Violent outbursts are one of the most costly, horrifying and damaging consequences of alcohol consumption, representing one of the most significant problems for the public health and criminal justice systems. The proposed research aims to increase our understanding of the neural mechanisms via which alcohol escalates aggressive behavior in some individuals but not in others. The proposal focuses on two types of aggression that are related to alcohol, escalated aggression after acute alcohol intoxication and aggression during withdrawal from intermittently accessible alcohol. The overarching hypothesis is to assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of two neurocircuits that are modulated by the CRF system. (1) We plan to functionally characterize ethanol-withdrawal aggression which appears defensive in nature, and contrast it with the aggression-heightening effects that follow the self- administration of an acut low alcohol dose, modeling the violence associated with acute alcohol intoxication. (2) The proposed studies will test the hypothesis that dysphoria and defensive aggression during the abstinence interval between consecutive access periods to alcohol is based on increased CRF activity in limbic forebrain structures, which in turn alters the adaptations in glutamate - GABA inputs to monoaminergic pathways. By contrast, we propose to test the hypothesis that antagonism of CRF-R1 modulates ascending serotonin impulse flow from the dorsal raph? nucleus to the prefrontal cortex and thus reduces the aggression- stimulating effects of acutely self-administered alcohol. (3) We aim to use molecular genetic tools to characterize the CRF and GABA receptor systems during escalated intermittent alcohol drinking and during the ensuing withdrawal aggression. We will use inducible knock-down technology in order to define the relative importance of GABAA receptor subtypes in the amygdala in alcohol-heightened aggression and alcohol- withdrawal aggression. The experimental work relies on quantitative ethological methodology for the analysis of species-normative and escalated forms of aggression, voluntary alcohol self-administration, real time PCR, in situ hybridization histochemistry, genetic manipulations, in vivo microdialysis and HPLC, and intracerebral microinfusions. The anticipated outcome will identify targets for therapeutic interventions.

Public Health Relevance

The proposed research aims to discover critical brain circuits that are active in alcohol-related aggression. We focus on escalated aggression as a result of acute intoxication in comparison to alcohol withdrawal aggression. We seek to determine key neurotransmitters in specific brain regions that mediate these types of aggression, and we seek to identify promising targets for new drug treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA013983-11
Application #
8506142
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Grakalic, Ivana
Project Start
2003-01-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$321,629
Indirect Cost
$104,510
Name
Tufts University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
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Hwa, Lara S; Kalinichev, Mikhail; Haddouk, HasnaĆ  et al. (2014) Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice. Psychopharmacology (Berl) 231:333-43
Hwa, Lara S; Debold, Joseph F; Miczek, Klaus A (2013) Alcohol in excess: CRF? receptors in the rat and mouse VTA and DRN. Psychopharmacology (Berl) 225:313-27
Miczek, Klaus A; de Boer, Sietse F; Haller, Jozsef (2013) Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology (Berl) 226:445-58
Miczek, Klaus A; de Almeida, Rosa M M (2012) The case for basic research on the psychopharmacology of aggression. J Clin Psychopharmacol 32:1-2

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