Role of GPR55 in glutamatergic and dopaminergic signaling: A review of preclinical evidence in neuropsychiatric disorders.

G protein-coupled receptor 55 (GPR55) has gained increasing attention for its involvement in various neuropsychiatric disorders. Emerging evidence highlights the critical role of this receptor in modulating brain functions through complex interactions with glutamate and dopamine neurotransmitters. Recent studies suggest that GPR55 is involved in key processes, including synaptic plasticity and reward signaling. Moreover, central GPR55 participated in the pathophysiology of neuropsychiatric conditions such as schizophrenia, depression, anxiety disorders, and addiction. This review aims to provide the current understanding of GPR55, focusing on its molecular and cellular mechanisms, its interactions with glutamatergic and dopaminergic systems, and its potential as a therapeutic target. By exploring the role of GPR55 in regulating neuronal excitability, synaptic dynamics, and brain reward circuitry, we propose GPR55 as a novel and integrative player in the complex network of neurotransmission implicated in neuropsychiatric diseases. Furthermore, we discuss the challenges and opportunities associated with targeting GPR55 for therapeutic intervention in neuropsychiatric conditions that currently have limited therapeutic options. SIGNIFICANCE STATEMENT: This review highlights G protein-coupled receptor 55 (GPR55) as a critical modulator of glutamatergic and dopaminergic signaling, influencing synaptic plasticity and reward processing. Its involvement across multiple neuropsychiatric disorders positions GPR55 as a promising target for developing new therapeutic strategies.