Nicotine receptor knockouts or null mutants have been very useful for determining the roles of the different nicotinic receptor subtypes in neurobehavioral function as well as response to nicotine. In general, β2-containing nicotinic receptors have been found to be involved in more neurobehavioral functions than α7 nicotinic receptors in studies using receptor knockouts [10
] or pharmacological manipulations [11
]. β2-containing nicotinic receptors have been found to be important for nicotine self-administration as well as cognitive function. Animals lacking β2-containing nicotinic receptors have been shown to be insensitive to the nicotine cue [28
]. Also it has been demonstrated that substitution to the nicotine discriminative stimulus required high intrinsic activity at β2- but not at β4- or α7-containing receptors [29
]. Until recently α7 receptors nicotinic receptors have not appeared to be substantially involved in either nicotine reinforcement or cognitive function [13
]. The current studies determined in greater detail the involvement of both β2 and α7-containing nicotinic receptors in cognitive function and nicotine self-administration.
The neural substrates of nicotine self-administration have been the focus of considerable study because it is believed that this will point to the neural bases of tobacco addiction and better treatments for smoking cessation. Several animal models have been developed to study different aspects of nicotine reinforcement. These include intravenous (IV) nicotine self-administration, oral nicotine self-administration, conditioned place preference and locomotor activity sensitization. Each model provides a piece in the puzzle of tobacco addiction. One piece missing from the range of models is the comparison of the differential bases of induction of nicotine self-administration from the long-term persistence of self-administration.
Animal models of nicotine self-administration have shown the importance of high affinity nicotinic receptors, particularly α4β2 receptors, in the foundation of nicotine self-administration. In rats, application of the α4β2 nicotinic antagonist DHβE into the ventral tegmental area (VTA) substantially interferes with nicotine self-administration [11
]. In mice, genetic manipulations have shown the decrease in nicotine self-administration with knockouts of the β2 receptor subunit [10
]. In contrast, application of an α7 antagonist to the ventral tegmental area (VTA) in rats or knockout of nicotinic α7 receptors in mice have been found to have little or no impact on nicotine self-administration [11
]. However, definitive conclusions concerning the relative involvement of different nicotinic receptor subtypes should be held in abeyance because of the limitations of the models in which the receptor involvement are being conducted.
Nicotinic α4β2 receptors provide the generalization of discriminative stimulus properties to nicotine, whereas α7 receptors does not seem to play a role [29
]. Animals lacking α7 nicotinic receptors learn to discriminate nicotine as well as wild-type animals [30
]. Thus, it has been suggested that the α7 receptors may play little role in nicotine reinforcement [29
There is some evidence in the literature supporting the involvement of α7 nicotinic receptors in drug abuse. Both α4β2 and α7 nicotinic receptors in the ventral striatum are involved in cocaine-induced dopamine release [33
]. Recently it has been found that both α7 and α4β2 nicotinic receptors are necessary for development of sensitization to cocaine effects on dopamine release in the ventral striatum [33
There are a variety of limitations to animal models of nicotine self-administration. One of the most relevant is the time limitation. Humans self-administer nicotine through tobacco use for years and decades, whereas nicotine self-administration is only studied over a period of week in the typical rodent study. There may be very different mechanisms in the short vs. long-term phases of nicotine self-administration. In the current study, we examined nicotine self-administration through drinking water in mice with knockout of either α7 or β2 receptor subunits during a period of five months.
In addition to the roles nicotinic receptors play in tobacco addiction, they also are critically involved in a wide variety of neurobehavioral functions. Prominently among these, nicotinic systems have also been found to be crucial for cognitive function [20
]. In particular, nicotine has been shown in a variety of studies to significantly improve memory. Pharmacological studies have pointed to the importance of both α4β2 and α7 nicotinic receptors in the basis of memory function. Infusion of either DHβE, an α4β2 antagonist, or MLA, an α7 antagonist, into the hippocampus significantly impairs working memory in the radial-arm maze [1
]. In addition, systemic administration of either α4β2 or α7 agonists can improve working memory accuracy on the radial-arm maze [17
]. Mice with β2 null mutations show cognitive impairments [9
]. Pharmacological manipulations show the importance of β2 containing nicotinic receptors for nicotine-induced improvements in cognitive function [12
]. To date fewer significant behavioral effects have been found in α7 null mutant mice [14
], though response to ethanol seems to be affected by α7 deletion [8
]. It has been found that α7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating in Acra 7 homozygous mutant mice [24
]. However, Fernandes et al. reported an impairment in α7 knockout mice in the delayed matching-to-place task of the Morris water maze, which is a measure of working/episodic memory [13
]. Also, recently it has been shown that α7 knockout mice have impaired attentional performance in the 5-choice serial reaction time task [15
]. We have found that local infusion of the α7 nicotinic receptor antagonist into the ventral or dorsal hippocampus significant impairs spatial working memory in the radial-arm maze [21
]. We and others have found that α7 agonists significantly improve learning, memory and attentional function in rodents [6
] and reverses aging–induced cognitive impairments [4
To complement our studies on nicotinic receptor subtype involvement with nicotine self-administration, we tested α4β2 and α7 knockout mice and their wildtype controls for learning and memory on the radial-arm maze as well. Studies with α7 and β2 knockout mice can lend insight into the involvement of nicotinic receptor subtypes in neurobehavioral function.