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Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

Shin, Jung Hoon, Adrover, Martín F., Wess, Jíürgen, Alvarez, Veronica A.
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.26 pp. 8124-8129
acetylcholine, cholinergic receptors, dopamine, glutamic acid, motivation
Cholinergic transmission in the striatum functions as a key modulator of dopamine (DA) transmission and synaptic plasticity, both of which are required for reward and motor learning. Acetylcholine (ACh) can elicit striatal DA release through activation of nicotinic ACh receptors (nAChRs) on DA axonal projections. However, it remains controversial how muscarinic ACh receptors (mAChRs) modulate striatal DA release, with studies reporting both potentiation and depression of striatal DA transmission by mAChR agonists. This study investigates the mAChR-mediated regulation of release from three types of midbrain neurons that project to striatum: DA, DA/glutamate, and glutamate neurons. We found that M ₅ mAChRs potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain. We also show that M ₂/M ₄ mAChRs depress the nAChR-dependent mechanism of DA release in the striatum. These results suggest that M ₅ receptors on DA neuron terminals enhance DA release, whereas M ₂/M ₄ autoreceptors on cholinergic terminals inhibit ACh release and subsequent nAChR-dependent DA release. Our findings clarify the mechanisms of mAChR-dependent modulation of DA and glutamate transmission in the striatum.