Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

TLDR

Dopamine plays a critical role in motor control, addiction, and reward‑seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. The cholinergic activation triggers dopamine release through direct action on terminals, independent of midbrain neuron firing, and requires glutamatergic receptor activity. Selective activation of cholinergic interneurons, both in vitro and in vivo, elicits real‑time dopamine release in the nucleus accumbens, showing that endogenous cholinergic activity controls accumbal extracellular dopamine via a complex convergence of neurotransmitter systems that may drive motivated behavior.

Abstract

Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.