ReviewThe behavioral actions of lithium in rodent models: Leads to develop novel therapeutics
Introduction
The development of novel therapeutics for bipolar disorder, as well as other mood disorders, has been hindered by limited knowledge both of the underlying neurobiology of the disorders, and of how the most useful medications actually exert their beneficial effects (Gould et al., 2004; Quiroz et al., 2004). Without a firm understanding of these issues, new treatments for mood disorders are not likely to be discovered by any method other than testing medications previously approved for other conditions (such as antipsychotics and anticonvulsants), or by pure serendipity. Thus, ongoing studies to elucidate both the complex etiologies of these disorders and the relevant direct and downstream actions of mood-stabilizers hold the promise of important future discoveries.
Over the past five decades, preclinical studies have investigated the actions of lithium on a number of levels, including the biochemical (identifying either direct targets or secondary signaling pathways), physiological, and behavioral effects of the drug (Fig. 1). However, we have yet to determine with certainty how lithium exerts its therapeutic effects. Much of the work on the behavioral actions of lithium was accomplished early in the history of the drug (reviewed by Smith, 1980). The advanced techniques that have since developed have given us greater insight into why certain behaviors are elicited or modified upon administration of lithium, and biochemical studies suggest that the targets relevant to the behavioral actions of this cation could soon be decisively identified. The behavioral actions of lithium have received far less attention recently than the biochemical actions; however, we are currently in a situation where, using novel genetic and pharmacological approaches, we can more firmly relate the behavioral and biochemical actions of lithium to one another, and perhaps even to the direct action of the drug. By integrating the knowledge gathered from modern techniques with behaviors that have long been familiar but incompletely understood, we are armed with a new approach with which to confront behavioral complexity.
As our knowledge and tools have developed, we have increasingly recognized the diagnosis heterogeneity inherent within our current psychiatric classification system, the American Psychiatric Association Diagnostic and Statistical Manual (Charney et al., 2002). At the present time, the search for a complete animal model of a particular disorder may be naïve; no single genetic mutation, pharmacological manipulation, or behavior will reveal all the intricacies behind a human syndrome. However, if animal models are to make a contribution to the long process of unraveling such diseases, their relevance must be assessed in light of observations and data obtained from human patients (Matthews et al., 2005). The endophenotype approach to deconstruct complex diseases has been increasingly utilized in psychiatric research (Gottesman and Shields, 1973; Gottesman and Gould, 2003). This approach identifies a quantifiable measure—neuropsychological or electrophysiological abnormalities are two examples—which is ideally strongly influenced by genes known to be associated with a given illness. It is an intermediate phenotype, found in (perhaps only a subset of) patients with a disorder, which can begin to unfold the convoluted pathway from genes to behavior in psychiatric illness. Animal models are being used both to demonstrate the validity of endophenotypes by their reproduction in relevant models, and to understand the genetic and biological underpinnings of endophenotypes themselves (Seong et al., 2002; Gould and Gottesman, 2006; Cryan and Slattery, 2007).
The utility of animal models is not, however, limited to their ability to replicate a particular physiological process or endophenotype, and the premature dismissal of traditional behavioral models should be avoided. Indeed, animal models are often studied for their ability to predict treatment response, and in this case the phenomenology of the model is secondary to its empirical validity. For example, a model in which rodent behavior is responsive to antidepressants should not, without appropriate validation, be considered a model of depression. Much of the criticism stems from the fact that a distinction is seldom made between the various goals of different behavioral models, as McKinney describes (McKinney, 1984). It is unlikely that an animal model of any psychiatric disease will ever simultaneously mirror the etiology, pathophysiology, symptoms, and treatment response characteristic of a psychiatric illness. Instead, these models permit the controlled study of a particular aspect of illness and treatment; as such, an evaluation of their validity—and thus, utility—demands consideration of which aspect(s) a model purports to address. Models intended to study particular symptoms, which would have face validity, should be distinguished from models of endophenotypes, which might exhibit no phenotypic similarity whatsoever to the diseases they probe. Although the endophenotype approach offers a promising route to understanding pathophysiology, more traditional models remain invaluable. The fundamental limitations of all models should be acknowledged, an effort which requires that the three-pronged face-construct-predictive validity prototype not be taken too literally.
Here we review the literature reporting the effects of lithium on rodent behavior. As the drug is primarily used in the treatment of mania and bipolar disorder, our discussion of the models relevant to these disorders will be the most extensive; however, studies have also explored the effect of lithium on preclinical models of conditions such as aggression, depression, circadian rhythms, schizophrenia, and tardive dyskinesia, and we will also review those data. For the interested reader we include a table describing the existing literature for the effects of lithium on each behavior. The differences in species, strain, and specific procedures across laboratories complicate generalization; however, Table 1 provides our overall interpretation of the consistency of the effects of lithium on each behavior.
