Beta2* and beta4* nicotinic acetylcholine receptor expression changes with progressive parkinsonism in non-human primates.

Autoradiography was used to investigate nicotinic acetylcholine receptor (nAChR) binding in the brains of two groups of macaque monkeys with parkinsonism produced by different types of MPTP exposure: animals with cognitive deficits but no motor symptoms (motor-asymptomatic) and animals with typical motor symptoms of parkinsonism (motor-symptomatic). Motor-asymptomatic animals had no significant changes in [125I]epibatidine binding to beta2*-beta4* nAChRs and [125I]A85380 binding to beta2* nAChRs in cognition-related cortical regions such as Broadman's area 46, orbitofrontal cortex, the anterior cingulate sulcus and the hippocampus, but binding of both radioligands was decreased 70-80% in the caudate and putamen. Motor-symptomatic animals had decreases in beta2* and beta4* nAChR in the principal sulcus (40-60%), anterior cingulate sulcus (30-55%), and orbitofrontal cortex (30-41%), but not in the hippocampus, plus significant decreases in binding (70-80%) in the caudate and putamen.

[125I]Iodomethyllycaconitine binds to alpha7 nicotinic acetylcholine receptors in monkey brain.

We examined the binding of the novel nicotinic acetylcholine receptor (nAChR) ligand [125I]iodomethyllycaconitine (iodoMLA) in the brains of M. cynomologous (macaque) monkeys. [125I]iodoMLA bound throughout the brain with the greatest density in the thalamus and moderate intensity in the basal ganglia and cortical regions.

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.

Differences in alpha7 nicotinic acetylcholine receptor binding in motor symptomatic and asymptomatic MPTP-treated monkeys.

We studied [(125)I]alpha-bungarotoxin (btx) binding to alpha7 nicotinic acetylcholine receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed macaque monkeys. [(125)I]alpha-Btx binds throughout the normal monkey brain, with the greatest density in the thalamic nuclei and with moderate to low binding in the hippocampus, prefrontal cortex, caudate, putamen, and substantia nigra. Chronic administration of low doses of MPTP resulted in animals with stable cognitive deficits without overt parkinsonian motor symptoms.

Nicotine and nicotinic receptors; relevance to Parkinson's disease.

The development of nicotinic agonists for therapy in neurodegenerative disorders such as Parkinson's disease is an area currently receiving considerable attention. The rationale for such work stems from findings that reveal a loss of nicotinic receptors in Parkinson's disease brains. These results, coupled with reports that nicotine treatment relieves some of the symptoms of this disorder, provides support for the contention that nicotine and/or nicotinic agonists may be beneficial for acute symptomatic treatment.

Declines in different beta2* nicotinic receptor populations in monkey striatum after nigrostriatal damage.

In the present study we used the nicotinic ligand 5-iodo-A-85380 [5-iodo-3(2(S)-azetidinylmethoxy)pyridine], which selectively binds to beta2-containing nicotinic acetylcholine receptors, to elucidate the nicotinic receptor subtypes affected by nigrostriatal damage in the monkey. Autoradiographic studies in control monkeys showed that 5-[(125)I]A-85380 ([(125)I]A-85380) binds throughout the brain with the characteristics of a nicotinic receptor ligand. Competition experiments with cytisine and nicotine yielded K(i) values of approximately 1 and 10 nM, respectively, with complete inhibition of [(125)I]A-85380 binding at a 10(-6) M concentration of these ligands.

5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes.

Recent work suggests that 5-iodo-A-85380, a radioiodinated analog of the 3-pyridyl ether A-85380, represents a promising imaging agent for non-invasive, in vivo studies of alphaAbeta2* nicotinic acetylcholine receptors (nAChRs; *denotes receptors containing the indicated subunits), because of its low non-specific binding, low in vivo toxicity and high selectivity for alpha4beta2* nAChRs. As an approach to elucidate nAChR subtypes expressed in striatum, we carried out competitive autoradiography in monkey and rat brain using 5-[125I]iodo-A-85380 ([125I]A-85380) and [125I]alpha-conotoxin MII, a ligand that binds with high affinity to alpha6* and alpha3* nAChRs, but not to alpha4beta2* nAChRs. Although A-85380 is reported to be selective for alpha4beta2* nAChRs, we observed that A-85380 completely inhibited [125I]alpha-conotoxin MII binding in rat striatum and that A-85380 blocked >90% of [125I] alpha-conotoxin MII sites in monkey caudate and putamen.

Loss of nicotinic receptors in monkey striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment is due to a decline in alpha-conotoxin MII sites.

Nicotinic acetylcholine receptors (nAChRs) in the basal ganglia are a potential target for new therapeutics for Parkinson's disease. As an approach to detect expression of nAChRs in monkeys, we used 125I-epibatidine, an agonist at nAChRs containing alpha2 to alpha6 subunits. 125I-Epibatidine binding sites are expressed throughout the control monkey brain, including the basal ganglia.