TY - JOUR T1 - Zhx2 is a candidate gene underlying oxymorphone metabolite brain concentration associated with state-dependent oxycodone reward JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.122.001217 SP - JPET-AR-2022-001217 AU - Jacob A Beierle AU - Emily J Yao AU - Stanley I Goldstein AU - William B Lynch AU - Julia L Scotellaro AU - Anyaa A Shah AU - Katherine D Sena AU - Alyssa L Wong AU - Colton L Linnertz AU - Olga Averin AU - David E Moody AU - Christopher A. Reilly AU - Gary Peltz AU - Andrew Emili AU - Martin T Ferris AU - Camron D Bryant Y1 - 2022/01/01 UR - http://jpet.aspetjournals.org/content/early/2022/06/10/jpet.122.001217.abstract N2 - Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared to the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared to BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of CYP enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. Significance Statement Our findings show genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite following oxycodone administration, and reinforces the need for sex as a biological factor in pharmacogenomic studies. The co-occurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics. ER -