β2AR as a target in methamphetamine addiction: Divergent mechanisms from TAAR1

Methamphetamine (METH) abuse poses a growing global health crisis, yet the molecular mechanisms underlying its addictive effects remain poorly understood. While METH is an established agonist of trace amine-associated receptor 1 (TAAR1), our study indicates β2-adrenergic receptor (β2AR) as a METH target, demonstrating its role in G_s-mediated cAMP signaling. Using cryo-electron microscopy and mutagenesis studies, we reveal the structural basis for METH's differential ligand efficacies and stereoselectivity at β2AR and TAAR1. We further investigated synaptic plasticity of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key neural substrate for reward learning, and demonstrate that β2AR inhibition via the selective antagonist zenidolol elevates GluA1-Ser831 phosphorylation and augments excitatory inputs onto D2-MSNs in the NAc shell. In contrast, TAAR1 activation fails to elicit these synaptic modifications. Taken together, structural, behavioral, and synaptic plasticity findings highlight β2AR as a pivotal mediator of METH addiction, providing a framework for targeted therapeutic development.