GPR158, a class C orphan G protein-coupled receptor, has been shown to function as a metabotropic glycine receptor. The nucleus accumbens (NAc), a significant basal ganglia component that integrates data from cortical and subcortical structures to drive goal-directed behaviors, exhibits high levels of GPR158 expression. It is unknown, however, how GPR158 activation affects the NAc's neuronal activity. Using whole-cell patch-clamp recordings we found that glycine-dependent activation of GPR158 elevates evoked firing of NAc medium spiny neurons (MSNs), while activation of GPR158 in cholinergic interneurons (CIN) failed to significantly affect excitability. Consistent with the negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7.2/7.3 channels, GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization. The increased MSN excitability was associated with decreased M-currents and selective pharmacological inhibition of Kv7 channels mimicked and occluded the increased excitability induced by GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blockaded, modulation of MSN excitability by GPR158 activation was strongly suppressed. Collectively our findings indicate that GPR158/PKA/ERK signaling controls MSN excitability via Kv7 modulation. Thus, glycine-dependent activation of GPR158 may significantly affect MSN spike firing in vivo, making it a possible mechanism for mediating specific aspects of goal-induced behaviors.Grant Support: Italian Ministry for University Education and Research (Prin: P20222WFZ3 )