LM Raji1, S Saxena1, EA Duecker1, S Khanam1, BM Moore II2, MK Mulligan1

We compared behavioral and cortical transcriptional responses between sexes and genotypes to identify shared and unique pathways that play a role in tolerance to repeated THC (10 mg/kg, i.p.). C57BL/6J and DBA/2J mice of both sexes (n=4) were assigned to THC or vehicle (VEH). Following injection of VEH on day 0, mice received four consecutive daily injections of THC or VEH. THC initially induces antinociception, hypomobility, and hypothermia and these traits were quantified daily to track tolerance. On the 5^th day, cortex was collected and RNA extracted for RNAseq analysis. DSeq2 and GSEA were used to identify differentially expressed genes (DEGs) within groups due to treatment and to identify enriched pathways.

Behavioral trait PCA revealed weaker contributions of treatment-associated PCs over exposure days. More treatment DEGs (p<0.05) were detected in C57BL/6J (1,291) and DBA/2J (786) females relative to C57BL/6J (216) and DBA/2J (517) males. There was little overlap between groups. Comparison of top enriched genes and pathways between groups revealed shared and unique responses. Ribosome and protein translation was upregulated in C57BL/6J and male DBA/2J but downregulated in female DBA/2J. Mitochondrial metabolic processes were upregulated in C57BL/6 and downregulated in female DBA/2J. Cellular components of neurons were downregulated in C57BL/6. ERK, GTPase, glucocorticoid receptor, and TNFA-NFKB signaling was upregulated in females or DBA/2J females and downregulated in males or C57BL/6 males. Vascular processes were downregulated in males. Identification of individual and shared mechanisms underlying drug tolerance is important for treatment efficacy and understanding the progression towards problem use and addiction.

1Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA, 2Deparment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA

Funding Support: NIH/NIDA R01DA056523