| dc.description.abstract | Pathological reactive aggression is a neurodevelopmental disorder characterized by exaggerated violent and explosive responses that are disproportionate to provocation, and a propensity for cannabis abuse. The susceptibility to pathological aggression is shaped by several genes. In particular, substantial evidence has highlighted a major role of the gene which encodes monoamine oxidase A (MAOA), the primary catabolic enzyme for monoamine neurotransmitters. In fact, one of the strongest predictors of male pathological aggression is the gene by environment (GxE) interaction between the low transcriptional activity polymorphisms of MAOA (MAOA-uVNTR) and early life stress such as childhood neglect or abuse. Given that reactive aggressive individuals tend to consume cannabis, it was hypothesized that this GxE interaction leads to neurobiological changes that confer a sensitivity to the effects of cannabis consumption. In line with this idea, numerous previous studies have concluded that cannabinoid receptor 1 (CB1), the receptor that is activated by the major psychoactive ingredient in cannabis, Δ9-tetrahydrocannabinol (THC), is responsible for the anti-aggressive effects of cannabis consumption. In particular, it has been shown that these effects are mediated by CB1 localized on glutamatergic neurons. Cannabinoid receptor 2 (CB2) has been shown to a lesser extent to reduce aggression. To uncover the connection between cannabis consumption and pathological reactive aggression, our lab recently developed the first mouse model of this GxE interaction, based on subjecting a transgenic MAOA hypomorphic mouse model (MAOANeo) to early-life stress (ES). Unlike their wild-type and non-stressed controls, MAOANeo male pups subjected to ES from postnatal day (PND) 1 through 7 developed a marked increase in aggression from the onset of adolescence at PND28, throughout adulthood. This developmental trajectory strikingly mimics the ontogeny of pathological reactive aggression in humans; making this the most relevant and translatable model available. To test whether the GxE interaction leads to neurobiological changes in CB1 and CB2, ES-MAOANeo males were euthanized, as well as their non-stressed (NS) and wild type (WT) littermates, then their hypothalamus, amygdala, and midbrain was isolated. These regions compose the major aggression circuit in the brain. ES-MAOANeo mice develop elevated hypothalamic CB1 in response to early life stress compared to ES-WT littermates. Additionally, MAOANeo mice develop increased amygdalar CB1, though this effect is independent of ES conditions. Neither midbrain CB1 nor CB2 in any analyzed region change in response to either genetic or condition factor. Based on these findings, it was hypothesized that ES-MAOANeo mice would be selectively sensitive to the anti-aggressive effects of ultra-low-dose (0.03 mg/kg) THC. Indeed, the ES-MAOANeo mice fought for a smaller duration at both juvenile and adult stages, and this dose does not induce locomotor- or anxiety-related effects. However, ultra-low-dose THC did not show an improvement in risk assessment, suggesting that the effect of THC is to selectively reduce aggression, not to rescue the pathological aggressive behavioral phenotype. Despite being unable to determine if these effects are mediated by CB1, an inhibitor of glutamate release (riluzole) strongly reduced aggression in both fighting bouts and duration. Together, these results suggest that ES-MAOANeo interaction confers a sensitivity to the anti-aggressive effects of THC. Based on these findings, it is proposed that CB1 is posited to be a biomarker that may predict pathological aggression in humans. Future studies should be done to determine if ultra-low-dose THC treatments activate CB1 on glutamatergic or GABAergic neurons, if the upregulation event in hypothalamic CB1 occurs on glutamatergic or GABAergic neurons, and should also examine CB1 changes in other pertinent brain regions. | |
