beta-Adrenergic dysfunction exacerbates impairment of working memory induced by hippocampal NMDA receptor blockade in rats

To clarify the interactions between hippocampal glutamatergic and adrenergic systems in the working memory function of rats, the effects of hippocampal NMDA receptor blockade combined with noradrenaline depletion or alpha- and beta-adrenoceptor blockade on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the potent and competitive NMDA receptor antagonist(+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at a dose of 32 ng/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel gates at four choice points) in the working memory task, whereas the 3.2 ng/side dose of CPP did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg i.p. produced marked reductions in hippocampal and cortical noradrenaline contents, but it had no effect on working memory errors. Intrahippocampal administration of 3.2 ng/side CPP, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted rats. The alpha-adrenoceptor antagonist phentolamine (3.2 mg/kg i.p.) did not affect working memory errors whether administered alone or in combination with intrahippocampal CPP (3.2 ng/side). The beta-adrenoceptor antagonist propranolol(10 mg/kg i.p.) also had no effect on working memory errors. However, propranolol (10 mg/kg) produced a significant increase in working memory errors when administered together with intrahippocampal CPP (3.2 ng/side). These results suggest that hippocampal NMDA/beta-adrenergic interactions are involved in neural processes mediating working memory function of rats.