Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP.
Translational psychiatry April 21, 2026 Paul A Parcon, Amanda Bardhoshi, Amanda Olsen-Dufour et al.
Ketamine, a rapid-acting antidepressant, increases cyclic adenosine monophosphate (cAMP) activity in the brain within an hour of infusion, likely by affecting phosphodiesterase-4 (PDE4), an enzyme that normally terminates cAMP signaling. In rats given 10 mg/kg ketamine, binding of a radioligand to PDE4 increased by a mean of 24% (range 3%–42%); in rhesus macaques given 0.5 mg/kg, binding increased by a mean of 14% (range 12%–16%). A radioligand selective for the PDE4B subtype showed a mean increase of 28% (range 16%–37%) in monkeys. Control experiments ruled out blood-flow effects. The findings suggest that boosting cAMP activity through PDE4 inhibition, particularly the PDE4B subtype, may underlie ketamine's rapid antidepressant effects and point to a common pathway for antidepressant action.