Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC

Abstract

As a highly addictive psychostimulant drug, paternal methamphetamine (METH) exposure enhances the risk of developing addiction to drugs in descendants, however the underlying mechanism remains unclear. Medial prefrontal cortex (mPFC) is a key brain region that implicated in susceptibility to drugs. Here, male adult mice were exposed to METH for 30 days, followed by mating with naive female mice to create the first-generation (F1) mice. In METH-sired mice, baseline levels of c-Fos were decreased but β1-adrenergic receptor (ADRB1) were increased in mPFC by paternal METH exposure. Trained with subthreshold-dosed administration of METH, METH-sired mice exhibited significant METH-preferred behaviors, accompanied with higher levels of c-Fos, ADRB1 and dendritic spines density in mPFC. Importantly, local blocking ADRB1 activity or specific knockdown of ADRB1 on excitatory neurons of mPFC, both efficiently inhibited METH-preferred behaviors in METH-sired mice. In parallel, levels of p-ERK1/2 and ΔFosB, as well as dendritic spine density were reduced by knocking-down mPFC ADRB1 in METH-sired mice. Collectively, these findings suggested that targeting ADRB1 signals in mPFC may represent a promising therapeutic strategy for preventing drug addiction, particularly in progeny with a history of paternal drugs exposure.