P.3.e.009 Cognitive enhancement in schizophrenia: the role of dopamine and noradrenaline in the prefrontal cortex

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The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 μg kg−1 or 1500 μg kg−1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300–2000 μg kg−1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 μg kg−1, but not 300 μg kg−1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 μg kg−1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 μg kg−1, but not 500 μg kg−1, slightly ameliorated the scopolamine-induced (200 μg kg−1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 μg kg−1 or St-587 at doses 500 μg kg−1 or 1500 μg kg−1 did not have any significant influence on the scopolamine-induced (200 μg kg−1) increase of swimming speed. Furthermore, d-cycloserine at the dose of 300 μg kg−1 but not 1000 or 3000 μg kg−1 reversed the scopolamine (200 μg kg−1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that d-cycloserine may be effective in alleviating states of central cholinergic hypofunction.