Dopamine triggers rise in intracellular calcium concentration in astrocytes and depresses excitatory synaptic transmission in the nucleus accumbens

Dopaminergic inputs to the nucleus accumbens (NAc), originating in the ventral tegmental area, are key for motor control and reward. Previous reports suggested that dopamine reduces excitatory synaptic transmission by acting on presynaptic D1 receptors, and by altering adenosine signaling. What remains unknown is how dopamine changes the functional properties of NAc astrocytes. Given that various neurotransmitters increase the intracellular calcium concentration in astrocytes, Corkrum et al.  hypothesize that dopamine may be able to evoke similar effects.

To test this hypothesis, Corkrum et al. used a combination of transgenic mice, optogenetics and pharmacogenetics to show that dopamine evokes a rise in the intracellular calcium concentration in NAc astrocytes by activating D1 dopamine receptors. The work is based on the use of elegant controls, like those relying on the use of astrocyte-specific deletion of D1 dopamine receptors. Dopamine also impairs excitatory synaptic transmission through signaling pathways that rely on activation of presynaptic A1 receptors in NAc neurons. The hypothesized chain of events include a rise in intracellular calcium concentration evoked by activation of D1 receptors in astrocytes that promotes ATP/adenosine release from these cells. Adenosine binds to presynaptic A1 receptors in neurons, thereby reducing excitatory synaptic transmission.

Since dopamine is also implicated with drug addiction, the authors analyzed the effects of the amphetamine, a psycho-stimulant known to disrupt dopamine release, re-uptake and degradation. Just like dopamine, amphetamine increased the intracellular calcium concentration in astrocytes evoked by dopamine release, and inhibited excitatory transmission.

These findings are important because they show that astrocytes modulate excitatory glutamatergic transmission in the NAc by responding to changes in dopamine release. Therefore, future strategies to understand the molecular basis of addiction, should take into account the contribution of these cells to the regulation of synaptic strength.

Saad Ahmad and Nikhita Kumar

Reference

Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A (2020). Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron 105(6):1036-1047.e5.