Accepted Manuscript

Current status of the neurobiology of aggression and impulsivity

David A. Slattery, Jared W. Young

PII: S0028-3908(19)30211-4
DOI: https://doi.org/10.1016/j.neuropharm.2019.107665
Article Number: 107665
Reference: NP 107665

To appear in: Neuropharmacology

Please cite this article as: Slattery, D.A., Young, J.W., Current status of the neurobiology of aggression
and impulsivity, Neuropharmacology, https://doi.org/10.1016/j.neuropharm.2019.107665.

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Current status of the neurobiology of aggression and impulsivity
ACCEPTED MANUSCRIPT
David A. Slattery1 and Jared W. Young2,3

1
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am
Main, Germany
2
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804,
USA

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3
Desert-Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego,
CA, USA

Aggression is a physiological trait that has important roles throughout evolution in both defense and

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predation, while impulsivity is the predisposition to rapid and unplanned actions without adequate forethought.
When expressed in humans in inappropriate contexts (e.g. sexual interactions, risk taking, gambling, substance use,

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to name but a few), aggressive and impulsive behavior can lead to social maladjustment, crime, accidents,
culminating in negative outcomes. These traits, commonly observed across many psychiatric disorders, in particular
during a developmental trajectory from conduct disorder to Attention Deficit/Hyperactivity Disorder (ADHD). ADHD

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is the most prevalent neurodevelopmental disorder in childhood (ca. 5%) and features significant persistence into
adulthood (adult prevalence, ca. 2.5%). The socio-economic impact of these disorders is high, not only due to direct
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healthcare costs, but also because e.g. adults with ADHD and bipolar disorder show higher rates of unemployment
and other negative outcomes. In addition, these individuals show a significant increase in substance use disorders
(SUD), depression and anxiety disorders, as well as personality disorders. In this Special Issue (SI), we invited
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researchers to submit research and review articles to provide a state-of-the-art collection of manuscripts on this
topic and have compiled 11 research articles and 3 review articles in the issue.
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The neuropeptides oxytocin and vasopressin have repeatedly been associated with aggressive behavior and
two articles in the SI further our understanding of their role in the etiology and potential treatment of aggression. In
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their study, de Moura Oliveira et al., (2019) reveal that post-weaning social isolation results in increased aggressive
behavior in both male and female rats, and concurrent regional alterations in oxytocin receptor and vasopressin-1A
receptor binding demonstrated via autoradiography studies. Interestingly, while there are common alterations as a
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result of post-weaning isolation, there are sex-specific alterations in receptor expression, which provide regions of
interest for future studies. In a similar study, in mice, Tan et al., (2019) show that social-isolation induced aggressive
behavior can be dose-dependently reduced by both oxytocin and vasopressin administration. Of note, the effects of
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oxytocin were blocked by pre-administration of an oxytocin receptor antagonist and a high- but not low- dose of a
vasopressin 1A receptor antagonist; providing further support that exogenously administered oxytocin may mediate
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some of its behavioral effects via vasopressin 1A receptor activation.

Other potential treatment for disorders with features of aggression and impulsivity are dietary in nature. In
their study, Gorlova et al., (2019) reveal that ultrasound-induced elevations in aggressive behavior are associated
with alterations in AMPA receptor subunit expression, concomitant reductions in plasticity-associated markers, and
increased oxidative stress in the prefrontal cortex. These ultra-sound induced alterations could be attenuated by
vitamin B1, or its derivative benfotiamine, supplementation via the drinking water. While the studies described
above focused on aggression and impulsivity, Okada et al., (2019) in a series of elegant microdialysis studies reveal
neurotransmitter profiles of different treatment regimens of guanfacine, an alpha2 adrenoceptor agonist that
attenuates hyperactivity.

