Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson's disease in rats

SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was tested for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA and its effects were compared to those of nicotine, d-amphetamine and amantadine in the sam...

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Published in:The Journal of pharmacology and experimental therapeutics 1997-01, Vol.280 (1), p.393-401
Main Authors: Menzaghi, F, Whelan, K T, Risbrough, V B, Rao, T S, Lloyd, G K
Format: Article
Language:English
Subjects:
Amantadine - pharmacology
Animals
Antiparkinson Agents - pharmacology
Corpus Striatum - drug effects
Dextroamphetamine - pharmacology
Dopamine - metabolism
Ion Channels - agonists
Levodopa - pharmacology
Male
Motor Activity - drug effects
Nicotinic Agonists - pharmacology
Olfactory Pathways - drug effects
Parkinson Disease - drug therapy
Pyridines - pharmacology
Pyrrolidines - pharmacology
Rats
Rats, Sprague-Dawley
Reserpine - pharmacology
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Summary:SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was tested for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA and its effects were compared to those of nicotine, d-amphetamine and amantadine in the same conditions. Consistent with previous reports, reserpine-induced hypolocomotion was reversed by L-DOPA (plus benserazide), d-amphetamine and amantadine in a dose-dependent manner and the effect 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 hypolocomotion. 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 hypolocomotion nor did it affect the action of L-DOPA on reserpine-treated rats. Biochemical analysis of levels of dopamine and its metabolites, dihydroxyphenylacetic and homovanillic acid, indicated that, in contrast to amphetamine, SIB-1765F did not inhibit dopamine reuptake. The effect of SIB-1765F in reserpine-treated rats was attenuated by alpha-methyl-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 deficits in patients with Parkinson's disease.
ISSN:0022-3565