8. Concluding remarks
A more thorough understanding of the implications of GPCR modulation of
dopaminergic transmission will require further investigation into the
distinct contributions of the various mechanisms driving dopamine
release. The rapid increase in tools available to observe and manipulate
circuit function with greater specificity regarding cell type and
connectivity will no doubt accelerate elucidation of how somatic vs.
local mechanisms that drive dopamine release contribute to motivated
behaviors, and how these processes are fine-tuned by GPCRs (for review,
see Lovinger et al., 2022). Conditional deletion of GPCRs from specific
genetically and/or anatomically defined neurons has facilitated
discovery of surprising mechanisms regulating dopaminergic transmission
(e.g., Foster et al., 2016). The recent invention of genetically-encoded
biosensors for dopamine has facilitated new progress in correlating
behavior and psychoactive drug effects with dopamine release on a
meaningful temporal scale (Labouesse & Patriarchi, 2021). Looking
forward, there are many opportunities to expand our understanding of
dopamine transmission and its involvement in various aspects of
psychoactive drug use. For example, subsets of midbrain dopamine neurons
co-release glutamate and GABA, yet there is relatively little known
about how these co-released neurotransmitters impact behavior in the
context of psychoactive drugs, or how GPCRs might differentially
modulate GABA and glutamate co-release from dopamine neurons. How sex
modulates GPCR regulation of dopamine transmission is another important
consideration. Although some sex differences in regulation of dopamine
transmission have been identified (see (Zachry et al., 2021), many
previous studies were only performed in one sex (typically male animals)
or do not report evaluation of sex differences, creating vast gaps in
knowledge that could have important translational implications when
using findings from preclinical studies to inform drug development
(Shansky & Murphy, 2021). Because there are many neurological and
psychiatric conditions that involve dysregulation of dopaminergic
transmission, discovery of detailed GPCR-mediated regulatory mechanisms
has the potential to broadly impact our understanding of the
neurobiological basis of normal and disordered behavior far beyond the
context of psychoactive drug use.