D2 dopamine receptors (D2R) are significantly downregulated in drug abusers of all types. However, both the functional consequences of D2R downregulation for drug abuse, and the molecular mechanisms that mediate drug-induced loss of D2R in vivo remain unresolved. Dopamine receptor-mediated signaling is regulated by numerous processes. One way is by endocytosis, whereby receptors are removed from the cell surface after activation. Following endocytosis, distinct dopamine receptors are sorted differentially: the D1Rs are recycled, while the D2Rs, are degraded. We have identified a protein, GASP1, that is responsible for the targeting of the D2R for degradation after endocytosis. We went on to propose that the balance of D1R-Gs signaling versus D2R-Gi signaling in circuits important to drug abuse becomes disrupted due to downregulation of D2R under conditions of high dopamine tone, and thereby promotes changes in plasticity and behavior. In support of this hypothesis, genetic disruption of GASP1, prevents cocaine induced downregulation of D2Rs and attenuates the development of locomotor sensitization to cocaine in mice. Here, we will examine how altering the balance of D2R and D1R signaling impacts sensitivity to both the locomotor (Aim 1) and rewarding (Aim 2) effects of cocaine. We will then assess whether changes in the balance of dopamine receptor signaling in selected neurons of the nucleus accumbens, ventral tegmental area, basolateral amygdala, or medial pre-frontal cortex are either necessary or sufficient to affect these behaviors (Aim 3). We will accomplish this, in part, with novel transgenic tools we have generated, including conditional and non-conditional GASP1 knock out (KO) mice, and a knock-in mouse expressing a D2R that does not bind GASP1. We will also approach the question of the role of D2R downregulation in altering behavior using commercially available, and therapeutically important, dopaminergic ligands. Although the pharmacology of these ligands have been studied for some time, the innovation in our approach lies in our examination of not only classical pharmacological properties, such as ligand affinity and selectivity, but also the effects of these ligands on both endocytic and post-endocytic receptor trafficking.
Loss of D2R is one of the common hallmarks of drug abuse, but the mechanisms mediating this downregulation and the role of this downregulation in behaviors that impact addition remain unknown. Here, we will examine how pharmacological and genetic manipulation of drug-induced D2R trafficking impact cocaine sensitivity.
| Yang, Sungchil; Ben-Shalom, Roy; Ahn, Misol et al. (2016) ?-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment. Cell Rep 16:1518-1526 |
| Luo, Sarah X; Timbang, Leah; Kim, Jae-Ick et al. (2016) TGF-? Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning. Cell Rep 17:3233-3245 |
