D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors

Abstract

Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptor (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons. These changes include a leftward shift in the dose-response to a D1-like agonist that indicates a behavioral D1R hypersensitivity, a shift from PKA to ERK intracellular signaling cascades upon D1R activation, and a reduction in the density of bridging collaterals from D1R-expressing neurons to pallidal areas. We hypothesize that the D1R hypersensitivity underlies abuse vulnerability by facilitating the behavioral responses to repeated cocaine, such as locomotor sensitization and drug self-administration. We found evidence that littermate control mice develop D1R hypersensitivity after they are sensitized to cocaine. Indeed, D1-like agonist and cocaine cross-sensitize in control littermates and this effect was potentiated in mice lacking striatal D2Rs from indirect-pathway neurons. To our surprise, mice with low striatal D2Rs acquired cocaine self-administration similarly to littermate controls and showed no significant change in motivation to take cocaine but lower seeking. These findings indicate that downregulation of striatal D2Rs triggers D1R hypersensitivity to facilitate cocaine locomotor sensitization, which by itself was not associated with greater cocaine taking or seeking under the conditions tested.

A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors

“…We propose that striatal D1R hypersensitivity is the substrate linking these vulnerability factors. In a recent publication, we showed D1R hypersensitivity under conditions of low striatal D2Rs in medium spiny neurons (Dobbs et al, 2019). Here, we demonstrate that this upregulation in D1Rs is functionally relevant, with D1Rs driving ethanol stimulation.…”

“…We hypothesized that acute ethanol exposure would also activate D1R activity and lead to protein kinase A (PKA)-dependent phosphorylation of downstream targets, such as pGLUA1 at serine-845. Furthermore, we predicted that iMSN-Drd2KO mice would display enhanced activation of targets downstream of D1R based on our recent findings that mice lacking medium spiny neuron D2Rs display D1R hypersensitivity at both the cellular/signaling and behavioral levels (Dobbs et al, 2019).…”

“…Decades of research on basal ganglia circuit function and models of Parkinson disease indicate that the balance between the activity and signaling of D2R and D1R is critical for striatal circuitry function (Dobbs et al, 2017; Freeze et al, 2013; Gerfen et al, 2002; Lobo and Nestler, 2011). Our previous findings indicate that a selective reduction of D2Rs on iMSNs does not affect striatal Drd1 mRNA levels but rather leads to a functional upregulation and signaling shift of striatal D1R (Dobbs et al, 2019). Administration of a D1-like receptor agonist known to increase downstream D1R targets, such as pGluA1 at serine-845 in the DMS, was confirmed in the present study.…”

Transient Chemogenetic Inhibition of D1-MSNs in the Dorsal Striatum Enhances Methamphetamine Self-Administration

“…Previous findings support the simultaneous requirement of activity of both striatal projection pathways (D1-MSNs and D2-MSNs) in the dorsal striatum for proper action initiation and for proper continuation of performance after initiation [64,65]. Supporting these findings, an imbalance in the activity of D1-MSNs and D2-MSNs is hypothesized to contribute to the development and persistence of addiction [66,67]. For example, a few studies have revealed opposing roles of D1Rs and D2Rs in the dorsal striatum in cocaine taking and seeking behaviors [67,68,69].…”

“…Supporting these findings, an imbalance in the activity of D1-MSNs and D2-MSNs is hypothesized to contribute to the development and persistence of addiction [66,67]. For example, a few studies have revealed opposing roles of D1Rs and D2Rs in the dorsal striatum in cocaine taking and seeking behaviors [67,68,69]. A recent study indicated that downregulation of striatal D2Rs triggers D1R hypersensitivity to facilitate greater cocaine taking behavior [67].…”