Fig. 1. Examples of GPCR modulation of dopamine neuron activity
in the midbrain.
A) SNc and VTA neurons modulate striatal activity via projections to the
dorsal striatum and NAc. Midbrain dopamine neurons receive both local
and long-range GABA inputs, including GABAergic projections from the
striatum, and glutamatergic inputs from a variety of brain regions (An
et al., 2021). B) D2 autoreceptors expressed in somatodendritic
compartments of dopamine neurons activate GIRK, causing
hyperpolarization. Activation of presynaptic
Gαi/o-coupled GPCRs including MOR reduces GABAergic
transmission in dopamine neurons, causing disinhibition. C) Activation
of Gαq-coupled GPCRs (e.g., orexin type 1 receptors, α1
adrenergic receptors) leads to eCB production and retrograde activation
of CB1 receptors on GABAergic inputs including local GABAergic
interneurons. Activation of Gαi/o-coupled GPCRs causes
presynaptic inhibition of GABA release and disinhibition of dopamine
neurons. Abbreviations: 2-AG- 2-arachidonoylglycerol; DA- dopamine; eCB-
endocannabinoid; GIRK- G protein-gated inwardly rectifying potassium
channel; GPCR- G protein-coupled receptor; NAc- nucleus accumbens; SNc-
substantia nigra pars compacta; SPN- striatal projection neuron; VTA-
ventral tegmental area.