Nicotinic α7- or β2-containing receptor knockout: Effects on radial-arm maze learning and long-term nicotine consumption in mice

Abstract

Classically, it has been thought that high-affinity nicotinic receptors containing β2 subunits are the most important receptor subtypes for nicotinic involvement in cognitive function and nicotine selfadministration, while low affinity α7-containing nicotinic receptors have not been thought to be important. In the current study, we found that knockout of either β2 or α7 subunits caused significant deficits in spatial discrimination in mice. The character of the impairment in the two knockouts was different. The β2 knockout preferentially impaired cognition in males while the α7 caused impairment regardless of sex. Both β2 and α7-containing nicotinic receptors also are important for nicotine selfadministration, also in different ways. Most animal model studies of nicotine self-administration are relatively short-term whereas the problem of tobacco addiction is considerably longer-term. To better model the impact of nicotinic receptor subtypes on nicotine self-administration over the long term, we studied the impact of genetic knockout of low affinity α7 receptors vs. high affinity β2 containing nicotinic receptors. Mice with knockouts of either of these receptors and their wildtype counter parts were given free access to a choice of nicotine-containing and nicotine-free solution in their home cages on a continuous basis over a period of five months. During the first few weeks, the β2-containing nicotinic receptor knockout mice showed a significant decrease in nicotine consumption relative to wildtype mice, whereas the α7 knockout mice did not significantly differ from wildtype controls at the beginning of their access to nicotine. Interestingly, in the longer-term after the first few weeks of nicotine access, the β2 knockout mice returned to knockout mouse levels of nicotine consumption, whereas the α7 knockout mice developed an emergent decrease in nicotine consumption. The α7 receptor knockout-induced decrease in nicotine consumption persisted for the five-month period of the study. Both α7 and β2 containing nicotinic receptors play critical roles in cognitive function and nicotine self-administration. Regarding cognitive function, β2-containing receptors are important for maintaining normal sex differences in spatial learning and memory, whereas α7 receptors are important for cognitive function regardless of sex. Regarding nicotine selfadministration high affinity β2-containing nicotinic receptors are important for consumption during the initial phase of nicotine access, but it is the α7 nicotinic receptors that are important for the longerterm regulation of nicotinic consumption.

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings

“…Conversely, working memory improved after administration of nicotinic agonists (Chan et al 2007;Gatto et al 2004;Levin et al 1999;Lippiello et al 1996;Tatsumi et al 2006). A study with knockout mice substantiates these results further: both β2* and α7 knockouts have been connected to radial arm maze performance (Levin et al 2009). In a recent study, Rushforth et al (2010) have underlined the involvement of both the α4β2* and the α7 subtype in rats' working memory using not a maze task, but an odour span task.…”

In Vivo Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107: Preclinical Considerations in Alzheimer's Disease

“…Nicotine's reinforcing properties have been examined using a variety of behavioral, pharmacological antagonism, and genetic knockout approaches aimed at elucidating the nAChR subtype involved in nicotine reward (Picciotto et al, 1998). These studies generally indicate a greater importance of the ␣4␤2 subtype in mediating the reinforcing properties of nicotine, although it has been suggested ␣7 nAChRs may have a regulatory role for long-term maintenance of nicotine consumption (Levin et al, 2009). However, in a battery of studies comparing ABT-107 with nicotine we found no evidence of nicotine-like abuse liability.…”

Pharmacogenetics of smoking cessation therapy

“…Furthermore, nicotine intravenous self-administration [Picciotto et al, 1998] and drug discrimination [Shoaib et al, 2002] were attenuated in b2-knockout mice. In contrast, drug discrimination was normal in a7 knockouts [Stolerman et al, 2004], but this receptor might be important for the long-term regulation of oral consumption of nicotine solutions [Levin et al, 2009]. Moreover, varenicline reduced the expression of nicotine sensitization in nicotine-sensitized rats [Zaniewska et al, 2008], putting the nicotinic receptor subtypes as relevant aims for further genetic studies.…”