UC San Diego

The dorsal striatum is important for the development of drug addiction; However, the role of dorsal striatal dopamine D1 receptor (D1R) expressing medium-sized spiny neurons (MSNs) in regulating excessive methamphetamine (Meth) intake remains elusive. Here we seek to determine if reducing D1R expression in the dorsal striatum via RNA interference alters Meth self-administration. A viral vector-mediated approach was used to overexpress short hairpin RNA against D1Rs in the dorsal striatum. Dorsal striatal D1R knockdown increased active lever responses for Meth during a fixed-ratio (FR1) extended access paradigm compared to D1R-intact controls. Knocking down dorsal striatal D1Rs also produced a vertical and rightward shift in a self-administration dose-response paradigm. WB analysis revealed that dorsal striatal D1R knockdown (D1RshRNA) animals exhibit a reduction in D1R, PSD-95, and MAPK-1 expression in the dorsal striatum. Sucrose density gradient fractionation followed by semi-quantitative analysis of relative expression of proteins in subcellular membrane fractions demonstrated a redistribution of synaptic scaffolding proteins to membrane lipid raft (MLR) fractions in Meth-taking animals when compared to Meth-naïve animals. This redistribution occurred regardless of D1R knockdown. Our work indicates that reduced D1R expression-mediated enhancement of Meth addiction-like behaviors is associated with cellular adaptations that support dysfunctional dopamine signaling in the dorsal striatum.