Safinamide has been recently approved as an add-on to levodopa therapy for 
Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks 
sodium channels and modulates glutamate (Glu) release in vitro. Since this 
property might contribute to the therapeutic action of the drug, we undertook 
the present study to investigate whether safinamide inhibits Glu release also in 
vivo and whether this effect is consistent across different brain areas and is 
selective for glutamatergic neurons. To this aim, in vivo microdialysis was used 
to monitor the spontaneous and veratridine-induced Glu and GABA release in the 
hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide 
were measured as well. To shed light on the mechanisms underlying the effect of 
safinamide, sodium currents were measured by patch-clamp recording in rat 
cortical neurons. Safinamide maximally inhibited the veratridine-induced Glu and 
GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations 
of 1.89-1.37 µM. This dose attenuated veratridine-stimulated Glu (but not GABA) 
release in subthalamic nucleus, globus pallidus, and substantia nigra 
reticulata, but not in striatum. Safinamide was ineffective on spontaneous 
neurotransmitter release. In vitro, safinamide inhibited sodium channels, 
showing a greater affinity at depolarized (IC50 = 8 µM) than at resting (IC50 = 
262 µM) potentials. We conclude that safinamide inhibits in vivo Glu release 
from stimulated nerve terminals, likely via blockade of sodium channels at 
subpopulations of neurons with specific firing patterns. These data are 
consistent with the anticonvulsant and antiparkinsonian actions of safinamide 
and provide support for the nondopaminergic mechanism of its action.