Elsevier

Brain Research

Volume 1746, 1 November 2020, 147013
Brain Research

Research report
Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender

https://doi.org/10.1016/j.brainres.2020.147013Get rights and content

Highlights

  • Orexins are involved in the regulation of both reward and stress response.

  • The HCRTR1 rs2271933 G > A genotype is associated with aggressiveness.

  • The more aggressive A/A homozygote males have high reward sensitivity.

  • Insatiability by reward, not openness to rewards is associated with aggressiveness.

  • Only in the A/A homozygotes aggressiveness is associated with openness to rewards.

Abstract

Orexins/hypocretins maintain wakefulness, increase appetite and participate in the coordination of stress response. We have recently provided evidence on the role of orexins in aggression, showing the association of the HCRTR1 genotype.

(rs2271933 G > A; leading to amino acid substitution Ile408Val) with aggressiveness or breach of law in four independent cohorts. Aggressive behaviour can be reward driven and hence we have examined the association of HCRTR1 rs2271933 genotype with different aspects of reward sensitivity in the birth cohort representative Estonian Children Personality Behaviour and Health Study. HCRTR1 genotype was associated with reward sensitivity in a gender dependent manner. Male HCRTR1 A/A homozygotes had higher Openness to Rewards and the overall reward sensitivity score while, in contrast, female A/A homozygotes scored lower than G-allele carriers in Openness to Rewards. In the total sample, aggressiveness correlated positively with reward sensitivity, but this was on account of Insatiability by Reward. In contrast, the HCRTR1 A/A homozygotes had a positive association of aggressiveness and Openness to Rewards. Experience of stressful life events had a small but significant increasing effect on both aspects of reward sensitivity, and correlated in an anomalous way with reward sensitivity in the HCRTR1 A/A homozygotes. Conclusively, the higher aggressiveness of HCRTR1 A/A homozygotes appears based on a qualitative difference in sensitivity to rewards, in the form that suggests their lower ability to prevent responses to challenges being converted into overt aggression.

Introduction

Orexins or hypocretins are neuropeptides first described in 1998 (Sakurai et al., 1998, de Lecea et al., 1998) that are expressed in clusters of dorsomedial and lateral hypothalamus (Broberger et al., 1998) and involved in multiple physiological functions (Sutcliffe and de Lecea, 2000, Broberger and Hökfelt, 2001, Schwartz and Kilduff, 2015, Ferrario et al., 2016), including participation in the coordination of defence response (Johnson et al., 2012). Orexin release modulates the expression and extinction of fear memories (Flores et al., 2015) and the orexin neurons are activated in acute response to a variety of stressors; however, their role in chronic stress appears complex (Sargin, 2019), leading to the hypothesis that the role for orexins in neurotransmission is promoted during aversive conditions that elicit high arousal (Berridge et al., 2010). We have recently found evidence for a role of orexins in the other side of the flight/fight response, aggressiveness, by association of the HCRTR1 gene encoding the orexin OX1 receptor (Harro et al., 2019). The HCRTR1 gene variant (rs2271933, G1222A) in exon 7 that leads to amino acid substitution (Ile408Val) (Meerabux et al., 2005) was linked to aggressive behaviour or breach of law in four independent population samples by use of self-reports, interviews, and databases. In two population-representative birth cohort samples, male HCRTR1 rs2271933 A/A homozygotes were more aggressive than G-allele carriers. Female A/A homozygotes were also more aggressive if they had experienced higher number of adverse life events. The HCRTR1 genotype was also associated with re-occurrence of driving while impaired by alcohol and with involvement in traffic accidents (Harro et al., 2019). Another recent study has revealed that with each A-allele of the HCRTR1 rs2271933 there is less fMRI-measured activition in the inferior frontal cortex and more activation in the locus coeruleus (Gottschalk et al., 2019).

The only previous implication of orexins in human aggressiveness-related states had come from a unique study on epileptic patients that monitored release of orexin A in amygdala, and found an increase while subjects reported higher levels of anger (Blouin et al., 2013). Curiously, the highest increase of orexin levels was however related to experiencing positive emotions and during episodes of social interactions. Concluding from this and their previous animal studies showing activation of orexin neurons during positively but not during negatively motivated tasks (McGregor et al., 2011), the authors suggested that orexin activity is necessary for positive emotion and motivation that drives social interaction.

