via stimulation of distinct dopamine receptor subtypes: by positively modulating excitatory glutamatergic input through D1 receptor signaling via Gs or Golf, which stimulates adenylyl cyclase leading to increased PKA activity, whereas dopamine negatively modulates this input through D2-receptor signaling via Gi and Go which inhibit adenylyl cyclase causing decreased PKA activity (Surmeier et al., 2007; Gerfen and Surmeier, 2011). In reality, each receptor exerts complex effects on many additional downstream signaling pathways. At rest, the two MSN subtypes are generally inhibited, they are in what researchers have termed the down-state. Excitatory glutamatergic synaptic activity can release the MSNs from this down-state and shift them into a more depolarized state (the up-state). Dopamine oppositely modulates the excitatory glutamatergic shift to the up-state. D1 activation of PKA enhances Cav1 L-type Ca2+ channel activity, decreases somatic K+ channel activity, and downregulates Cav2 Ca2+ channels that control activation of Ca2+ dependent, small-conductance K+ (SK) channels, resulting in increased spiking in these MSNs (Surmeier et al., 2007; Gerfen and Surmeier, 2011). In contrast, D2 signaling inhibits the up-state transition, thereby preventing increased spiking, via reduction of Cav1 L-type Ca2+ channel activity and Nav1 Na+ channel activity while increasing K+ channel currents (Surmeier et al., 2007;
