The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo

Abstract

We used immunoprecipitation with subunit‐specific antibodies to examine the distribution of heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) that contain the α5 subunit in the adult rat brain. Among the regions of brain we surveyed, the α5 subunit is associated in ∼37% of the nAChRs in the hippocampus, ∼24% of the nAChRs in striatum, and 11–16% of the receptors in the cerebral cortex, thalamus, and superior colliculus. Sequential immunoprecipitation assays demonstrate that the α5 subunit is associated with α4β2* nAChRs exclusively. Importantly, in contrast to α4β2 nAChRs, which are increased by 37–85% after chronic administration of nicotine, the α4β2α5 receptors are not increased by nicotine treatment. These data thus indicate that the α4β2α5 nAChRs in rat brain are resistant to up‐regulation by nicotine in vivo, which suggests an important regulatory role for the α5 subunit. To the extent that nicotine‐induced up‐regulation of α4β2 nAChRs is involved in nicotine addiction, the resistance of the α4β2α5 subtype to up‐regulation may have important implications for nicotine addiction.

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…However, there were no differences in expression pattern between the two isoforms. 88 Mao et al 172 estimated that (a4b2) 2 a5 receptors constitute 11-37% of the total a4b2* nAChR population, depending on the brain region. Accordingly, the potential influence of the a4b2a5N398/a4b2a5D398 variant on total brain a4b2* receptor response to nicotine is probably substantial.…”

“…172 However, while a4b2* nAChR upregulate after chronic nicotine administration, it seems that the particular (a4b2) 2 a5 subtype does not. (a4b2) 2 a5 resistance to nicotine-induced upregulation probably has implications for the mechanism of ND, due to the suggested contribution of a4b2* nAChR upregulation to ND.…”

“…(a4b2) 2 a5 resistance to nicotine-induced upregulation probably has implications for the mechanism of ND, due to the suggested contribution of a4b2* nAChR upregulation to ND. 172 As mentioned, a5 is an accessory subunit, and some of the variants described in the CHRNA5-CHRNA3-CHRNB4 cluster may be involved in the upregulation resistance mechanisms.…”

“…27,172,227,228 Indeed, variation in rs16969968 influences the maximal response of a4b2a5 receptors to nicotine. 88 Although a5-KO mice are viable, so far only limited research on ND-related features has been reported, including that mutant mice are less sensitive to nicotine-induced seizure and locomotor activity 158,229 than WT, and show a reduction in physical withdrawal symptoms 143 (See Table 4).…”

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

“…An asterisk denotes the possible presence of other subunits in the nAChR complex, for example a5, a6 and b3 [9]. These additional subunits are likely to be important regulators of neurotransmission as it has been estimated that a4b2a5 nAChRs constitute 10 to 37% of the total a4b2* nAChR population depending on the brain region [10,11]. The various nAChR subtypes differ in their subcellular, cellular and tissue expression profiles as well as in their basic functional properties such as ion selectivity, pharmacology and current kinetics [1,[7][8][9]; especially the latter properties, that is the transitions between different receptor states, are important to bear in mind with regard to nAChR function and thereby drug development.…”