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-hM(4)D) or stimulatory (G(s) coupled-rM(3)D) 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 hM(4)D 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 rM(3)D did not alter responding for methamphetamine, demonstrating specificity for hM(4)D-CNO interaction in increasing self-administration. Postmortem tissue analysis reveals that hM(4)D-CNO animals had reduced Fos immunoreactivity in the dorsal striatum compared to rM(3)D-CNO animals and DREADD naïve-CNO animals. Cellular mechanisms in the dorsal striatum in hM(4)D-CNO animals reveal enhanced expression of D1R and Ca(2+)/calmodulin-dependent kinase II (CaMKII). Conversely, rM(3)D-CNO animals had enhanced activity of extracellular signal-regulated kinase (Erk1/2) and Akt in the dorsal striatum, supporting rM(3)D-CNO interaction in these animals compared with drug naïve controls, DREADD naïve-CNO and hM(4)D-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.