Dopamine—a neurotransmitter responsible for influencing motivation, pleasure, mood and learning in the brain—has experienced a bit of fame in recent years, acting as a sort of buzzword to describe a fleeting satisfaction from social media, food or shopping. Because of this, most people know that dopamine acts within the brain. In particular, it is associated with the mesolimbic pathway, which is a brain circuit connecting the ventral tegmental area (VTA) to the nucleus accumbens (NAc), amygdala, and hippocampus.
However, a recent study, published in Science Advances, indicates that the vagus nerve, which bridges the brain and gut, also plays a crucial role in regulating behaviors related to reward and motivation.
The gut-brain-vagal axis
The vagus nerve is the main pathway of the gut-brain axis, a complex communication network linking peripheral organs to the brain by transmitting interoceptive signals about mood, digestion, inflammation, and stress.
The authors of the new study explain, “Among metabolically active peripheral organs, the gut emerges as a central player in coordinating the body-brain tango through a multitude of long-range mechanisms, including hormonal signaling, microbiota-derived metabolites, and both local and gut-brain neuronal connections.”
While most prior studies have focused on brain-centric models of reward, some work has shown that gut-vagal signals have an effect on food-driven dopamine activity and eating behaviors. Yet it was still unclear whether this would extend to other forms of addiction fueled by dopamine.
Disrupted vagal signaling affects dopamine activity
To determine the extent to which the gut-brain-vagal axis is involved in dopamine reward activity, the research team conducted an array of experiments involving mice. Some experiments involved cutting the vagus nerve via subdiaphragmatic vagotomy (SDV) and comparing food and drug reward behaviors between SVA mice and unaltered (sham) mice. In vivo dopamine activity was also monitored through fiber photometry, molecular assays, and electrophysiology.
Results showed that the gut-brain vagal axis is essential for both food- and drug-induced reward behaviors in mice. In experiments featuring foods that mice would normally find addictive in nature, the SDV mice showed a slower and lower rate of food consumption, while the unaltered mice exhibited a rapid increase in food consumption over a 10-day period.
The team noted increased excitement in sham mice, but not SDV mice. They write, “Using our model, in combination with telemetric locomotor activity monitoring, we observed that sham mice displayed an increased locomotor activity before (food-anticipatory activity) and during (consumption) food intake.
“In contrast, SDV mice exhibited dampened locomotor activity during both phases. This reduction was not due to preexisting locomotor deficits, as both sham and SDV mice had similar locomotor profiles during the dark period (foraging period) or under basal conditions.”
Similar results were found with some experiments involving drugs, including cocaine, morphine and amphetamines. The team observed reductions in the elicited locomotor response in SDV mice for both morphine and cocaine, indicating that the vagus nerve might modulate dopamine dynamics and/or its postsynaptic integration. Amphetamines showed no significant differences and also depended on dose in conditioning experiments.
The study authors explain, “While sham mice were positively conditioned to cocaine, no significant preference was observed in SDV mice. The effect of amphetamine-induced CPP in SDV mice depended on the conditioning doses. At 2 mg/kg, we observed that both experimental groups were positively conditioned.
“However, when mice were conditioned with a lower dose of amphetamine (1 mg/kg), we observed a lower conditioning index in SDV mice compared to controls, suggesting that the physiological consequences of neuronal adaptations observed in SDV mice may be overridden at higher [dopamine] levels.”
Furthermore, in vivo experiments showed that vagal integrity is required for normal dopamine neuron firing, dopamine-dependent molecular changes and structural plasticity in reward circuits. Fiber photometry showed that when the vagus nerve was cut, dopamine responses were delayed within the nucleus accumbens or reduced during food anticipation, eating, and after drug administration.
However, dopamine function overall was not compromised, as it still functioned in processes related to movement. Still, activity was reduced, as dopamine neurons fired less and received weaker excitatory input.
Implications for addiction treatment in humans
The study helps to confirm that our gut, via the vagus nerve, plays a direct and essential role in how we experience reward and motivation. However, addiction treatments involving the reduction of vagus nerve signaling are still a way off.
Simply cutting the vagus nerve off surgically, as in the mouse study, is most likely not an option for humans and may have further side effects. In addition, the team notes that the gut may even induce compensatory changes over time to make up for lost signaling.
Clearly, more research is needed to refine these methods. The team suggests using more targeted genetic or viral tools to dissect specific vagal circuits in the future or exploring different methods for modulating vagal signaling. However, upon refining, there is a potential for eating disorders and addiction treatments in the future.