Osmosensitive response of glutamate in the substantia nigra

Previous studies have suggested the increase of extracellular glutamate (GLU) in the substantia nigra (SN) as a cause of dopamine-cell degeneration (excitotoxicity) in Parkinson's disease (PD). However, the mechanisms involved in this increase remain unknown. The present work studied osmoregulation as a cause of GLU release in the SN. Microdialysis was used to change extracellular osmolarity, to administer drugs and to quantify the extracellular non-synaptic GLU (EnS-GLU). Two osmolarity modifications were performed, a moderate decrease (5%) resembling physiological modifications and a substantial decrease (≥ 20% decrease) similar to that observed under pathological conditions. Hypo-osmolarity induced a dose–response (285–80 mOsm) increase of EnS-GLU which was detected after small osmolarity modifications (15 mOsm) and which was very marked (> 1000%) after more intense osmolarity changes. This response disappeared after pre-treating rats with a P2 purinergic-receptor antagonist (pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid; 1 mM) suggesting ATP involvement in the osmosensitive EnS-GLU response. The EnS-GLU increase observed after administration of ATP (0.1–100 μM) and 2-methylthioadenosine triphosphate tetrasodium (P2-receptor agonist; 100 μM) and the lack of effects of adenosine administration (1 mM) suggest that the ATP action on P2 receptors is an amplificatory mechanism in the osmosensitive EnS-GLU response. The marked action of osmolarity on extracellular Glu suggests osmolarity regulation as a possible source for excitotoxicity in the SN.