D3 receptor and β-Arrestin2 modulation of spiny projection neuron intrinsic excitability

The nucleus accumbens (NAc) is a critical node of the mesolimbic DA system that regulates drug-induced behaviors. Spiny projection neurons (SPNs) make up 95% of the neurons in the NAc, and are subdivided into two populations, D1 and D2 expressing. Each subpopulation also expresses D3 receptors, and μ opioid receptors, which have also been shown to be critical components in reward related behavior. Nucleus accumbens dopamine and μ receptors are G-protein coupled receptors that are coupled to β-Arrestin2 (βarr2), which is involved in receptor desensitization, but also activates signaling cascades independent of conventional G-protein dependent signaling. The purpose of my thesis work is to 1) Determine if inhibition of D3 receptors alters dopamine-induced changes in D1 or D2 SPN neuronal excitability and 2) uncover the role of βarr2 in dopamine- and morphine- induced excitability changes in D1 and D2 SPNs. In order to address these questions, I employed the use of pharmacology, slice electrophysiology, transgenic mouse models, and behavior assays.

I had found that D3 antagonism enhances dopamine-induced excitability in D1, but not D2 SPNs, suggesting that D3 receptors act to dampen neuronal excitability during periods of dopamine release. Next, I showed that βarr2 modulates dopamine and morphine -induced changes in excitability in D2, but not D1 SPNs, which suggests that βarr2 mediates cellular excitability in separate populations of neurons. Overall, this work demonstrates a unique and separate role for D3 receptors and βarr2 in modulating D1 and D2 SPNs cellular excitability.