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.