Cheryl Reed¹, Grant Moen¹, Sahana Srinivasan¹, Shauna Rakshe², Suzanne Fei², Jason Erk¹, Tamara Phillips^1,3

Selective breeding for methamphetamine (MA) intake identified a null mutation in the trace amine-associated receptor 1 (Taar1) gene that negates TAAR1 function and increases genetic risk for MA intake in mice. A knock-in (KI) was produced on an isogenic C57BL/6J background, replacing the reference Taar1⁺ allele with the mutant Taar1^m1J allele. Increased MA intake in Taar1^m1J mice was verified. Here, we examined the effects of Taar1^m1J on MA-induced locomotor stimulation and conditioned taste aversion (n=15-16 and 6-9 mice/genotype/sex/dose, respectively) and characterized the transcriptome using RNA-sequencing data from MA-naïve mice (n=12 mice/genotype/sex) for the nucleus accumbens, prefrontal cortex, and ventral midbrain (VMB). The allele replacement did not alter MA-induced locomotor stimulation but attenuated MA-induced conditioned taste aversion (2 and 4 mg/kg MA; ps<0.001). Transcriptome analysis identified 1,326 differentially expressed genes (p<0.05), with 56 shared across brain regions. QIAGEN Ingenuity Pathway Analysis identified 265 enriched pathways, three of which included Taar1 (NF1 RAS Signaling Pathway, Phagosome formation, and Cellular Effects of Sildenafil). Weighted gene co-expression network analysis identified modules that differed (ps < 0.05) between Taar1 genotypes only in the VMB. Enriched gene ontology processes included: neuron ensheathment, myelination, glial cells, synaptic transmission, synaptic assembly, synaptic regulation, and neural development/regulation. Nineteen hub genes were identified including: Litaf, Trp53inp2, Insc, Gltp, Tmprss5, Gpr37, Car14, Ids, Lonrf2, Camsap2, Dzank1, Ppp1r9a, Arhgap20, Cmtm4, Sox10, Fa2h, Plekhg3, Tmem63a, and Jup. The underlined hub genes were previously found to be involved in MA-related behavioral and molecular changes. These processes may underlie TAAR1-mediated MA aversion impacting MA intake.

1. Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR, United States

2. Bioinformatics & Biostatistics Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United States

3. VA Portland Health Care System, Portland, OR, United States

Support provided by NIH/NIDA R01DA046081, R01DA057420, and U01DA041579; NIH/OD P51OD011092 and S10OD034224; Department of Veterans Affairs IK6 BX006342