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 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.
Menzaghi
F
F
SIBIA Neurosciences, Inc., La Jolla, California, USA.
Whelan
K T
KT
Risbrough
V B
VB
Rao
T S
TS
Lloyd
G K
GK
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D007473:Ion Channels / Q000819:agonists*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009833:Olfactory Pathways / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology*
D000978:Antiparkinson Agents; D007473:Ion Channels; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D007980:Levodopa; D012110:Reserpine; D000547:Amantadine; C100989:altinicline maleate; D003913:Dextroamphetamine; D004298:Dopamine