Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving mPFC ADRB1CaMKII

Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Here, male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 mice were subjected to conditioned place preference (CPP) test to evaluate sensitivity to METH. Subthreshold dose of METH, that is insufficient to induce CPP normally, were used in F1 mice (METHF1). We found that only METH-sired male F1, but neither METH-sired female F1 nor saline (SAL)-sired F1 mice acquired METHF1-induced CPP, indicating that paternal METH exposure increase sensitivity to METH in male F1 mice. Compared with SAL-sired male F1, we found that CaMKII-positive neurons activity was normal without METHF1, but strongly evoked after METHF1 treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher β1-adrenergic receptor (ADRB1) levels without METHF1, which was kept at higher levels after METHF1 treatment in mPFC. Either blocking ADRB1 with betaxolol, or knocking-down ADRB1 on CaMKII-positive neurons (ADRB1CaMKII) efficiently reduced METHF1-evoked mPFC, and ultimately blocked METHF1-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. Collectively, our study identified a novel role of mPFC ADRB1CaMKII in the paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising target for predicting or treating susceptibility of drug addiction in offspring. Highlights Paternal methamphetamine (METH) exposure induces higher sensitivity to METH in male F1 during adulthood, accompanied with higher ADRB1 levels in mPFC. METH use in F1 (METHF1) triggers more mPFC CaMKII-positive neurons in METH-sired male F1 than that in saline-sired male F1. Blocking ADRB1 or knocking-down ADRB1 on CaMKII-positive neurons (ADRB1CaMKII) efficiently reduces METHF1-evoked mPFC activity, and ultimately attenuates paternal METH exposure-induced higher sensitivity to METH in male F1.