Selective changes in nicotinic acetylcholine receptor subtypes related to tobacco smoking: an immunohistochemical study

Abstract

Increases in neuronal nicotinic receptors (nAChRs) in response to nicotine exposure have been reported in cell cultures, rodent brains, and in the brains of human smokers. The present study examines alterations in alpha4 and alpha7 nAChR subunit cellular expression in human hippocampus and entorhinal cortex from normal elderly individuals with known smoking history. There were significant increases in the intensity of alpha4 immunoreactive neuropil, but not the number of cell bodies, in many regions of hippocampus and entorhinal cortex in smokers compared to age-matched non-smokers and ex-smokers. There was also an increase in alpha7 immunoreactive perikarya in the granular cell layer of dentate gyrus in smokers but not other regions examined. There was, in contrast, a significant reduction in alpha7 immunoreactive astrocytes in smokers and ex-smokers compared to non-smokers. These findings suggest exposure to tobacco smoke acutely up-regulates alpha4 receptors in axon terminals and dendrites but not perikarya, whereas tobacco smoking induced down-regulation of alpha7 expression on astrocytes is a long-term effect. As the alpha4 subunit decreases with ageing and degenerative diseases such as Alzheimer's disease, whereas alpha7 increases in astrocytes in Alzheimer's disease, the findings further indicate the therapeutic relevance of nicotinic agonists such as nicotine.

Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

“…The result of the increased Vt of the 123 I-5IA was in agreement with the upregulation of the nAChRs in the brains of smokers reported in postmortem human studies (10)(11)(12) and in animal studies (6)(7)(8)(9). Staley et al have described similar findings in human brain (13).…”

“…Previous animal studies have shown that chronic nicotine treatment induces an increase in high-affinity nicotinic receptor binding (6)(7)(8)(9), and human postmortem studies have found a similar increase in 3 H-nicotine binding to high-affinity receptors in the postmortem cortex, cerebellum, and hippocampus of smokers compared with that in nonsmokers (10)(11)(12).…”

“…This upregulation is not permanent, returning to control levels within 7-10 d in mice (6) and 15-20 d in rats (8,9) after cessation of (2)-nicotine treatment. Previous efforts to demonstrate nAChR upregulation in the human brain have also been reported primarily in in vitro binding assays (10,11). Kassiou et al reported the upregulation of nAChRs with chronic (2)-nicotine treatment in the brain of a live baboon (12).…”

Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

“…These observations are in complete agreement with a substantial number of reports, which have established that nAChR upregulation is a time and dose dependent phenomenon, varying quantitatively and qualitatively according to nAChR subunit composition (Marks et al, 1985;Marks et al, 1986;Pauly et al, 1989;Sanderson et al, 1993), and cell-specific neuronal distribution (Nashmi et al, 2007). Thus, α4β2* nAChRs, which have high affinity for nicotine, are more readily upregulated compared with low-affinity α7 nAChRs, a differential regulation that occurs in mice (Sparks and Pauly, 1999), rats (Mugnaini et al, 2002) and humans (Teaktong et al, 2004). For α7 nAChRs, in particular, we observed a 30% overall increase in [ 125 I]α-bungarotoxin binding sites in nicotine treated WT mice, which is consistent with the magnitude of nicotine-induced upregulation previously reported for the α7 receptor subtype by in vitro (Barrantes et al, 1995;Peng et al, 1997;Ridley et al, 2001) and in vivo studies (Pauly et al, 1991;Rasmussen and Perry, 2006).…”

Nicotine Exacerbates Brain Edema during In Vitro and In Vivo Focal Ischemic Conditions

“…Long-term smoking has been associated with an alteration of nAChR expression in the brain with ␣4 subunit expression increased in neurons and dendritic processes (Teaktong et al, 2004) and decreased in ␣7 subunit expression in astrocytes and hippocampal regions (Teaktong et al, 2004). We previously have demonstrated that nicotine decreases NKCC activity in bovine brain microvessel cells, which also express ␣-3, ␣-5, ␣-7, ␤-2, and ␤-3 nAChR subunit proteins .…”