Synaptic mechanisms underlying reward seeking and compulsive drug use

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Project A: Pathway-specific depression of lateral inhibition by dopamine requires serotonin receptors in the nucleus accumbens. Dopamine modulation of nucleus accumbens (NAc) circuitry is central to theories of reward seeking and reinforcement learning. Despite decades of effort, the acute dopamine actions on the NAc microcircuitry remain puzzling. Here, we dissect out the direct actions of dopamine on lateral inhibition between medium spiny neurons (MSNs) in mouse brain slices and find that dopamine's acute actions on NAc lateral inhibition are pathway-specific. Dopamine potently and selectively depresses GABAergic transmission from presynaptic dopamine D2 receptor-expressing MSNs (D2-MSNs), while it potentiates transmission from presynaptic dopamine D1 receptor-expressing MSNs. To our surprise, presynaptic D2 receptors mediate only half of the depression induced by either dopamine neuron stimulation or dopamine application. Presynaptic serotonin 5-HT1b receptors are responsible for a significant component of dopamine-induced synaptic depression. Thus, this study clarifies the mechanistic understanding of dopamine actions in the NAc by showing pathway-specific modulation of lateral inhibition and the involvement of both D2 and 5-HT1b receptors in dopamine depression of D2-MSN synapses. Project B: Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in the striatum and biases against heavy and persistent alcohol drinking. Transition from hedonic alcohol drinking to problematic heavy drinking is a hallmark of alcohol use disorder (AUD). Long-lasting changes on the synaptic drive and activity of striatal neurons expressing dopamine D1 receptor (D1R) are known to be required for this transition, but the molecular mechanisms underlying this vulnerability are less understood. Here we report that the Parkinson's Disease-related protein Leucine-rich repeat kinase 2 (LRRK2) modulates D1R function within the striatonigral pathway and, by doing so, it regulates alcohol related behaviors and the transition to heavy and persistent alcohol drinking. Deletion of the Lrrk2 gene specifically from D1R-expressing striatal neurons potentiates D1R function at the cellular and synaptic level, enhancing alcohol stimulation and promoting heavy alcohol drinking that is insensitive to punishment. These findings identify a novel role for Lrrk2 function in the striatum and suggest that Lrrk2 limits D1R signaling and promotes resilience against heavy and persistent alcohol drinking. Project C: Low expression of dopamine D2 receptor drives GABA and cAMP-related gene networks in striatal indirect Medium Spiny Neurons. Background: Misused drugs hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Dopamine released in the striatum signals mainly via activation of D1 and D2 receptors. The expression of these receptors is segregated in the two main types of striatal MSNs. The balance of activity of D1 and D2 receptors is thought to be critical for how the striatum functions and controls behaviors. Diminished D2R function is associated with vulnerability for addiction and also with the pathophysiology of the disorder. Further, repeated exposure to stimulant drugs leads to maladaptive downregulation of striatal D2R. We previously reported that in mice low expression of striatal D2 receptors drives D1 receptor hypersensitivity, facilitating selected cocaine-induced behaviors. Here, we sought to identify gene expression changes specific to D2 receptor expressing neurons or iMSNs (indirect pathway Medium Spiny Neurons) consequent to genetically-driven low expression of Drd2. Methods: Transcriptome analysis was performed on mRNA purified from iMSNs of heterozygous and wild type mice for the Drd2 gene. The Translating Ribosome Affinity Purification (TRAP) system was used to conditionally target iMSNs. Follow-up experiments include postmortem brain tissue from humans with cocaine misuse history; and electrophysiology. Results: Genetically-driven low expression of Drd2 resulted in differential expression of genes involved in GABA and cAMP pathways, neural synapse formation and remodeling, modulation of the Na/K pump, lipid metabolism and inflammation. Differentially expressed genes were strongly enriched in Creb1 targets, suggesting Creb1 as an upstream regulator. Fxyd2, a subunit of the sodium potassium pump, showed a negative correlation with Drd2 expression. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. Conclusions: Genes networks implicated in cell-to-cell communication, more specifically synapse formation and regulation, are strongly impacted by deficiency in Drd2 expression within the same D2R expressing striatal neurons. Electrophysiological experiments show functional implications such as enhanced striatal inhibition, and together with our previously published work, they indicate that low striatal D2R expression is sufficient to significantly alter the state of the striatal microcircuitry.