While motivation for positive social interaction does not pose direct health risks, simultaneous association of orexin release with anger brings about a possibility that the role of orexinergic neurotransmission in motivational activation can in occasion lead to less desirable behaviours. If resources are limited, aggression is a strategy to obtain rewards, and neurobiology of aggression and reward-related behaviour is closely intertwined (Panksepp, 1998, Aleyasin et al., 2018). Animal studies have strongly implicated orexins in reward processing (Harris et al., 2005, Moorman et al., 2017) and OX1 receptor antagonists are actively pursued as a potential avenue for treating drug addiction (Perrey and Zhang, 2020). It has been proposed that the role of orexins in reward seeking is in coordinating motivational activation when higher effort is required or external stimuli interfere with reward stimuli (James et al., 2017), and that OX1 receptor mediated signaling is an evolutionally conserved promoter of foraging (Barson, 2020). All this eveidence together suggests that orexins may be involved in the emergence of aggressive impulses in the context of reward seeking, possibly in particular in social contexts. Thus, we aimed at exploring whether the HCRTR1 rs2271933 genotype found to be associated with aggressiveness would also be associated with reward sensitivity. Reward sensitivity reflects the individually characteristic level of behavioural activation (Gray, 1994) and is a major component of temperament and personality reflecting the tendency to detect, pursue and derive pleasure from positive stimuli (Corr, 2009, Gray and McNaughton, 2000). It appears to emerge from neural networks with the mesotelencephalic dopaminergic circuitry at its core (Fu and Depue, 2019), and the latter receives a prominent input from the orexinergic neurons (Peyron et al., 1998, Marcus et al., 2001). Because the higher aggressiveness in HCRTR1 rs2271933 A/A homozygotes had a different relationship with lifetime adversities in males vs females, being independent of stressful life events in males, we hypothesized that reward sensitivity could contribute to the higher aggressiveness in HCRTR1 rs2271933 A/A males.

Section snippets

HCRTR1 genotype and reward sensitivity in population-representative birth cohorts

Based on previous results on the association of the HCRTR1 rs2271933 genotype with aggressiveness, we had hypothetized that the relationship of the HCRTR1 rs2271933 genotype with reward sensitivity would be found in males but possibly not in females. Indeed, two-way ANOVA revealed statistically significant interaction effects for the Openness to Rewards scale and three of the four subscales, and several main effects of gender or genotype were also present. The HCRTR1 genotype was statistically

Discussion

We have found that the HCRTR1 rs2271933 (G1222A) genotype that causes an amino acid substitution (Ile408Val) of the OX1 receptor protein in a region that is suggested to interact with G proteins or other proteins (Thompson et al., 2014) and has been associated with aggressiveness or accident-prone law-breaching behaviour in multiple cohorts (Harro et al., 2019) is also associated with reward sensitivity. Aggressiveness belongs to the behavioural repertoire of coordinated adaptive response to

Sample

This study was carried out on the Estonian sample of the European Youth Heart Study (1998/1999), which was subsequently incorporated into the longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). The rationale and procedure of sample formation, and further data collection waves have been described elsewhere in detail (Harro et al., 2001, Harro et al., 2019). ECPBHS is highly representative of two birth cohorts of a local population, as 79% of subjects of the randomized

CRediT authorship contribution statement

Aleksander Pulver: Conceptualization, Formal analysis, Methodology, Resources, Writing - review & editing. Evelyn Kiive: Conceptualization, Data curation, Investigation, Methodology, Writing - review & editing. Margus Kanarik: Investigation, Methodology, Writing - review & editing. Jaanus Harro: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We are grateful to the ECPBHS study participants, their parents and the whole ECPBHS Team. This work was supported by Estonian Research Council Project IUT20-40, the EC Horizon 2020 project CoCA (H2020-PHC-2015-667302), and the Tallinn University ASTRA project TU TEE financed by the European Union European Regional Development Fund (2014-2020.4.01.16-0033).

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