PDE10A

Class

inhibitor

Phosphodiesterase 10A (PDE10A) is an enzyme that breaks down two intracellular second messengers, cyclic AMP and cyclic GMP, which relay signals from cell-surface receptors to downstream effectors inside the cell. PDE10A is expressed at unusually high density in the striatum, a brain region central to motor control and to the integration of cortical and dopaminergic signaling. By degrading cyclic nucleotides, PDE10A dampens signaling initiated by dopamine and glutamate receptors on striatal neurons. Inhibiting the enzyme raises intracellular cyclic AMP and cyclic GMP levels, thereby amplifying signaling through pathways implicated in reward processing, movement, and cognition. This rationale has made PDE10A inhibition a longstanding area of interest for conditions involving striatal circuit dysfunction, including schizophrenia, where abnormal dopaminergic and glutamatergic signaling are thought to underlie psychotic and cognitive symptoms, and Huntington's disease, in which striatal medium spiny neurons progressively degenerate. Because PDE10A is expressed almost exclusively in this circuit, inhibitors were designed with the aim of achieving centrally restricted, circuit-specific modulation rather than broad, systemic effects on cyclic nucleotide signaling elsewhere in the body.