Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

Abstract

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines’ effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

An energetic view of stress: Focus on mitochondria

“…Further insights for a key role of mitochondrial function in specific brain regions in influencing complex social behaviors have been provided by a series of studies in rats relating anxiety with diminished social competitiveness (Hollis et al, 2015; van der Kooij et al, 2017), a phenomenon that has also been highlighted in humans (Goette et al, 2015). In rats, lower mitochondrial function in the nucleus accumbens was observed in high-anxious animals compared to their less anxious littermates, and was causally implicated in their low social competitiveness (Hollis et al, 2015).…”

“…Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in anxious rats (Hollis et al, 2015). Additionally, treatment with a low dose of the anxiolytic diazepam was effective to facilitate social dominance, ameliorating both the competitive disadvantage and low mitochondrial function in the nucleus accumbens displayed by high-anxious rats (van der Kooij et al, 2017). …”

Stress‐Induced Depression: Is Social Rank a Predictive Risk Factor?

“…In addition, low exploratory mice are more submissive in the resident/intruder test than high exploratory mice. Given the existing link between anxiety and social competition, future studies should address the potential contribution of anxiety trait for rank‐related susceptibility to stress.…”

Biogenic amines and activity levels alter the neural energetic response to aggressive social cues in the honey bee Apis mellifera

“…The neural energetic state of neurons and glial cells, however, also alters signaling potential of neural circuits and responds to signaling events. Several studies have demonstrated that neural energetic state, described as the activity of metabolic pathways, including glycolysis and oxidative phosphorylation, predicts the outcome of social interactions (Hollis et al, ; van der Kooij et al, ; Li‐Byarlay, Rittschof, Massey, Pittendrigh, & Robinson, ; Rittschof, Vekaria, Palmer, & Sullivan, ), and is regulated by social experience (Alaux et al, ; Chandrasekaran et al, ; Dong et al, ; Li‐Byarlay et al, ; Rittschof et al, ). These studies observe such relationships at the whole brain level as well as in behavior‐relevant brain regions.…”