Targeting Substantia Nigra through Oxytocin Receptors

TARGETING SUBSTANTIA NIGRA THROUGH OXYTOCIN RECEPTORS. Recent studies suggest a role of oxytocin in the control of locomotor activity. Interestingly, studies in the brain of rats and humans have shown that oxytocinergic nerve endings and receptors are present in the substantia nigra (SN), a brain area of basal ganglia circuitry. Accordingly, a loss of nigrostriatal dopaminergic neurons causes Parkinson disease, characterized by severe motor disturbances including hypomotility. In order to prove a functional oxytocin-dopamine interaction in the SN, the effect of the injection into the SN of the novel cytotoxin Oxytocin-Saporin (Oxy-SAP), which selectively destroys cells expressing oxytocin receptors, was studied in male rats. Male Sprague Dawley rats (n=24) were monolaterally or bilaterally injected into the SN with OxySAP or vehicle (PBS). Locomotor activity was assessed before and two and four weeks after injection (Digiscan Animal Activity Analyser). Immunohistochemistry was used to verify the presence and extent of the lesion in the dopaminergic neurons and to investigate any modifications in the GABAergic and glutamatergic systems. After four weeks, animals bilaterally injected with Oxy-SAP showed a significant increase in horizontal locomotor activity (50-60%) and in vertical locomotor activity as well, when compared to PBS-injected rats. In Oxy-SAP injected animals, Tyrosine Hydroxylase (TH) immunoreactivity (-ir) was reduced in SN compacta somas and dendrites coursing into the pars reticulata. TH-ir decrease was more pronounced in the areas of the SN adjacent to the injection site and less, although still present, in those further away from it. No evident variation in Glutamate Decarboxylase-ir was observed. Interestingly, preliminary results showed a reduction in SN vesicular glutamate transporters (VGluT1, VGluT2 and VGluT3)-ir, possibly correlated with the dopaminergic lesion extent, suggesting the potential induction of alterations also in the glutamatergic system. In particular, VGluT1-ir reduction was almost complete in SN reticulata and slightly less in the compacta, while VGluT2- and VGluT3-ir were reduced in both compacta and reticulata, with VGlut2 being the most affected. In line with these results, an increase in locomotor activity was also observed in rats with a loss of the nigrostriatal dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine, when antagonists of glutamatergic receptors were injected into the SN. In conclusion, oxytocin receptors in the SN seem to be involved in the control of dopaminergic and glutamatergic neurons but not of GABAergic neurons. Moreover, these results confirm the importance of the modulation of nigral glutamatergic transmission as a possible treatment of basal ganglia movement disorders.