TY - JOUR

T1 - M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor's location

AU - Foster, Daniel J

AU - Gentry, Patrick R

AU - Lizardi-Ortiz, Jose E

AU - Bridges, Thomas M

AU - Wood, Michael R

AU - Niswender, Colleen M

AU - Sulzer, David

AU - Lindsley, Craig W

AU - Xiang, Zixiu

AU - Conn, P Jeffrey

PY - 2014/2/26

Y1 - 2014/2/26

N2 - Of the five muscarinic receptor subtypes, the M5 receptor is the only one detectable in midbrain dopaminergic neurons, making it an attractive potential therapeutic target for treating disorders in which dopaminergic signaling is disrupted. However, developing an understanding of the role of M5 in regulating midbrain dopamine neuron function has been hampered by a lack of subtype-selective compounds. Here, we extensively characterize the novel compound VU0238429 and demonstrate that it acts as a positive allosteric modulator with unprecedented selectivity for the M5 receptor. We then used VU0238429, along with M5 knock-out mice, to elucidate the role of this receptor in regulating substantia nigra pars compacta (SNc) neuron physiology in both mice and rats. In sagittal brain slices that isolate the SNc soma from their striatal terminals, activation of muscarinic receptors induced Ca2+ mobilization and inward currents in SNc dopamine neurons, both of which were potentiated by VU0238429 and absent in M5 knock-out mice. Activation of M5 also increased the spontaneous firing rate of SNc neurons, suggesting that activation of somatodendritic M5 increases the intrinsic excitability of SNc neurons. However, in coronal slices of the striatum, potentiation of M5 with VU0238429 resulted in an inhibition in dopamine release as monitored with fast scan cyclic voltammetry. Accordingly, activation of M5 can lead to opposing physiological outcomes depending on the location of the receptor. Although activation of somatodendritic M5 receptors on SNc neurons leads to increased neuronal firing, activation of M5 receptors in the striatum induces an inhibition in dopamine release.

AB - Of the five muscarinic receptor subtypes, the M5 receptor is the only one detectable in midbrain dopaminergic neurons, making it an attractive potential therapeutic target for treating disorders in which dopaminergic signaling is disrupted. However, developing an understanding of the role of M5 in regulating midbrain dopamine neuron function has been hampered by a lack of subtype-selective compounds. Here, we extensively characterize the novel compound VU0238429 and demonstrate that it acts as a positive allosteric modulator with unprecedented selectivity for the M5 receptor. We then used VU0238429, along with M5 knock-out mice, to elucidate the role of this receptor in regulating substantia nigra pars compacta (SNc) neuron physiology in both mice and rats. In sagittal brain slices that isolate the SNc soma from their striatal terminals, activation of muscarinic receptors induced Ca2+ mobilization and inward currents in SNc dopamine neurons, both of which were potentiated by VU0238429 and absent in M5 knock-out mice. Activation of M5 also increased the spontaneous firing rate of SNc neurons, suggesting that activation of somatodendritic M5 increases the intrinsic excitability of SNc neurons. However, in coronal slices of the striatum, potentiation of M5 with VU0238429 resulted in an inhibition in dopamine release as monitored with fast scan cyclic voltammetry. Accordingly, activation of M5 can lead to opposing physiological outcomes depending on the location of the receptor. Although activation of somatodendritic M5 receptors on SNc neurons leads to increased neuronal firing, activation of M5 receptors in the striatum induces an inhibition in dopamine release.

KW - Animals

KW - Animals, Newborn

KW - Brain/cytology

KW - CHO Cells

KW - Calcium/metabolism

KW - Cricetulus

KW - Dopamine/metabolism

KW - Dopaminergic Neurons/drug effects

KW - Dose-Response Relationship, Drug

KW - In Vitro Techniques

KW - Indoles/pharmacology

KW - Membrane Potentials/drug effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Protein Binding/drug effects

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptor, Muscarinic M5/genetics

KW - Transfection

U2 - 10.1523/JNEUROSCI.4896-13.2014

DO - 10.1523/JNEUROSCI.4896-13.2014

M3 - Journal article

C2 - 24573284

VL - 34

SP - 3253

EP - 3262

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 9

ER -