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 in fluenced research on learning and memory over the last decade. However , there has been limited success treating AD dementia with cholinomime tics. Furthermore, there are indications that other neurotransmitter s ystems 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 investiga te this interaction in a step-down passive avoidance paradigm after co administration of acetylcholinesterase inhibitors and alpha(2)-adrenoc eptor antagonists. Administration of acetylcholinesterase inhibitors h eptylphysostigmine (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 select ed 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 fai led to enhance learning in this paradigm. Coadministration of a subthr eshold dose of heptylphysostigmine (0.625 mg/kg, IP) with doses of ida zoxan, yohimbine or P86 7480 enhanced passive avoidance learning. This synergistic interaction may represent effects of antagonism of presyn aptic az-adrenoceptor since coadministration of heptylphysostigmine an d the selective postsynaptic alpha(2)-adrenoceptor antagonist SKF10485 6 did not result in enhanced learning. Taken together these data sugge st noradrenergic activation through pre-synaptic alpha(2)-adrenoceptor blockade may potentiate cholinergic activity in the formation of a lo ng-term memory trace. These observations may have implications for the treatment of AD with cholinergic and adrenergic agents.