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  • To explore the mechanism behind differential activation

    2019-09-12

    To explore the mechanism behind differential activation kinetics, Marcott et al. (2018) manipulate local dopamine dynamics. They show that differences in dopamine concentrations are not responsible for different D2R activation kinetics, since D2-IPSCs reach similar amplitudes at different rates in NAc MSNs and DStr MSNs using iontophoresed dopamine or low-intensity stimulation. Although dopamine clearance is linked to D2R decay rate, neither pharmacologic blockade nor knockout (KO) of dopamine transporter DAT explains the difference in D2R activation kinetics between striatal divisions. Together, this suggests that despite native differences in dopamine release and uptake, these parameters alone are not responsible for the differences in D2R activation rate. Differential kinetics are also independent of D2R availability since partial D2R blockade does not change activation rate in DStr or NAc MSNs. With obvious extracellular mechanistic candidates eliminated, Marcott et al. (2018) turned to intracellular regulatory molecules. Regulator of G protein signaling (RGS) and G-protein-coupled receptor kinases (GRKs) can control the timing and termination of G-protein-coupled receptor (GPCR) signaling. Through KO and pharmacologic manipulation, Marcott et al. (2018) show that RGS7/9, but not GRK2/3, regulate D2R kinetics and may partially explain regional differences. In addition to differences in kinetics, Marcott et al. (2018) also determine that NAc MSN D2Rs are more sensitive to dopamine. Smaller concentrations elicit maximal D2R activation in NAc compared to DStr, aligning with differences in dopamine release between the two regions (Figure 1A). NAc D2Rs can be saturated by lower dopamine concentrations, thus when D2-IPSCs are evoked over a background of bath-applied dopamine, NAc D2Rs cannot respond with the same amplitude as DStr D2Rs. This suggests that under conditions of high tonic dopamine, D2Rs in DStr MSNs may have a greater “signal-to-noise ratio” since phasic release is more readily detected over a high tonic background. D2Rs expressed on local axon collaterals also differ in sensitivity between NAc and DStr, suggesting that regional differences are not restricted to dendritic D2Rs. Gα subunit composition can determine GPCR sensitivity, and differences in Gα Manumycin A kinase may control the differences in D2R sensitivity. Marcott et al. (2018) confirm that dopamine more potently activates Gαo compared to Gαi (Figure 1B). They then show that conditional KO of Gαo in NAc reduces D2R dopamine sensitivity to that of DStr Manumycin A kinase D2Rs, suggesting that D2Rs in NAc may be more readily coupled to Gαo and thus have greater sensitivity. Reduced sensitivity of NAc D2Rs is recapitulated in cocaine-exposed mice, indicating that D2R Gα subunits may also control D2R dopamine sensitivity after cocaine (Figure 1A). Finally, D2Rs are not the only Gi/o-coupled GPCRs in the striatum. Marcott et al. (2018) determine that regional heterogeneity is restricted to D2Rs, since Gi/o-coupled opioid and M4 receptors in DStr and NAc do not differ in activation kinetics or agonist sensitivity in drug-naive mice. Intriguingly, drug exposure appears to abolish some regional differences in D2Rs. Chronic cocaine reduces NAc D2R dopamine sensitivity such that it more closely resembles DStr D2R sensitivity. There may be a unique molecular mechanism driving changes specifically to NAc D2Rs since drug exposure does not reduce DStr D2R sensitivity. This could occur at the transcriptional level, where methyltransferases, such as H3K9me3 or G9a, can regulate D2R expression or by alternative splicing to modify Gα subunits and their downstream signaling cascades (Pierce et al., 2018). If epigenetic modifications drive region-specific D2R changes, studying them may provide information on altered dopaminergic function at both receptor and circuit level. Moving forward, there are several factors that should be considered. First, dopamine release differs between striosome and matrix compartments of the striatum, and cocaine enhances dopamine to a greater extent in DStr striosomes compared to matrix (Salinas et al., 2016). Since dopamine release is compartmentally altered by cocaine in DStr, D2Rs may respond with a change in sensitivity specifically in striosomes that was undetected by the current study. Second, Marcott et al. (2018) show that differences in DStr and NAc D2Rs are found in dendrites and axons of striatal MSNs. However, D2Rs expressed on interneurons or expressed presynaptically on dopamine terminals may also exhibit regional differences in sensitivity or kinetics. Presynaptic D2Rs differentially control dopamine release from SNc and VTA dopamine neurons (Fox et al., 2016), which may result from the different Gα coupling proposed to occur postsynaptically. Differences in both pre- and postsynaptic D2R signaling are important to consider in dopaminergic circuitry since striato-nigro-striatal loops may depend on such specificities. These spiraling pathways support communication between midbrain dopamine structures and striatal regions to associate limbic and motor aspects of behavior. Interestingly, dorsal tier midbrain dopamine neurons have low D2R mRNA while ventral tier have higher D2R mRNA expression (Haber and Knutson, 2010). By regionally altering presynaptic D2R-Gα coupling, cocaine could alter the transfer of information from NAc to DStr and promote habit formation and addiction. To understand how dopamine acts on D2-MSNs to drive addiction, further work is needed to dissect precisely how striatal D2Rs couple to Gαi/o in both drug-exposed and drug-naive animals. These future studies should (1) rely on quantitative methods to establish regional differences in Gα coupling on MSNs and dopamine terminals, (2) make use of intersectional tools that could allow for effective Gα subunit null mutations in specific D2-MSN populations in each subregion, and (3) establish how manipulating Gα coupling in the striatum can drive the acquisition of drug self-administration or drug relapse.