'Runner's high' abolished by leptin signalling in dopamine neurons in the ventral tegmental area

Running is associated with a feeling of euphoria—known as a 'runner's high'—but the mechanisms underpinning this phenomenon are poorly understood. Now, new research suggests that leptin suppresses this feeling by activating signal transducer and activator of transcription 3 (Stat3)-mediated signalling in the brain.

The investigators generated a mouse strain that lacked Stat3 in dopamine neurons of the ventral tegmental area (VTA) in the brain (Stat3^{DAT KO}). These Stat3^{DAT KO} mice were found to voluntarily run more than control mice (∼11 km per day versus ∼6 km per day), an effect that was reversed by reintroducing Stat3 into the VTA. “Abolishing the function of a single leptin receptor signalling molecule from dopamine neurons rendered the mice much more motivated to move and run,” explains investigator Stephanie Fulton.

Credit: NPG

To assess if Stat3-mediated leptin signalling modulates the rewarding effects of running, mice were subjected to a conditioned place preference task using a two chamber enclosure. Stat3^{DAT KO} mice spent more time on the side of the chamber associated with running than the control mice. Importantly, the running reward response was completely absent in control mice that were injected with leptin in the VTA; however, this treatment did not attenuate the reward-seeking behaviour in Stat3^{DAT KO} mice.

Synaptic overflow from dopamine neurons has been associated with the control of wheel running. However, this overflow was considerably reduced in Stat3^{DAT KO} mice.

Finally, the team found expression of the δ opioid receptor was increased in Stat3^{DAT KO} mice. This increase might enhance opioid signalling and contribute to the reward effect. Indeed, other research has suggested that opioids contribute to the 'runner's high' in humans.

“Leptin has direct actions in the VTA to the rewarding effects of running, [which] implies that an adipose-derived hormone communicates ... to a key motivation circuit and modifies the incentive to engage in physical activity,” concludes Fulton.