NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.

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 M. 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 (IC = 8 M) than at resting (IC = 262 M) 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.

Background and Purpose l‐DOPA‐induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5‐HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5‐HT‐based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5‐HT antidyskinetic treatments. Experimental Approach Buspirone was studied using in vivo single‐unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6‐hydroxydopamine (6‐OHDA)‐lesioned or 6‐OHDA‐lesioned and l‐DOPA‐treated (6‐OHDA/l‐DOPA) rats. Key Results Local buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6‐OHDA‐lesioned rats (with or without l‐DOPA treatment), whereas 8‐OH‐DPAT, a full 5‐HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8‐OH‐DPAT markedly modified the low‐frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6‐OHDA‐lesioned rats but no effect in 6‐OHDA/l‐DOPA rats. In the 6‐OHDA/l‐DOPA group, increased 5‐HT transporter and decreased 5‐HT1A receptor expression was found. Conclusions and Implications The effects of buspirone in SNr are influenced by dopamine loss and l‐DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.

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