Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery

Abstract

Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4β2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials.

Implications: The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.

Figure 1.

Illustration of the several domains of cognition often targeted in rodent models by nicotinic acetylcholine receptor ligands in drug discovery programs for neuropsychiatric disorders.

Figure 2.

Diagrams of representative rodent tasks often used in drug discovery programs that were developed to model specific domains of cognition. (A) Sustained attention: the five-choice serial reaction time task (5-CSRTT). In the 5-CSRTT, subjects are required to scan five apertures in an operant chamber for the appearance of a brief light stimulus and to make a nose-poke response in the correct spatial location (ie, the aperture where the light stimulus was presented) to receive a food reward. (B) Spatial learning and reference memory: the Morris water maze (MWM). The MWM task assesses the ability of rodents to learn and remember the spatial location of visual cues in a room to find and escape onto a hidden platform located in a pool of water. In probe trials (reference memory) conducted after hidden platform tests, the platform is removed from the pool and the time spent and distance traveled in the quadrant that previously contained the platform is measured. (C) Spatial working memory: the radial arm maze (RAM). In The RAM, subjects move down adjacent arms in a radial maze to retrieve food pellets without reentering empty (ie, unbaited) arms. By remembering which arms were previously entered (ie, by using spatial cues in the room on each trial) the rats use “spatial working memory” to successfully complete the task. (D) Recognition memory: spontaneous novel object recognition (NOR). During the sample trial (A/A), the subject is presented with two identical objects and allowed to explore the objects for a predetermined length of time. After a delay interval, a choice test trial (A/B) is performed in which the subject is presented with one of the previously observed “familiar” objects and a “novel”, unfamiliar object. Recognition memory is demonstrated in the NOR task when the subject explores the novel object more than a previously observed familiar one. (E) Executive function: -attentional set-shifting task (AST). In the food cup-based version of the AST, rodents are trained to retrieve food rewards buried in containers that contain fillers of different textures and (typically) different scents (olfactory cues). To obtain rewards the subjects have to be able to discriminate between the different textures and odors and then to switch between different textures or between odors (intradimensional set shift) or to shift from a specific texture to an odor (extradimensional set shifts) or vice versa. They are also required to perform reversals either within or between dimensions. SD = simple discrimination; CD = complex discrimination; ID = intradimensional set shift; ED = extradimensional set shift.