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.