanding variability. Trends Cogn Sci15: 227–239.
46.
PineAShinerTSeymourB, et al. (2010) Dopamine, time, and impulsivity in humans. J Neurosci30: 8888–8896.
47.
PoosehSBernhardtNGuevaraA, et al. (2018) Value-based decision-making battery: A Bayesian adaptive approach to assess impulsive and risky behavior. Behav Res Methods50: 236–249.
48.
PoulosCXParkerJLLeAD (1996) Dexfenfluramine and 8-OH-DPAT modulate impulsivity in a delay-of-reward paradigm: Implications for a correspondence with alcohol consumption. Behav Pharmacol7: 395–399.
49.
SchmittJAJorissenBLSobczakS, et al. (2000) Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers. J Psychopharmacol14: 21–29.
50.
SchweighoferNBertinMShishidaK, et al. (2008) Low-serotonin levels increase delayed reward discounting in humans. J Neurosci28: 4528–4532.
51.
TanakaSCSchweighoferNAsahiS, et al. (2007) Serotonin differentially regulates short- and long-term prediction of rewards in the ventral and dorsal striatum. PLoS One2: e1333.
52.
WinklerAMRidgwayGRWebsterMA, et al. (2014) Permutation inference for the general linear model. Neuroimage92: 381–397.
53.
WogarMABradshawCMSzabadiE (1993) Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on choice between delayed reinforcers. Psychopharmacology111: 239–243.
54.
WorbeYSavulichGVoonV, et al. (2014) Serotonin depletion induces ‘waiting impulsivity’ on the human four-choice serial reaction time task: Cross-species translational significance. Neuropsychopharmacology39: 1519–1526.
55.
XuSDasGHueskeE, et al. (2017) Dorsal raphe serotonergic neurons control intertemporal choice under trade-off. Curr Biol27: 3111–3119 e3.
56.
YoungSNSmithSEPihlRO, et al. (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl)87: 173–177.
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