A series of preclinical and clinical articles in the SI probe the involvement of novel candidate genes that have
been implicated in aggressive and impulsive behavior. Polymorphisms in adhesion G-protein-coupled receptor L3
have been linked with an increased risk of ADHD and in their study, Mortimer et al., (2019) show that mice that are
deficient for the gene display hyperlocomotion, increased impulsivity, decreased aggressive behavior, as well as
learning impairments. In addition to thisACCEPTED MANUSCRIPT
behavioral phenotype, the mice also show differential gene expression in
ADHD-relevant pathways including those involved in dopaminergic synapses such as Slc6a3. The first human studies
in the SI investigated the involvement of two novel gene polymorphisms in aggressive behavior; namely
orexin/hypocretin and mu 1 subtype opioid receptor (OPRM1). Harro et al., (2019) show that the rs2271933
polymorphism, which leads to an amino acid substitution in the orexin/hypocretin protein, is associated with higher
self-reported aggression, and increased incidence of traffic accidents. Interestingly, there was an interaction
between stressful life experiences and this SNP, such that woman with high self-reported stressful experiences and
the SNP had the highest association with aggression. Weidler et al., (2019) investigated the A118G OPRM1
polymorphism using a modified aggression paradigm in an fMRI study. They show that G allele carries displayed
higher general aggression levels, as well as self-reported physical aggression. Interestingly, these individuals also

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showed an increased activation of a number of cortical regions when choosing high levels of punishment for
opponents. A gene that has long been associated with aggressive behavior is monoamine oxidase A (MAOA) and in

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their article, Wagels et al., (2019) assess its interaction with testosterone on neural responses to provocation in men.
Their results demonstrate that circulating testosterone levels are higher in carriers of the long MAOA allele and show
an interaction between exogenous testosterone administration and the MAOA polymorphism in the cuneus.

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Moreover, testosterone increased default mode network activation, which may be related to increased engagement
of regions involved in social cognition.

The next articles in the issue assessed resting-state connectivity in relation to aggression and cognitive

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variability. Resting state data was used to assess cognitive variability in bipolar disorder patients in comparison with
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healthy controls. The cluster-analytic approach used by Kollmann et al., (2019) identified three clusters that were
characterized by deficits in cognitive flexibility, impulsive decision making, and improved visuospatial planning (see
front cover of the Special Issue). These clusters may go some way to explaining the phenotypic heterogeneity in
bipolar disorder. The study by Gan et al., (2019) reveals that reactive aggressive men have lower resting state
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functional connectivity between the left habenula (a region chosen based on preclinical evidence showing this to be
an important region in rodent aggressive behavior), and the left ventrolateral prefrontal cortex (a key region in
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inhibitory control). Further evidence for a role of the prefrontal cortex comes in the next article, in which antero-
and dorsolateral prefrontal regions are implicated in deficits in emotional control in patients with borderline
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personality disorder. In their study, Bertsch et al., (2019) reveal that male patients show reduced activity in these
regions during emotional action control and that this is related to self-reported anger. These findings suggest that
lateral prefrontal regions show reduced activity in patients with high levels of aggression.
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The Special Issue is completed by three review articles, which cover important topics related to aggression
and impulsivity. The first, by Been et al., (2019) covers an often understudied and neglected aspect in the field,
namely the neurobiology of female aggression. In their review, the authors collate the current status of female
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aggression research, including topics such as neural sites and hormonal regulation of aggression, as well as
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summarizing the methods and techniques that should be employed to assess the underpinnings of female
aggression. In his article, Will Norton, (2019) discusses the utility and increasing use of zebrafish as a model to assess
the circuitry and behavioral pharmacology of aggression. He summarizes the current protocols that are used to
measure aggression in zebrafish, the neural circuitry underlying this behavior and how they can be used to screen a
wide range of drugs to increase our knowledge of their role in the regulation of aggression. The final article in the SI
by Sebastian et al., (2019) highlight the higher prevalence of borderline personality disorder and ADHD in violent
offenders and the potential link between the two. Given the prevalence and characteristics of the population, they
proceed to discuss the therapeutic approaches that can be used for such offenders, as well as the challenges for
treating them in prison settings.

This special issue provides a current overview of both preclinical and clinical findings regarding the
neurobiology of aggression and impulsivity covering aspects from novel gene candidates and novel animal models to
resting state connectivity and the importance of assessing sex differences. Taken together, this collection of articles
represents an important resource for researchers interested in the fields of aggression and impulsivity.
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The influence of the OPRM1 (A118G) ACCEPTED
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on behavioral and neural correlates of aggression in
healthy males. Neuropharmacology, 156.

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