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

The dorsal striatum is important for the development of drug addiction; however, the role of dopamine D1 receptor (D1R) expressing medium-sized spiny striatonigral (direct pathway) neurons (D1-MSNs) in regulating excessive methamphetamine intake remains elusive. Here we seek to determine if modulating D1-MSNs in the dorsal striatum alters methamphetamine self-administration in animals that have demonstrated escalation of self-administration. A viral vector-mediated approach was used to induce expression of the inhibitory (G_i coupled-hM₄D) or stimulatory (G_s coupled-rM₃D) designer receptors exclusively activated by designer drugs (DREADDs) engineered to specifically respond to the exogenous ligand clozapine-N-oxide (CNO) selectively in D1-MSNs in the dorsal striatum. CNO in animals expressing hM₄D increased responding for methamphetamine compared to vehicle in a within subject treatment paradigm. CNO in animals that did not express DREADDs (DREADD naïve-CNO) or expressed rM₃D did not alter responding for methamphetamine, demonstrating specificity for hM₄D-CNO interaction in increasing self-administration. Postmortem tissue analysis reveals that hM₄D-CNO animals had reduced Fos immunoreactivity in the dorsal striatum compared to rM₃D-CNO animals and DREADD naïve-CNO animals. Cellular mechanisms in the dorsal striatum in hM₄D-CNO animals reveal enhanced expression of D1R and Ca²⁺/calmodulin-dependent kinase II (CaMKII). Conversely, rM₃D-CNO animals had enhanced activity of extracellular signal-regulated kinase (Erk1/2) and Akt in the dorsal striatum, supporting rM₃D-CNO interaction in these animals compared with drug naïve controls, DREADD naïve-CNO and hM₄D-CNO animals. Our studies indicate that transient inhibition of D1-MSNs-mediated strengthening of methamphetamine addiction-like behavior is associated with cellular adaptations that support dysfunctional dopamine signaling in the dorsal striatum.