Nigrostriatal damage leads to a reduction in striatal nicotinic acetylcholine receptors (nAChRs) in rodents, monkeys, and patients with Parkinson's disease. The present studies were undertaken to investigate whether these nAChR declines are associated with alterations in striatal nAChR function and, if so, to identify the receptor subtypes involved. To induce nigrostriatal damage, mice were injected with the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP

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 a4b2* 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 a4b2* nAChRs. As an approach to elucidate nAChR subtypes expressed in striatum, we carried out competitive autoradiography in monkey and rat brain using 5-[ Development of radiotracers for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs) is of interest because these receptors are expressed throughout the brain and are implicated in tobacco addiction as well as a wide range of neurological disorders including Alzheimer's disease, Parkinson's disease, Tourette's syndrome, schizophrenia and epilepsy (Sihver et al. 2000). Although changes in nAChR expression can be evaluated using post-mortem brain tissue (Gotti et al. 1997;Court et al. 2000), a lack of suitable ligands has impeded in vivo quantitative imaging of nAChRs until the recent development of 5-iodo-A-85380 (Villemange et al. 1998). This ligand appears promising for single photon emission computed tomography because of its high affinity, low non-specific binding and lack of toxicity in mammals (Chefer et al. 1998;Fujita et al. 2000;Sihver et al. 2000;Kassiou et al. 2001;Wong et al. 2001).To date, multiple nAChR subunit mRNAs have been identified in the brain, including a2-a7 and b2-b4, which may combine to form diverse pentameric nAChR subtypes (Jones et al. 1999). The high affinity of A-85380 and 5-iodo-A-85380 for [ 3 H]cytisine-sensitive sites in brain, and low affinities for a7, ganglionic (a3b4*) and muscle (a1b1cd) subtypes of nAChRs has lead researchers to suggest that A-85380 and its derivatives selectively interact with a4b2* nAChRs (Sullivan et al. 1996;Mukhin et al. 2000). The a4b2* receptors appear to be the most abundant nAChRs in the rodent brain (Flores et al. 1991;Davila-Garcia et al. 1997), but significant proportions of other nAChRs are expressed in areas such as the nigrostriatal, visual and interpeduncular nucleusmedial habenula pathways (Whiteaker et al. 2000;Grady et al. 2001;Quik et al. 2001;Kulak et al. 2002).As an approach to investigate the specificity of interaction of A-85380 with a4b2* nAChRs, we tested whether A-85380 interacts with Champtiaux et al. 2002). These studies were performed in rat striatum because A-85380 selectivity to date has primarily been investigated in this species. In addition, we also conducted studies in monkey brain because there are a significantly higher proportion of [ 125 I]a-conotoxin MII sites in monkey striatum (50%) as compared with rodent striatum (15% of all high-affinity nAChRs) (Whiteaker et al. 2000;Kulak et al. 2002). Materials and methods Materials

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