EFFECTS OF EARLY LIFE STRESS ON MESOCORTICOLIMBIC DOPAMINE SYSTEM FUNCTION AND RELATED DISORDERS IN PRE-ADOLESCENT HYPOMORPHIC MAOA MICE

Monoamine oxidase A (MAOA) is the degrading enzyme of monoamines (e.g., serotonin and dopamine (DA)), which plays an age-specific role in the etiopathogenesis of aggressive behavior (AB). AB is a multifaceted disorder based on the interaction between genetic (i.e., low activity of MAOA gene) and early life adversities (i.e., child neglect/abuse) (GxE). Furthermore, both early life adversities and AB display high comorbidity with substance abuse, raising the possibility that MAOA may act as a risk/predictive factor for subsequent drug abuse. In this thesis, we investigated the impact of this GxE interaction on DA function at pre-adolescence by exposing hypomorphic MAOA (MAONeo) mice to early life stress (ES). Then, we performed behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC) to determine whether i) synaptic alterations of mesocorticolimbic DA system are necessary and sufficient for the genesis of AB during pre-adolescence and ii) GxE interaction enhances the vulnerability to psychostimulant effects of cocaine. We found that in MAOANeoES mouse DA neurons, the manifestation of AB is associated with enhanced post-synaptic responsiveness to excitatory inputs and aberrant plasticity in the PFC during pre-adolescence. Moreover, systemic administration of the selective antagonist at DA DAD1 receptors SCH23390 fully restored PFC function and rescued AB. On the other hand, we found that MAOANeo ES mice were more sensitive to psychostimulant effects of cocaine after subchronic administration and following one week of withdrawal. While the analysis of excitatory properties of VTA DA neurons did not reveal any significant difference in these synapses among groups, we showed that in MAOANeo ES mice, subchronic cocaine reduced synaptic efficacy of inhibitory inputs and the probability of GABA release, effects that persisted after one week of withdrawal. The study of the role of endocannabinoids (eCB) signaling in the regulation of these alterations revealed that cocaine enabled 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in MAOANeo ES mice an effect that persisted also after one week of withdrawal. We also discovered that in vivo pretreatment with DAD2 and CB1 receptor antagonists, sulpiride and AM281 respectively, restored inhibitory synaptic efficacy and probability of GABA release in MAOANeo ES mice, as well as prevented DSI. Collectively, these results reveal that dysfunctional mesocortical DA signaling at pre-adolescence ties to AB in the MAOANeo ES mouse model and that it cross-sensitizes to psychostimulant effects of cocaine through a reduced GABA synaptic transmission on VTA DA neurons.