Nicotinic α5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers

Neuronal nicotinic acetylcholine receptor subunit alpha 5 mRNA is widely expressed in the CNS. An alpha 5 gene polymorphism has been implicated in behavioral differences between mouse strains, and alpha 5-null mutation induces profound changes in mouse acute responses to nicotine. In this study, we have examined the distribution and prevalence of alpha 5* nicotinic acetylcholine receptor in mouse brain, and quantified the effects of alpha 5-null mutation on pre-synaptic nicotinic acetylcholine receptor function (measured using synaptosomal 86Rb(+) efflux) and overall [I-125]epibatidine binding site expression. alpha 5* nicotinic acetylcholine receptor expression was found in nine of fifteen regions examined, although alpha 5* < 20% of the total nicotinic acetylcholine receptor population in any region contained (alpha 5. Deletion of the (alpha 5 subunit gene resulted in localized loss of function (thalamus, striatum), which was itself confined to the DHPE-sensitive receptor population. No changes in receptor expression were seen. Consequently, functional changes must occur as a result of altered function per unit of receptor. The selective depletion of high agonist activation affinity sites results in overall nicotinic function being reduced, and increases the overall agonist activation affinity. Together, these results describe the receptor-level changes underlying altered behavioral responses to nicotine in nicotinic acetylcholine receptor a5 subunit-null mutants.