Pharmacological alleviation of combined cholinergic/noradrenergic lesion-induced memory deficits in rats

Data derived from a number of preclinical studies examining the effects of combined cholinergic and noradrenergic lesions in a rat model of Alzheimer's disease are reviewed. Results from these studies indicated that a nucleus basalis of Meynert (nbM) lesion combined with a lesion of the ascending noradrenergic bundle (ANB) did not exacerbate 72-h passive avoidance retention deficits beyond the degree of impairment produced by nbM lesions alone. However, the addition of an ANB lesion did block the efficacy of two choiinomimetics (physostigmine and oxotremorine) to reverse the lesion-induced memory impairment. Memory in combined lesioned rats was restored when cholinomimetic therapy was administered in combination with low doses of clonidine. Studies investigating a number of Hoechst-Roussel Pharmaceuticals compounds have produced memory-enhancing effects in animals prepared with combined nbM/ANB lesions without the need for clonidine supplementation. These compounds include P128, P86-7493, and P87-8184. Moreover, these compounds have also been shown to be effective in reversing passive avoidance memory deficits in animals with nbM lesions and treated with the noradrenergic toxin DSP-4. Implications for pharmacotherapeutic approaches for the treatment of Alzheimer's disease are discussed.