Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a robust, rapid-acting antidepressant whose molecular effects have not been fully elucidated. Phosphodiesterase-4 (PDE4), which terminates cyclic adenosine monophosphate (cAMP) activity, may underlie antidepressant response. In particular, previous studies found that whole brain binding of the positron emission tomography (PET) radioligand [11C](R)-rolipram to PDE4 was decreased in individuals with major depressive disorder; eight weeks of antidepressant treatment rescued this decrease in [11C](R)-rolipram binding. This study used [11C](R)-rolipram, which targets all PDE4 subtypes, and [18F]PF-06445974, which is preferential for PDE4B over PDE4D, to determine whether ketamine infusion could rapidly increase cAMP activity in rats (at 10 mg/kg) and rhesus macaques (at 0.5 mg/kg). Ketamine increased [11C](R)-rolipram binding to PDE4 in rats (mean standardized uptake value (SUV) increase=24% ± 14%, range=3%-42%, p = 0.004) and in monkeys (mean distribution volume (VT) increase=14% ± 2%, range=12%-16%, p = 0.003). Ketamine also increased [18F]PF-06445974 binding in monkeys within one hour of infusion (mean VT increase 28% ± 7%, range=16%-37%, p = 0.008). When [11C](S)-rolipram, which has no specific binding to PDE4, was used to control for the effects of ketamine on blood flow and radioligand delivery in rats, no consistent effects were observed for ketamine. Collectively, the results suggest that ketamine infusion rapidly increases cAMP activity and may be an underlying mechanism for ketamine's rapid antidepressant effects. These data support a common pathway for cAMP and antidepressant action and suggest that PDE4 inhibition, particularly PDE4B, may be an effective and rapid-acting antidepressant mechanism.