Elevation of met-enkephalin-like immunoreactivity in the rat striatum and globus pallidus following the focal injection of excitotoxins

Abstract

The present study examined the effects of excitotoxins which activate distinct excitatory amino acid (EAA) receptor subtypes on the levels of Methionine-enkephalin-like immunoreactivity (ME-i.r.) in the striatum and globus pallidus, with a view to developing a model of the striatopallidal enkephalin deficit that prevails in Huntington's disease (HD). Each of the 4 excitotoxins, N-methyl- d-aspartate (NMDA, 50–150 nmol), quisqualate (QUIS, 26.5–102 nmol), kainate (KA, 0.5–7 nmol) and quinolinate (QUIN, 18–288 nmol), were unilaterally infused into the right striatum under halothane anaesthesia. Seven days after the injection, levels of ME-i.r. in the ipsilateral and contralateral striatum or globus pallidus were measured by radioimmunoassay (RIA). Injection of each of the 4 excitotoxins produced dose-related and bilateral elevations in ME-i.r. in both brain regions. Generally, the oxcitotoxin-induced contralateral response mirrored that on the ipselateral side and the globus pallidus showed a greater change in ME-i.r. levels than did the striatum. The rank order of apparent efficacy for these 4 agents, based on the magnitude of the maximal effect produced by the excitotoxin, was QUIN=KA>NMDA=QUIS. In contrast, the rank order of apparent potency, based on the doses producing a maximal effect, was KA>QUIN>QUIN>NMDA. Histological examination of brain sections revealed that in all cases of excitotoxin injection, the dose producing a maximal increase in ME-i.r. was associated with tissue damage in the injection area. However, no tissue damage was apparent in the globus pallidus or the contralateral striatum. To determine the involvement of EAA receptors in the observed elevations of ME-i.r., the action of 3 EAA antagonists was evaluated in co-injection experiments. Kynurenate (KYN), but not CNQX, antagonized the actions of QUIS on pallidal ME-i.r. levels. Both KYN and CPP, a potent NMDA receptor antagonist, blocked the effect of QUIN. The possibility that contralateral changes in the striatum or globus pallidus were due to mobilization of an endogenous EAA was investigated by injection of CPP into the striatum contralateral to the QUIN infusion. This injection of CPP (1.8–3.6 nmol) did not block the QUIN-induced contralateral response, but reduced the elevation in ME-i.r. in the ipsilateral pallidum. Although the excitotoxin-induced changes in ME-i.r. levels do not appear to correspond to the enkephalin deficit seen in HD, such a deficit may be discernible in different parameters of enkephalinergic cell function. Several possible mechanisms contributing to the excitotoxin-induced elevations in ME-i.r. are discussed.