INTRACEREBROVENTRICULAR ADMINISTRATION OF QUINOLINIC ACID INDUCES A SELECTIVE DECREASE OF INOSITOL(1,4,5)-TRISPHOSPHATE RECEPTOR IN RAT-BRAIN

[H-3]inositol(1,4,5)-trisphosphate (IP3) binding studies have shown de creased [H-3]IP3 binding to brain tissue in several neurodegenerative diseases, including Alzheimer's and Huntington's diseases. In addition , previous results obtained from brains of Alzheimer patients indicate d a reduction of IP3-receptor protein correlated to neuronal loss. The neurotoxic effect of the glutamate receptor agonist quinolinic acid ( QUIN) was therefore examined with respect to the level of IP3-receptor immunoreactivity in rat brain, Neuronal lesions were estimated with a ntibodies to marker proteins for striatal medium-sized spiny neurons ( dopamine- and cyclic AMP-regulated phosphoprotein, M-r 32,000; DARPP-3 2), synaptic vesicles (synaptophysin), mitochondria (phosphate-activat ed glutaminase; FAG) and glial cells (glial fibrillary acidic protein; GFAP). Injection of QUIN into rat neostriatum induced a massive loss of striatal medium-sized spiny neurons, and led to a comparable loss o f IP3-receptor and FAG immunoreactivity, suggesting a neuronal localis ation of both these proteins. In an effort to induce less pronounced e xcitotoxic damage, intracerebroventricular infusion of QUIN was perfor med. Following this lesion, the neostriatum showed a negligible loss o f DARPP-32 immunoreactivity (divided by 11 +/- 5%), but contained only 43 +/- 3% of IP3-receptor immunoreactivity levels compared to control s. In the hippocampus, cerebellum and entorhinal cortex, the IP3-recep tor loss was less pronounced. The decrease in the level of IP3-recepto r immunoreactivity appears to be selective with respect to the other p roteins studied, and the IP3-receptor thus shows extreme sensitivity t o QUIN neurotoxicity in the neostriatum. (C) 1998 Elsevier Science Ltd . All rights reserved.