Presynaptic and postsynaptic mesolimbic dopamine D3 receptors play distinct roles in cocaine versus opioid reward in mice.

BACKGROUND: Past research illuminated pivotal roles of dopamine D3 receptors (D3Rs) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms underlying these actions remain unclear. METHODS: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1R-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics, microdialysis, and behavioral assays (n≥8) to functionally characterize the roles of presynaptic versus postsynaptic D3Rs in cocaine and opioid actions. RESULTS: Our results revealed D3R expression in ∼20% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While D2R was expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3Rs from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked NAc dopamine release. Conversely, D3R deletion from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, D3R deletion from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. CONCLUSIONS: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. The mesolimbic D3Rs are critically involved in the actions of opioids but not cocaine.

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking.

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson's-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.