Mapping the neurocircuitry of impulsive aggression through the pharmacologic review of anti‐impulsive aggressive agents

Joe Bou Nassif, Alan R. Felthous


Impulsive aggression, in contradistinction to premeditated aggression in humans or predatory aggression in animals, corresponds to defensive aggression in animal models. At the core of the neurocircuitry of impulsive aggression, from murine to feline to human species, it is the medial amygdala‐mediobasal hypothalamus‐dorsal periaqueductal gray pathway. Here, we update current knowledge on the neurocircuitry of impulsive aggression by placing the neurocircuitry and its neurophysiological substrates into the top‐down/bottom‐up hypothesis of impulsive aggression. We then reverse the neurotranslational approach, which applies neuroscience to developing therapeutic drugs, and apply current understanding of potential mechanisms of anti‐impulsive aggression agents to further clarify, at least heuristically and hypothetically, the dynamic biochemical components of the neurocircuitry of impulsive aggression. To do this, we searched the medical literature for studies attempting to clarify the neurobiological and neurochemical effects of the five most widely studied anti‐impulsive aggressive agents, particularly as they pertain to the top‐down/bottom‐up hypothesis. Multiple different mechanisms are discussed, all of which fitting in the hypothesis by way of either promoting the "top‐down" part (i.e., enhancing inhibitory neurotransmitters), or suppressing the "bottom‐up" part (i.e., decreasing excitatory neurotransmitters). The hypothesis appears consistent with the current psychopharmacological understanding of these agents, as well as to account for the likely multifactorial etiology of the condition. Limitations of the hypothesis and future directions are finally discussed.