Alcohol plays a key role in at least half of all violent assaults, incidents of domestic violence, homicides and murders. However, the neural and behavioral processes underlying the link between alcohol and violence remain poorly understood. This research proposal aims to delineate the neural mechanisms by which alcohol persistently escalates the motivation to commit intense aggressive acts in some individuals.
These aims are empirically pursued using a fixed interval (FI) schedule of operant responding which will be reinforced by the opportunity to engage in an aggressive encounter, allowing us to directly quantify aggressive motivation. Here, the role of corticotropin-releasing factor (CRF) in both (1) the motivation to engage in aggressive acts, and (2) the performance of aggressive behaviors will be quantitatively and qualitatively examined. By isolating the motivation to engage in aggression, we will be able to identify the underlying neural mechanisms that relate to subsequent aggressive behaviors. The overarching hypothesis is that escalated aggression, particularly when engendered by repeated exposures to alcohol, is a function of dysregulated CRF-modulated neurocircuits, namely the hypothalamus-ventral tegmental area (VTA) and hypothalamus-dorsal raph nucleus (DRN) pathways. These circuits may be fundamental to the modulation of emotional processing via dopaminergic and serotonergic systems, respectively. In a specific subset of individuals, we predict that subpopulations of CRF neurons contribute to escalated motivation to seek out aggressive opportunities after alcohol consumption. In the first aim, we plan to fully characterize the enduring nature of alcohol-escalated aggressive motivation as a function of alcohol dose and as it relates to the duration since alcohol consumption.
Aim two will use cellular and molecular tools to investigate plasticity in neuropeptidergic mechanisms that contribute to the persistent escalation of aggressive motivation after repeated alcohol intake. This work will reveal changes in overlapping, intersecting or parallel CRF mechanisms that ultimately converge on dopaminergic and serotonergic systems that are critical for emotional processing. We will also use transgenic technology to define the relative importance of CRF-expressing cell populations in hypothalamus-VTA and hypothalamus?DRN circuits. The proposed experimental work portrays highly translational and ethologically valid analyses of species-normative and escalated forms of aggression engendered by alcohol. Novel targets for therapeutic interventions are anticipated based on the results of these studies.

Public Health Relevance

The proposed research aims to discover critical patterns of neural plasticity resulting from alcohol administrations that progressively escalates aggression. We focus specifically on the persistence and neuropharmacology of the motivation to commence aggressive acts as a result of repeated exposures to alcohol. We will determine how key neuropeptides, particularly CRF, in certain brain circuits control the enduring nature of an increased desirability for violence, and we seek to identify novel targets for advanced treatment strategies for alcohol-induced explosive aggression.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Grakalic, Ivana
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Tufts University
Schools of Arts and Sciences
United States
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Newman, Emily L; Albrechet-Souza, Lucas; Andrew, Peter M et al. (2018) Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism. Psychopharmacology (Berl) 235:1807-1820
Ahmed, Serge H; Badiani, Aldo; Miczek, Klaus A et al. (2018) Non-pharmacological factors that determine drug use and addiction. Neurosci Biobehav Rev :
Covington 3rd, Herbert E; Newman, Emily L; Tran, Steven et al. (2018) The Urge to Fight: Persistent Escalation by Alcohol and Role of NMDA Receptors in Mice. Front Behav Neurosci 12:206
Newman, Emily L; Terunuma, Miho; Wang, Tiffany L et al. (2018) A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression. Neuropsychopharmacology 43:1224-1234
Niederkofler, Vera; Asher, Tedi E; Okaty, Benjamin W et al. (2016) Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior. Cell Rep 17:1934-1949
Newman, Emily L; Gunner, Georgia; Huynh, Polly et al. (2016) Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice. Alcohol Clin Exp Res 40:2445-2455
Holly, Elizabeth N; Miczek, Klaus A (2016) Ventral tegmental area dopamine revisited: effects of acute and repeated stress. Psychopharmacology (Berl) 233:163-86
Hwa, Lara S; Shimamoto, Akiko; Kayyali, Tala et al. (2016) Dissociation of ?-opioid receptor and CRF-R1 antagonist effects on escalated ethanol consumption and mPFC serotonin in C57BL/6J mice. Addict Biol 21:111-24
Hwa, Lara S; Holly, Elizabeth N; DeBold, Joseph F et al. (2016) Social stress-escalated intermittent alcohol drinking: modulation by CRF-R1 in the ventral tegmental area and accumbal dopamine in mice. Psychopharmacology (Berl) 233:681-90
Norman, Kevin J; Seiden, Jacob A; Klickstein, Jacob A et al. (2015) Social stress and escalated drug self-administration in mice I. Alcohol and corticosterone. Psychopharmacology (Berl) 232:991-1001

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