Experience-dependent sex differences in the role of dorsal striatal dopamine D1 receptor activity in methamphetamine self-administration revealed by a novel TREND model.

BACKGROUNDThe role of dorsal striatal dopamine D1 receptor systems in the mechanism of methamphetamine self-administration (METH SA), and sex differences in this role, are unclear. We hypothesized that this role would be sex and METH experience-dependent. Because prior experience regulates subsequent effects of drugs, we developed a novel model to account for this interaction, termed the TREND model (Time-Related-Experience-Normalized-Dynamics) for drug SA analysis. We tested our hypothesis by comparing results from the new TREND model and the current model. METHODSFor model validation, we reanalyzed previous data (Job et al., 2020) with the aim of determining which model (current or TREND) was more effective as an analytical tool. We compared variables from each model with the effect of Clozapine-N-Oxide (CNO, chemogenetic ligand) on METH SA. We employed regression analysis, median split, ANOVA to see which could reveal sex and experience dependency of dorsal striatal dopamine D1 receptor system. RESULTSThe current model variables were unrelated to CNO effect, with no sex differences in these relationships. TREND model revealed new variables that were unrelated to current variables but related to CNO effect on METH in males and females, with sex differences in these relationships. TREND, but not the current model, detected sex differences when comparing males and females with prior high, but not low, behavioral response variables. CONCLUSIONSTREND model is more sensitive than the current model for detecting experience-dependent sex differences in the role of the dorsal striatal dopamine D1 receptor systems in the mechanism of METH SA.