Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Abstract

The present study examined the influence of dexefaroxan, a potent and selective ␣ 2 -adrenoceptor antagonist, on cognitive performance in rodents. In young adult rats, dexefaroxan reversed the deficits induced by UK 14304 [5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine], scopolamine, and diazepam in a passive avoidance task. In this test, dexefaroxan also attenuated the spontaneous forgetting induced by a 15-week training-testing interval. Moreover, dexefaroxan, given immediately after training, increased the memory performance of rats trained with a weak electric footshock in the passive avoidance test, facilitated spatial memory processes in the Morris water maze task in rats, and increased the performance of mice in an object recognition test. Thus, dexefaroxan appears to have a promnesic effect in these tests by facilitating the processes of memory retention, rather than acquisition or other noncognitive influences. The facilitatory effects of dexefaroxan in young adult rats persisted even after a 21-to 25-day constant subcutaneous infusion by using osmotic minipumps, indicating that tolerance to the promnesic effect of the drug did not occur during this prolonged treatment interval. Furthermore, in the passive avoidance and Morris water maze tests, dexefaroxan ameliorated the age-related memory deficits of 24-month-old rats to a level that was comparable to that of young adult animals, and reversed the memory deficits induced by excitotoxin lesions of the nucleus basalis magnocellularis region. Together, these findings support a potential utility of dexefaroxan in the treatment of cognitive deficits occurring in Alzheimer's disease.

The Alpha2-Adrenoceptor Antagonist Dexefaroxan Enhances Hippocampal Neurogenesis by Increasing the Survival and Differentiation of New Granule Cells

“…Enhancement of the survival and plasticity of newborn neurons by pharmacological activation of the locus coeruleus-noradrenergic system may therefore provide a way to facilitate certain types of hippocampal learning and memory. Dexefaroxan has indeed been shown to improve the performance of rodents in tests of both short-and longterm memory, and to ameliorate the performance of old rats on the Morris water maze and passive avoidance tasks to the level of young adult animals (Chopin et al, 2002). Although the increased survival of newborn neurons may result in the functional improvement reported, acute effects of BDNF on synaptic activity in the hippocampus cannot be excluded.…”

Activation of α2 Adrenergic Receptors Suppresses Fear Conditioning: Expression of c-Fos and Phosphorylated CREB in Mouse Amygdala

“…Our results support the concept that the noradrenergic system influences the acquisition of auditory cued memory while alternatively influencing the consolidation of contextual memory. Attempts have been made to enhance memory by modulating the adrenergic system to affect memory with most of the attention focused on the use a 2 antagonists, such as yohimbine (O'Carroll et al, 1999), idazoxan (Coull et al, 1996), and dexefaroxan (Chopin et al, 2002). Unfortunately, yohimbine has been reported to increase anxiety in PTSD patients (Southwick et al, 1999b) and to enhance fear memory when infused into rat amygdala (Ferry et al, 1999a).…”

Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation

“…animals with lesions in cholinergic structures or animals treated with for instance scopolamine, then these drugs in general did mediate cognitive enhancement (e.g. Riekkinen et al 1991Riekkinen et al , 1996Yamazaki et al 1991;Riekkinen and Riekkinen 1994;Kojima et al 1997;Ogura et al 2000;Chopin et al 2002). However, it should be noted that in the cholinergic deficiency models, the effects of metrifonate, donepezil, tacrine and physostigmine on passive avoidance learning were found not only on acquisition but also on consolidation (e.g.…”

“…However, in a cholinergic (medial septum) lesion model, metrifonate improved the acquisition of passive avoidance learning (Ikonen et al 1999). Recently, tacrine has been tested in the object recognition task with mice, and it was found to improve consolidation (Chopin et al 2002). Physostigmine has only been tested in the passive avoidance task and showed a positive effect on acquisition (e.g.…”

“…Both compounds have also thoroughly been investigated in one-trial passive avoidance learning tasks in combination with deficiency models and were found to ameliorate the impaired avoidance performance (e.g. Riekkinen et al 1991;Itoh et al 1997;Kojima et al 1997;Bejar et al 1999;Ogura et al 2000;Chopin et al 2002;Tokita et al 2002). The passive avoidance task is a one-trial learning paradigm similar to the object recognition task.…”