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.