Identification of the Nicotinic Receptor Subtypes Expressed on Dopaminergic Terminals in the Rat Striatum

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) expressed on mesostriatal dopaminergic neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Using immunoprecipitation and ligand-binding techniques, we have shown that both alpha6beta2* and alpha4(nonalpha6)beta2* nAChRs are expressed in the caudate-putamen and that only alpha6* nAChRs can bind alpha-conotoxin MII and methyllycaconitine with affinities of 1.3 and 40 nm, respectively. Further studies performed on 6-hydroxydopamine-lesioned striatum led to the identification of nAChR subtypes selectively expressed on dopaminergic terminals [alpha4alpha5beta2, alpha4alpha6beta2(beta3), and alpha6beta2(beta3)], nondopaminergic neuronal structures (alpha2alpha4beta2), or both structures (alpha4beta2). The identification of the nAChRs expressed on striatal dopaminergic terminals opens up the possibility of developing selective nAChR ligands active on dopaminergic systems and associated diseases, such as Parkinson's disease.

Nicotinic receptors as CNS targets for Parkinson's disease

“…These findings from receptor binding studies are in agreement with the results of in situ hybridization and RT-PCR work, which demonstrate the presence of α2 through α7 and β2 through β4 nAChR subunit transcripts in the striatum and/or substantia nigra [72][73][74][75][76][77]. The results of immunoprecipitation studies using subunit-selective nAChR antibodies suggest that the greater majority of these transcripts are translated into protein to form receptors [64,78]. These show that all but the α2, α3 and β4 subunits are present in the striatum and/or substantia nigra of mice and rats.…”

“…The loss of α6β2* receptors correlates well with declines in the striatal dopamine transporter, a dopaminergic neuronal marker [64,78,108], suggesting that this receptor subtype is located primarily on striatal dopaminergic nerve terminals. The results of immunoprecipitation studies using nAChR subunit-targeted antibodies support these findings and show that the largest reductions are in α6 and β3 subunit proteins, followed by smaller declines in α4, α5 and β2 subunits [64,78]. There was no change in α7 nAChRs, while the α2, α3 and β4 subunit proteins are not expressed in rodent striatum.…”

“…Nigrostriatal damage also leads to dramatic declines in binding of 125 I-α-conotoxinMII [108], a ligand that identifies α6β2* in rodent striatum [80,109]. The loss of α6β2* receptors correlates well with declines in the striatal dopamine transporter, a dopaminergic neuronal marker [64,78,108], suggesting that this receptor subtype is located primarily on striatal dopaminergic nerve terminals. The results of immunoprecipitation studies using nAChR subunit-targeted antibodies support these findings and show that the largest reductions are in α6 and β3 subunit proteins, followed by smaller declines in α4, α5 and β2 subunits [64,78].…”

Motor deficits and altered striatal gene expression in aphakia (ak) mice

“…In this study, we identified reduced Chrnα6 expression in ak striata. α6-subunit containing nicotinic receptors are selectively expressed on dopaminergic terminals in the striatum (Wonnacott et al, 2000;Zoli et al, 2002). Therefore, it is possible that reduced Chrnα6 expression reflects a presynaptic striatal alteration due to the failure of dorsal striatonigral afferents to develop in these mice (Nunes et al, 2003).…”

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

“…These α6* subtypes are, presumably, the nAChRs that bind [ 125 I]-α-CtxMII with high affinity. Comparable studies done with the rat identified α4α5β2, α4α6β2(β3) and α6β2(β3) nAChRs in striatum (the (β3) designation was used to indicate the possible presence of the β3 subunit) [93]. Thus, immunological approaches indicate that a minimum of five nAChR subtypes (α4β2, α4α5β2, α4α6β2β3, α6β2β3 and .…”