alpha(2)-Adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat

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 az-adrenoceptor since coadministration of heptylphysostigmine and the selective postsynaptic alpha(2)-adrenoceptor antagonist SKF104856 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.