Fig. 2. Examples of GPCR modulation of dopamine release in the striatum. Dopamine release from VTA and SNc projections to the striatum is driven by both somatic action potential firing and local action potential generation produced by nAChR activation in dopamine neuron axons. D2 activation causes autoinhibitory feedback. Heteroreceptors expressed near dopamine release sites include CB2 and KOR (inhibitory) and M5 (typically excitatory). GPCRs expressed in dopamine neuron axons can also affect dopamine reuptake through DAT by modulating surface expression and transporter kinetics. M4 activation can inhibit dopamine release via several mechanisms, including inhibition of ACh release from CINs and mobilization of eCB signaling in D1-expressing SPNs. Retrogarde eCB signaling can then activate CB2 receptors on dopamine neurons to reduce dopamine release. The endogenous KOR agonist dynorphin is produced by D1-expressing SPNs, and can inhibit dopamine release by activating KORs. CIN activity and subsequent nAChR-dependent dopamine release can be driven by glutamatergic afferents from cortical and thalamic regions. Presynaptic GPCRs that inhibit glutamatergic inputs to CINs (e.g., mGlu2, CB1) can indirectly inhibit acetylcholine-dependent dopamine release. Abbreviations: ACh- acetylcholine; CIN- cholinergic interneuron; DA- dopamine; DAT- dopamine transporter; Glu- glutamate; nAChR- nicotinic acetylcholine receptor; SNc- substantia nigra pars compacta; SPN- striatal projection neuron; VTA- ventral tegmental area.