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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 micrograms kg-1 or 1500 micrograms kg-1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300-2000 micrograms kg-1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 micrograms kg-1, but not 300 micrograms kg-1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 micrograms kg-1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 micrograms kg-1, but not 500 micrograms kg-1, slightly ameliorated the scopolamine-induced (200 micrograms kg-1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 micrograms kg-1 or St-587 at doses 500 micrograms kg-1 or 1500 micrograms kg-1 did not have any significant influence on the scopolamine-induced (200 micrograms kg-1) increase of swimming speed. Furthermore, D-cycloserine at the dose of 300 micrograms kg-1 but not 1000 or 3000 micrograms kg-1 reversed the scopolamine (200 micrograms 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.

Background: Cerebral ischemia induces a massive release of norepinephrine associated with neuronal death in the brain. It has been demonstrated that alpha2-adrenoceptor agonists decrease the release and turnover of noradrenaline, and this might prove advantageous in counteracting the neurodegeneration in ischemic brain. Therefore, in the present study, the authors tested whether dexmedetomidine, a selective alpha2-receptor agonist, has neuroprotective effects in a gerbil transient global ischemia model., Methods: Ischemia was induced by bilateral carotid occlusion for 5 min in diethylether-anesthetized normothermic gerbils. Dexmedetomidine was administered subcutaneously in four different treatment paradigms (6-8 animals/group): 3 or 30 microg/kg 30 min before and thereafter at 3, 12, 24, and 48 h after the occlusion, or 3 or 30 microg/kg at 3, 12, 24, and 48 h after the occlusion. Control animals were subjected to forebrain ischemia but received only saline injections. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in the CA1 and CA3 regions of the hippocampus and in the hilus of the dentate gyrus was evaluated in silver-stained 60-microm coronal sections., Results: Compared with saline-treated ischemic animals, dexmedetomidine at a dose of 3 microg/kg given before and continued after the induction of ischemia reduced the number of damaged neurons in the CA3 area (2 +/- 3 vs. 17 +/- 20 degenerated neurons/mm2; P < 0.05). Also in the dentate hilus, the number of damaged neurons was reduced by dexmedetomidine (3 microg/kg) given before and continued after ischemia (5 +/- 7 vs. 56 +/- 42 degenerated neurons/mm2; P < 0.01)., Conclusions: The present data demonstrate that dexmedetomidine effectively prevents delayed neuronal death in CA3 area and in the dentate hilus in gerbil hippocampus when the management is started before the onset of ischemia and continued for 48 h after reperfusion. Inhibition of ischemia-induced norepinephrine release may be associated with neuroprotection by dexmedetomidine.

The aim of the present study was to investigate whether the activation of alpha-1 adrenergic receptors can influence intermediate-term memory. Therefore, the effects of ST 587 (30 or 100 micrograms/kg), a putative alpha-1 agonist, on the retention of the radial arm task using non-matching to sample with a 4-h delay were investigated in rats. The results indicated that the administration of ST 587 (100 micrograms/kg) before a sampling phase increased the time to complete the sampling phase which was due to an increased number of errors of repetition (regarded as working memory errors) and a reduced number of arms visited in a given time (regarded as behavioral activity). However, this treatment increased the number of correct choices before the first error during the retention phase in this task. Since we were also interested in investigating the role of NMDA receptors in memory encoding, we investigated whether NMDA receptor modulation by d-cycloserine (1 or 10 mg/kg), a partial agonist of the glycine site on the NMDA receptor, had any influence on the performance of rats in this task. The results indicated that d-cycloserine (10 mg/kg) given before the sampling phase did not influence the performance of rats during the sampling phase, but it did improve their choice accuracy during the retention phase of this task. These data suggest that the systemic administration of either an alpha-1 agonist or an indirect agonist of NMDA receptors can facilitate intermediate-term retention of spatial information.

The present experiments were designed 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 passive avoidance performance. Pretraining administration of scopolamine, a muscarinic antagonist, markedly impaired the acquisition of water maze task (a hidden platform version) as well as retention of this task. The drug also impaired slightly navigation to a visible platform. Pretraining subcutaneous administration of St-587 (alpha-1 agonist) at 2000 micrograms/kg slightly improved the water maze navigation to a hidden platform in control rats, but its effect was not augmented in scopolamine-treated rats. Pretraining administration of prazosin (alpha-1 antagonist) 1000 micrograms/kg or 2000 micrograms/kg did not significantly potentiate the scopolamine (muscarinic cholinergic antagonist)-induced (doses 200 micrograms/kg and 100 micrograms/kg, pretraining intraperitoneal injection) deficit in water maze navigation. Pretraining administration of prazosin at doses 1000 micrograms/kg and 2000 micrograms/kg or St-587 at doses 1000 micrograms/kg and 2000 micrograms/kg did not have any significant influence on scopolamine-induced (200 micrograms/kg or 400 micrograms/kg) disruption in passive avoidance performance. These findings suggest that alpha-1 adrenergic mechanisms do not participate or are not the most important component of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. The analysis of results indicates that activation of alpha-1 adrenoceptors might facilitate the acquisition of water maze task in its initial phase, for instance, switching from wall hugging strategy to an active exploration strategy. Furthermore, the present data suggest that muscarinic cholinergic blockade may affect both mnemonic and nonmnemonic processes in rats.

alpha 2-Adrenoceptors are known to be involved in a variety of physiological functions and pathological conditions, including epilepsy and the extent of excitotoxin-induced cell death. In this study we evaluated whether selective alpha 2-adrenergic drugs can modulate the release of neurotransmitter amino acids. The effect of the alpha 2-adrenoceptor agonist dexmedetomidine (5 micrograms/kg, s.c.) and the alpha 2-adrenoceptor antagonist atipamezole (0.1 mg/kg and 1 mg/kg, s.c.) on the release of extracellular glutamate, aspartate and gamma-aminobutyric acid (GABA) was studied with microdialysis in the hippocampus of freely moving rats under basal and K(+)-evoked conditions. Atipamezole (1 mg/kg) decreased K(+)-evoked glutamate efflux by 30% compared to the control group (P < 0.05) but did not affect significantly the effluxes of aspartate and GABA. Dexmedetomidine and the lower dose of atipamezole (0.1 mg/kg) did not significantly alter the evoked overflow of amino acids. The results suggest that alpha 2-adrenergic drugs have only modest effects on the K(+)-stimulated overflow of extracellular neurotransmitter amino acids in rat hippocampus.