INTERACTIONS BETWEEN A NOVEL CHOLINERGIC ION-CHANNEL AGONIST, SIB-1765F AND L-DOPA IN THE RESERPINE MODEL OF PARKINSONS-DISEASE IN RATS

SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was teste d for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA a nd its effects were compared to those of nicotine, d-amphetamine and a mantadine in the same conditions. Consistent with previous reports, re serpine-induced hypolocomotion was reversed by L-DOPA (plus benserazid e), d-amphetamine and amantadine in a dose-dependent manner and the ef fect of L-DOPA in reserpine-treated rats was potentiated by amantadine . SIB-1765F also increased the locomotor activity of reserpine-treated rats and potentiated the effect of L-DOPA on reserpine-induced hypolo comotion. The onset of potentiation of L-DOPA by SIB-1765F was rapid ( <5 min) compared to the onset of potentiation by amantadine (>105 min) . Interestingly, nicotine did not attenuate reserpine-induced hypoloco motion nor did it affect the action of L-DOPA on reserpine-treated rat s. Biochemical analysis of levels of dopamine and its metabolites, dih ydroxyphenylacetic and homovanillic acid, indicated that, in contrast to amphetamine, SIB-1765F did not inhibit dopamine reuptake. The effec t of SIB-1765F in reserpine-treated rats was attenuated by alpha-methy l-p-tyrosine, implying that SIB-1765F acts by releasing dopamine from both reserpine-insensitive and reserpine-sensitive pools. Our findings demonstrate that nicotinic acetylcholine receptor agonists may offer a new therapeutic approach to the symptomatic treatment of the motor d eficits in patients with Parkinson's disease.