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.
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.
|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|
|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|
|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 Î¼-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|
|Albrechet-Souza, Lucas; Hwa, Lara S; Han, Xiao et al. (2015) Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice. Alcohol Clin Exp Res 39:1609-18|
|Hwa, Lara S; Nathanson, Anna J; Shimamoto, Akiko et al. (2015) Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice. Psychopharmacology (Berl) 232:2889-902|
|Han, Xiao; Albrechet-Souza, Lucas; Doyle, Michelle R et al. (2015) Social stress and escalated drug self-administration in mice II. Cocaine and dopamine in the nucleus accumbens. Psychopharmacology (Berl) 232:1003-10|
|Newman, Emily L; Smith, Kiersten S; Takahashi, Aki et al. (2015) Î±2-containing GABA(A) receptors: a requirement for midazolam-escalated aggression and social approach in mice. Psychopharmacology (Berl) 232:4359-69|
Showing the most recent 10 out of 52 publications