α2-Adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat

Abstract

The cholinergic hypothesis of Alzheimer's disease (AD) has strongly influenced research on learning and memory over the last decade. However, there has been limited success treating AD dementia with cholinomimetics. Furthermore, there are indications that other neurotransmitter systems affected by this disease may be involved in cognitive processes. Animal studies have suggested that norepinephrine and acetylcholine may interact in learning and memory. The current experiments investigate this interaction in a step-down passive avoidance paradigm after coadministration of acetylcholinesterase inhibitors and alpha 2-adrenoceptor antagonists. Administration of acetylcholinesterase inhibitors heptylphysostigmine (0.625-5.0 mg/kg, IP), tacrine (2.5-10.0 mg/kg, PO), velnacrine (0.312-2.5 mg/kg, SC), and galanthamine (0.312-2.5 mg/kg IP) each enhanced retention of a passive avoidance response at selected moderate doses administered 30-60 min prior to training. The alpha 2-adrenoceptor antagonists idazoxan (0.312-2.5 mg/kg, IP), yohimbine (0.078-0.312 mg/kg, IP) and P86 7480 (0.156-0.625 mg/kg, IP) alone failed to enhance learning in this paradigm. Coadministration of a subthreshold dose of heptylphysostigmine (0.625 mg/kg, IP) with doses of idazoxan, yohimbine or P86 7480 enhanced passive avoidance learning. This synergistic interaction may represent effects of antagonism of presynaptic alpha 2-adrenoceptor since coadministration of heptylphysostigmine and the selective postsynaptic alpha 2-adrenoceptor antagonist SKF 104856 did not result in enhanced learning. Taken together these data suggest noradrenergic activation through pre-synaptic alpha 2-adrenoceptor blockade may potentiate cholinergic activity in the formation of a long-term memory trace. These observations may have implications for the treatment of AD with cholinergic and adrenergic agents.

The interactions between the cholinergic and catecholaminergic systems - focusing on memory and oxidative stress

“…Although, as previously mentioned, no studies have been found in which to be administered namely these 3 agonists in various combinations, there are studies that combine all three neurosystems [8,15], the results being similar and confirming those obtained by us. We especially should remind the study by Camacho et al [15], which used over 20 cholinergic and catecholaminergic agonists known at that time.…”

“…We especially should remind the study by Camacho et al [15], which used over 20 cholinergic and catecholaminergic agonists known at that time. The study did not, however, include pergolide, which began to be used for the various cognitive behavioral tests starting from the year of 2000.…”

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

“…In the object recognition task, administration of tacrine before the learning trial has recently been found to improve the memory performance (Moser et al 2002). The same tacrine treatment was also effective in the passive avoidance task (Camacho et al 1996), while administration immediately after the learning trial had no effect on the retention performance . These results of tacrine are in agreement with our metrifonate and donepezil data.…”

Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model

“…Dosages were chosen to ensure sufficient inhibition of ChE (and in case of galantamine, significant APL activity), and clinical relevance compared to human dosages based on dosage per kg of bodyweight and plasma levels (Fishkin et al 1993;Camacho et al 1996;Misztal et al 1996;Wang and Tang 1998;Bejar et al 1999). …”