Proton-Sensing Signaling in Substance Use Disorders: GPR4 and ASICs as an Emerging Frontier in Addiction Neurobiology

Substance use disorders (SUDs) involve drug-evoked adaptations in reward, stress, and relapse circuits. We propose that extracellular pH fluctuations may provide an additional, context-dependent regulatory signal. Neural activity, vesicle release, respiration, metabolism, lactate/proton transport, and vascular responses can produce local acidifying or alkalinizing changes whose direction and magnitude depend on compartment and buffering. Acid-sensing ion channels (ASICs) can respond rapidly to appropriate acidic excursions, whereas proton-sensing G protein-coupled receptors (GPCRs), including GPR4 and GPR68, may encode changes in ambient proton-dependent signaling over longer timescales. ASIC studies demonstrate effects on cocaine-related plasticity and behavior; global GPR4 deletion alters cocaine-induced locomotor responses and sensitization but does not identify the responsible cell population or establish a role in reinforcement or relapse. We critically examine the uncertain sign of synaptic pH transients, GPR65 and GPR132, astrocyte–neuron metabolic coupling, and potential human measurement strategies. We propose direct pH recording combined with circuit-resolved causal perturbations to test this two-arm model without presuming that drug exposure produces uniform acidosis.