2. Sites of GPCR-mediated modulation of dopamine transmission
Release of dopamine from midbrain dopamine neurons is regulated by a
variety of intrinsic and extrinsic factors that influence action
potential firing at the somatodendritic level and terminal release
mechanisms in target regions. These factors include activation of GPCRs
and ligand-gated ion channels, adaptive changes in gene expression,
regulation of dopamine synthesis and vesical release mechanisms, altered
capacity or kinetics of dopamine reuptake through dopamine transporters
(DAT), and modulation of synaptic inputs. In the midbrain,
Gαi/o-coupled GPCRs (e.g., D2) can activate G
protein-gated inwardly rectifying K+ (GIRK) channels
to hyperpolarize dopamine neurons (Fig. 1 ) (Rifkin et al.,
2017). Dopamine neurons receive both glutamatergic and GABAergic
synaptic inputs, and presynaptic inhibition of these inputs via
activation of inhibitory GPCRs (e.g., CB1) can modulate rates and
patterns of dopamine neuron firing (Fig. 1 ) (Wang & Lupica,
2014). In striatal target regions, GPCRs modulate dopamine release in a
variety of ways that include enhancing or inhibiting vesicular release
mechanisms, modifying surface expression and kinetics of DAT activity,
and altering synthesis and vesicular dynamics (reviewed in Nolan et al.,
2020; Sulzer et al., 2016).
In addition to dopamine release driven by somatic action potential
firing, synchronous release of acetylcholine (ACh) from cholinergic
interneurons (CINs) in both the dorsal striatum and NAc elicits dopamine
release via activation of nicotinic ACh receptors in dopamine neuron
axons (Fig. 2 ) (Cachope et al., 2012; Threlfell et al., 2012).
This form of local axo-axonal dopamine release is generated by
triggering local action potentials (Kramer et al., 2022; Liu et al.,
2022) and can be indirectly elicited by glutamatergic inputs to CINs
that originate from intralaminar thalamic nuclei (Cover et al., 2019;
Threlfell et al., 2012) and various cortical regions (Adrover et al.,
2020; Kosillo et al., 2016; Mateo et al., 2017). Thus, GPCRs that
regulate CIN excitability, ACh release from CINs, or glutamatergic input
to CINs are all putative modulators of striatal dopamine release
(Fig. 2 ). Although the functional consequences of having
multiple routes to dopamine release are not well understood, each
pathway is likely to make unique contributions to behavior (e.g., Mohebi
et al., 2019; Mohebi, 2022). Moreover, these mechanisms can interact
with one another, with ACh-dependent mechanisms acting as a low-pass
filter on simultaneously occurring somatic action potential-dependent
dopamine release (Lovinger et al., 2022; Threlfell et al., 2012). GPCRs
that differentially modulate these mechanisms of dopamine release could
therefore modify interactions between these mechanisms as well.