Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain. They differ in structural, pharmacological and biochemical properties, as well as in localization and internalization mechanisms. Our results indicate that disease-associated mutant G2019S LRRK2 impairs DRD1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect receptor turnover by decreasing the rate of DRD2 trafficking from the Golgi complex to the cell membrane. Collectively, our findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking. These findings have important implications for the complex role that LRRK2 plays in neuronal physiology and the possible pathological mechanisms that may lead to neuronal death in PD.

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.

D-aspartate levels in the brain are regulated by the catabolic enzyme D-aspartate oxidase (DDO). D-aspartate activates NMDA receptors, and influences brain connectivity and behaviors relevant to schizophrenia in animal models. In addition, recent evidence reported a significant reduction of D-aspartate levels in the post-mortem brain of schizophrenia-affected patients, associated to higher DDO activity. In the present work, microdialysis experiments in freely moving mice revealed that exogenously administered D-aspartate efficiently cross the blood brain barrier and stimulates L-glutamate efflux in the prefrontal cortex (PFC). Consistently, D-aspartate was able to evoke L-glutamate release in a preparation of cortical synaptosomes through presynaptic stimulation of NMDA, mGlu5 and AMPA/kainate receptors. In support of a potential therapeutic relevance of D-aspartate metabolism in schizophrenia, in vitro enzymatic assays revealed that the second-generation antipsychotic olanzapine, differently to clozapine, chlorpromazine, haloperidol, bupropion, fluoxetine and amitriptyline, inhibits the human DDO activity. In line with in vitro evidence, chronic systemic administration of olanzapine induces a significant extracellular release of D-aspartate and L-glutamate in the PFC of freely moving mice, which is suppressed in Ddo knockout animals. These results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.

Mutations in leucine‐rich repeat kinase 2 ( LRRK 2 ) gene have been pathogenically linked to Parkinson's disease, and pharmacological inhibition of LRRK 2 is being pursued to tackle nigro‐striatal dopaminergic neurodegeneration. However, LRRK 2 kinase inhibitors may have manifold actions, affecting not only pathological mechanisms in dopaminergic neurons but also physiological functions in nondopaminergic neurons. Therefore, we investigated whether LRRK 2 kinase inhibitors differentially modulate dopamine and glutamate release from the mouse striatum and cerebral cortex. Spontaneous and KC l‐evoked [ 3 H]‐dopamine and glutamate release from superfused synaptosomes obtained from wild‐type and LRRK 2 knock‐out, kinase‐dead or G2019S knock‐in mice was measured. Two structurally unrelated inhibitors, LRRK 2‐ IN ‐1 and GSK 2578215A, were tested. LRRK 2, phosphoSerine1292 and phosphoSerine935 LRRK 2 levels were measured in all genotypes, and target engagement was evaluated by monitoring phosphoSerine935 LRRK 2. LRRK 2‐ IN ‐1 inhibited striatal glutamate but not dopamine release; GSK 2578215A inhibited striatal dopamine and cortical glutamate but enhanced striatal glutamate release. LRRK 2‐ IN ‐1 reduced striatal and cortical phosphoSerine935 levels whereas GSK 2578215A inhibited only the former. Neither LRRK 2 inhibitor affected neurotransmitter release in LRRK 2 knock‐out and kinase‐dead mice; however, they facilitated dopamine without affecting striatal glutamate in G2019S knock‐in mice. GSK 2578215A inhibited cortical glutamate release in G2019S knock‐in mice. We conclude that LRRK 2‐ IN ‐1 and GSK 2578215A modulate exocytosis by blocking LRRK 2 kinase activity, although their effects vary depending on the nerve terminal examined. The G2019S mutation unravels a dopamine‐promoting action of LRRK 2 inhibitors while blunting their effects on glutamate release, which highlights their positive potential for the treatment of PD , especially of LRRK 2 mutation carriers.