Subunit composition of nicotinic receptors in monkey striatum: effect of treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA.
Nicotinic acetylcholine receptors (nAChRs) represent an important modulator of striatal function both under normal conditions and in pathological states such as Parkinson's disease. Because different nAChR subtypes may have unique functions, immunoprecipitation and ligand binding studies were done to identify their subunit composition. As in the rodent, alpha2, alpha4, alpha6, beta2, and beta3 nAChR subunit immunoreactivity was identified in monkey striatum. However, distinct from the rodent, the present results also revealed the novel presence of alpha3 nAChR subunit-immunoreactivity in this same region, but not that for alpha5 and beta4. Relatively high levels of alpha2 and alpha3 subunits were also identified in monkey cortex, in addition to alpha4 and beta2. Experiments were next done to determine whether striatal subunit expression was changed with nigrostriatal damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment decreased alpha6 and beta3 subunit immunoreactivity by approximately 80% in parallel with the dopamine transporter, suggesting that they are predominantly expressed on nigrostriatal dopaminergic projections. In contrast, alpha3, alpha4, and beta2 subunit immunoreactivity was decreased approximately 50%, whereas alpha2 was not changed. These data, together with those from dual immunoprecipitation and radioligand binding studies ([(3)H]cytisine, (125)I-alpha-bungarotoxin, and (125)I-alpha-conotoxin MII) suggest the following: that alpha6beta2beta3, alpha6alpha4beta2beta3, and alpha3beta2* nAChR subtypes are present on dopaminergic terminals and that the alpha4beta2 subtype is localized on both dopaminergic and nondopaminergic neurons, whereas alpha2beta2* and alpha7 receptors are localized on nondopaminergic cells in monkey striatum. Overall, these results suggest that drugs targeting non-alpha7 nicotinic receptors may be useful in the treatment of disorders characterized by nigrostriatal dopaminergic damage, such as Parkinson's disease.
The Parkinson's Institute, 1170 Morse Ave., Sunnyvale, CA 94089-1605, USA. mquik@parkinsonsinstitute.org
Maryka
M
Quik
Silvia
S
Vailati
Tanuja
T
Bordia
Jennifer M
JM
Kulak
Hong
H
Fan
J Michael
JM
McIntosh
Francesco
F
Clementi
Cecilia
C
Gotti
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000470:Alkaloids / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D001345:Autoradiography; D001392:Azocines / Q000493:pharmacokinetics; D001921:Brain / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D021122:Protein Subunits / Q000737:chemistry; D011725:Pyridines / Q000493:pharmacokinetics; D011807:Quinolizines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D012453:Saimiri; D000093843:Quinolizidine Alkaloids
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000470:Alkaloids; D000906:Antibodies; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D007980:Levodopa; D009538:Nicotine; D021122:Protein Subunits; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine