AT1R in Central Nervous System Disorders: Unveiling Novel Mechanisms and Therapeutic Avenues for Addiction

Although the angiotensin II type 1 receptor (AT1R), a pivotal component of the renin-angiotensin system (RAS), is associated with cardiovascular and renal homeostasis, burgeoning evidence implicates its critical role in neuropsychiatric disorders, particularly addiction. Beyond regulating haemodynamics, AT1R activation in the central nervous system (CNS) modulates neuroinflammatory cascades, dopaminergic signalling plasticity, and stress-responsive neural circuit processes central to addiction pathophysiology. Notably, preclinical studies reveal that AT1R blockade attenuates drug-seeking behaviours by normalizing mesolimbic dopamine dysregulation and reducing glutamatergic excitotoxicity in the nucleus accumbens. This review systematically integrates contemporary evidence elucidating the dual pathophysiological roles of AT1R in CNS disorders, with particular emphasis on neurodegenerative diseases and psychiatric conditions. Crucially, we delineate two mechanistically distinct yet interconnected functions of AT1R: (1) serving as a critical mediator of maladaptive neuroplasticity during protracted exposure to addictive substances and (2) functioning as a regulator of blood-brain barrier (BBB) integrity, thereby potentiating neurotoxicant infiltration in substance use disorders. Building upon these mechanistic insights, we propose a translational framework for repurposing clinically approved AT1R antagonists as novel pharmacotherapies targeting addiction-related neurocircuitry dysregulation. By bridging molecular insights with translational opportunities, this work positions AT1R as a novel therapeutic target to address unmet clinical needs in addiction.