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  • aminopyridine receptor In addition to G coupling it is impor


    In addition to Gα coupling, it is important to consider that the transition from goal-directed to habitual drug taking also relies on striatal D2R-A2AR heterodimers. Following cocaine self-administration, D2R-A2AR density is increased in the NAc, leading to greater antagonism of the inhibitory (anti-drug) actions of D2R homodimers. D2R-A2AR heterodimers are instead reduced in the DStr after cocaine, and the disappearance of antagonistic D2R-A2AR interaction is proposed to support habit formation (Pintsuk et al., 2016). Thus, in addition to the differences in D2R Gα subunits proposed by Marcott et al. (2018), regional differences in D2R-A2AR interaction might also support increased drug intake. Beyond drug addiction, understanding dopamine receptor signaling will provide insight into aminopyridine receptor diseases with regionally divergent dopaminergic adaptations. In Parkinson’s disease (PD), progressive dopaminergic cell loss generates an imbalance between mesolimbic and nigrostriatal functions and changes D2R expression dynamically across the DStr. These effects are further pronounced after dopamine replacement therapy. While changes in DStr D2Rs support motor impairments, they could also be involved in reward dysfunction, as seen with impulse control disorders some PD patients develop. Preclinically, the motivation to self-administer a D2/3R agonist is positively correlated with ΔFosB expression in the DStr of rats, whereas in “parkinsonian” rats, motivation is correlated with ΔFosB expression in the NAc. Regardless of parkinsonian state, animals with fewer dopamine neurons have increased motivation to self-administer D2/3R agonists (Engeln et al., 2013). In the parkinsonian state, regional heterogeneity in D2R sensitivity to dopamine may trigger differential downstream molecular alterations, such as ΔFosB, to cause motor and reward dysfunction. Schizophrenia is also associated with altered striatal dopamine release and D2R function. Dopamine release is increased in the DStr and is associated with symptoms of hallucination, while release is reduced in the NAc and is associated with decreased cognitive function. Striatal D2R density is generally increased in schizophrenic patients, and it is postulated that increased dopamine release results in an overstimulation of D2R to generate psychotic symptoms. Preclinically, transgenic mice with striatal D2R overexpression have altered basal ganglia connectivity and cognitive deficits along with decreased tonic VTA firing (Simpson and Kellendonk, 2017). Altered VTA firing may be responsible for decreased NAc dopamine release and associated cognitive symptoms. Although dopamine is decreased in the NAc, the relatively smaller concentrations of dopamine required to activate NAc D2Rs may indicate they can still be overstimulated to generate psychosis. Alternatively, low tonic dopamine in NAc may instead increase the ability of NAc D2Rs to respond to phasic dopamine release. Changes in dopamine signaling and D2R expression along the dorso-ventral axis of the striatum clearly play a role in a wide range of pathologies. Moving forward, it would be useful to examine how D2R activation kinetics, sensitivity, and Gα coupling are altered in dopamine-related disease states and contribute to symptomatology. Identification of compounds preferentially targeting Gαo over Gαi may enable us to manipulate specific populations of D2R expressing neurons, similar to recently described Gs-biased agonists (Yano et al., 2018). In this way, Gαi-biased ligands could more selectively modulate D2R activity in the DStr to address motor symptoms without the confounds of concurrent NAc receptor modulation. In summary, Marcott et al. (2018) provide a thorough foundation for how D2Rs encode dopamine signaling throughout striatal subregions. Differences in the degree of D2R-Gαo coupling are proposed to support regionally distinct responses to dopamine. These findings are relevant for understanding basal ganglia function in both normal and pathologic states. While improving our understanding of disease pathophysiology, knowledge of how dopamine receptors encode dopamine release throughout striatal subregions could also lead to new treatment developments. In the future, it will be critical to assess whether similar D2R differences are found outside the striatum, as well as how dopamine signaling is transduced by its other receptors. Together, this will provide a clearer picture of how dopamine signaling is encoded throughout the central nervous system.