M5 Receptor Activation Produces Opposing Physiological Outcomes in Dopamine Neurons Depending on the Receptor's Location

Of the five muscarinic receptor subtypes, the M-5 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 M-5 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 M-5 receptor. We then used VU0238429, along with M-5 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 M-5 knock-out mice. Activation of M-5 also increased the spontaneous firing rate of SNc neurons, suggesting that activation of somatodendritic M-5 increases the intrinsic excitability of SNc neurons. However, in coronal slices of the striatum, potentiation of M-5 with VU0238429 resulted in an inhibition in dopamine release as monitored with fast scan cyclic voltammetry. Accordingly, activation of M-5 can lead to opposing physiological outcomes depending on the location of the receptor. Although activation of somatodendritic M-5 receptors on SNc neurons leads to increased neuronal firing, activation of M-5 receptors in the striatum induces an inhibition in dopamine release.