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 self-administration, 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 self-administration, 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 5 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 wildtype 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 5-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 self-administration 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 longer-term regulation of nicotine consumption.