Quinolinic acid elevates striatal and pallidal met-enkephalin levels: the role of enkephalin synthesis and release

Abstract

Huntington's chorea (HC) is characterized, in part, by a substantial deficit in the striatal and pallidal enkephalin levels. Recently, an attempt was made to replicate this deficit by focally injecting quinolinic acid (QUIN), an excitotoxin, into the rat striatum. However, at 7 days post-injection, QUIN produced a dose-related and bilateral increase in the striatal and pallidal levels of met-enkephalin-like immunoreactivity (ME-i.r.), an effect which was attenuated in the presence of excitatory amino acid (EAA) receptor antagonists. In the present study, the action of QUIN was investigated further. To determine whether the QUIN (72 nmol)-induced elevations in ME-i.r. reflected the enhanced synthesis of the peptide, the striatal levels of proenkephalin mRNA were assayed 7 days following a unilateral injection of QUIN into the rat striatum. QUIN significantly depleted (50%) the proenkephalin mRNA level in the injected, but not the contralateral striatum when compared to that in the saline-injected animals. To determine whether the QUIN-induced increases in ME-i.r. were due to an impaired release of the peptide, the release of ME-i.r. from the striatal or pallidal slices obtained from animals 7 days after a saline- or QUIN-injection, was measured. The 30 mM K +-stimulated ME-i.r. release from the saline-injected and contralateral striatum represented an 8-fold increase above the spontaneous release level, while this stimulus induced a 6-fold increase in the ME-i.r. release from both the QUIN-injected and contralateral striatum. In the globus pallidus ipsilateral and contralateral to the saline-injection, 30 mM K + produced a 14- and an 18-fold increase in the ME-i.r. release, respectively. Similarly, stimulation of the ipsilateral and contralateral globus pallidus from the QUIN-injected rats resulted in - and a .5-fold increase in the ME-i.r. release, respectively. The K +-evoked release responses observed in the QUIN-injected animals did not differ from those observed in the saline-injected animals. To determine whether the QUIN-induced changes in the ME-i.r. were time-dependent, the striatal and pallidal ME-i.r. levels were measured in rats sacrificed at different times (2, 6, 12, 24, 48 h and 4, 7 and 14 days) following an intrastriatal QUIN-injection. QUIN produced a time-dependent increase in the striatal and the pallidal ME-i.r. levels. The peak effect, observed in both brain regions at 7 days following the QUIN-injection, represented increase in the striatal and the pallidal ME-i.r. levels of 200% and 255%, respectively, when compared to saline-treated control animals. Thus, the intrastriatal injection of QUIN produced a bilateral and time-dependent elevation in the striatal and the pallidal ME-i.r. levels, an effect not associated with an increase in the striatal proenkephalin mRNA level or an impared release of the peptide. Although the QUIN-induced increase in the striatal and the pallidal ME-i.r. do not appear to resemble the enkephalin deficit associated with a progressed stage of HC, they may more closely model the changes in enkephalin observed in the presymptomatic stages of the disease.