Epidemiological and criminal statistics as well as neurobiology, and pharmacotherapy all provide converging evidence that suggests links between alcohol consumption, impulsivity, and pathological aggression. The proposed research aims to dissect these links at the behavioral and neurochemical level, with particular focus on the relative role and interactions between GABAA and serotonin systems. A first specific aim seeks to analyze how alcohol-heightened aggression is related to other forms of escalated aggression. Experiments are designed to test the hypothesis whether or not a common behavioral profile of varied forms of escalated aggression characterizes individuals who engage in alcohol-heightened aggression. The second and third aims focus on pharmacological tools that are employed to characterize the relative contribution of 5-HT1A, 5-HT1B, and GABAA receptors, their pre- versus post-synaptic sites in brainstem, and prefrontal cortical regions in animals that engage in alcohol-heightened aggression.
The fourth aim examines how serotonergic modulation of GABAergic systems determines alcohol-heightened aggression. Inversely, how do neuropharmacological manipulations of the modulatory sites on the GABAA receptor, particularly via neurosteroids, enable 5-HT-mediated effects on aggressive behavior? Pharmacological experiments are designed to stimulate pre-synaptically 5-HT1A and 5-HT1B receptors or to neurotoxically lesion raphe nuclei in order to assess the importance of serotonergic inhibition on the activating effects of positive modulators like neurosteroids on alcohol-heightened aggression. A fifth aim is directed at the neural sites of the GABAergic and serotonergic mechanisms that are critical for the aggression-heightening effects of alcohol. Intracranial microinjections are used to determine whether activation of 5-HT receptors in the raphe nucleus or in terminal forebrain regions are the critical sites for reducing escalated fighting. Conversely, can blockade of the 5-HT autoreceptors in the raphe n. potentiate the aggression-heightening effects of alcohol and other positive modulators at GABAA receptors? Additional evidence will be obtained by in vivo microdialysis experiments, in order to learn whether behavioral changes are reflected in significant changes in the level of GABA and serotonin release in cortico-limbic and brainstem areas.
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