Because our focus in this review is the present status of animal behavioral models in which the effect of lithium has been studied (Table 1), our discussion of the biochemical antecedents of particular models will be limited, and focused within our concluding remarks. For a more extensive discussion of the biochemical and physiological actions of lithium, the interested reader is directed to a number of reviews of such data (Jope, 1999; Phiel and Klein, 2001; Shaldubina et al., 2001; Chuang, 2004; Gould et al., 2004; Williams et al., 2004). This review begins with a discussion of baseline behaviors, and the effect of lithium upon them. We subsequently address behavioral models induced by amphetamine, followed by models of aggressive, depression-like, and reward-related behaviors. These are followed by a discussion of circadian rhythms, lithium augmentation of pilocarpine-induced seizures, and finally by a discussion of adverse effects of lithium, such as taste aversion. Each section begins with a short introduction to the model, followed by any available relevant clinical findings addressing the effect of lithium on the disease state that the model is intended to mimic. Thereafter, we discuss the relevant tests more specifically, and describe the data relating the effects of lithium on rodents in those tests. If applicable, we also mention the effects of other mood stabilizers on the model.
Section snippets
Background
For the purposes of this review we define “baseline behaviors” as those behaviors not elicited by an influence beyond what the animal would experience during daily living. Therefore, locomotion and rearing that are not altered or induced by stress, drugs, or other such probes, are considered in this section. Animal behavior in a novel environment is, however, included in this section, since it is distinguished from “spontaneous” locomotion and rearing only by the length of time the animal has
Background
One of the most common models with which the mood-stabilizing action of lithium is studied requires the induction of hyperactivity by a stimulant. Most studies have focused primarily upon one stimulant, amphetamine, the central action of which is the release and reuptake inhibition of norepinephrine and dopamine. Amphetamine, which has been widely studied, is frequently used to induce a variety of behavioral patterns, and thus to model many behavioral states other than mania.
In rodents, both
Background
Unlike mania, schizophrenia, psychosis, or any of the other psychiatric disorders that the above stimulant-induced behaviors attempt to imitate, aggressive activity is arguably more straightforward to model in an animal. Nevertheless, the study of aggression in rodents is beset with many of the same difficulties as other models. Not least of these is the fact that aggression itself is a heterogeneous phenomenon, one which can be manifested both in isolation and as one of a constellation of
Background
As with models of all affective disorders, rodent models of major depression are limited by the fact that a behavior, rather than a mood, is the output measure. Nevertheless, many models thought to be related to depression exist. With classical models of depression, their utility is often founded on their predictive validity, as these models, which we describe in each section below, are responsive to a variety of antidepressants. However, in many cases their construct validity has often not
Background
A characteristic of mania is an elevated hedonic tendency. Due to lithium's action as anti-manic agent, its effect on behavioral models of such tendencies has been investigated. A common behavioral model for testing the addictive or hedonic effects of a drug is conditioned place preference, which will not be discussed in this section, as it will be addressed in the section below on the aversive effects of lithium. In other studies, however, the effect of lithium on drug consumption and
Background
Multiple preclinical tests purport to evaluate learning and memory in rodents, although not all monitor the same aspects of cognitive functioning (Crawley, 2000). For example, the Morris Water Maze is used to test two aspects of spatial memory. Spatial reference memory is measured by the animal's ability to learn the location of a hidden platform in a large pool of water. Once learning has occurred, the platform can be moved, and the ability of the animal to learn the new location is a
Ouabain-induced behaviors
Although its precise relationship to the disorder is unknown, a finding in patients with bipolar disorder is dysregulated ion balance, as seen by increased intracellular sodium and calcium, and decreased sodium pump activity in peripheral cells (Looney and el-Mallakh, 1997). In order to investigate this relationship in regard to rodent behavior, some investigators have administered ouabain, a sodium pump inhibitor, to rats. A short period of hyper locomotion was observed following ouabain
Background
The term “circadian rhythm” describes an approximately 24-h cycle of physiological and behavioral activity. The duration of these rhythms, which include the sleep/wake cycle as well as the regulation of hormones and temperature, is regulated centrally in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian rhythms are studied by monitoring these markers either continuously or at a range of time points over the course of the cycle. These sometimes take place in constant light or
Background
The aversive effects of lithium are those which cause the animal to avoid whatever substance is associated with the drug. These effects are not likely to be related to the therapeutic effects of lithium. They are described by some as possibly toxic effects, but, like the negative side effect profile seen in many lithium-treated bipolar patients, aversion to lithium can be elicited even when serum lithium levels are within the “therapeutic” range (Langham et al., 1975).
Lithium is frequently used
Possible mechanisms
The behavioral effects of lithium are many and varied (Table 1), and a number of hypotheses have been offered to describe the mechanism by which those effects may be mediated. While the purpose of this review is not to fully detail possible mechanisms for the behaviors we have described, to do so will be a critical step toward understanding the relevant biochemical actions of lithium. As detailed in Fig. 1, lithium has a number of direct inhibitory actions on cellular enzymes, as well as
Future applications of lithium-sensitive animal models
An understanding of both the immediate and the downstream effects of lithium is important for developing drugs that mimic its therapeutic actions, but this cannot be the sole purpose of such research. These models should also be investigated with a view toward understanding the underlying behavioral and biochemical dysfunctions characteristic of the illnesses it treats. Progress will require that a critical eye be cast on our work with behavioral models, so that we are not merely replicating
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2022, Advances in Biological RegulationCitation Excerpt :We also performed an elevated zero maze assessment of anxiety-like behaviors as a control experiment, and the tail-suspension test. ( Altered performance on the tail suspension test is associated with lithium treatment (O'Donnell and Gould 2007), which we deemed relevant as BPNT2 is a direct inhibitory target of lithium.) However, we did not observe statistically significant alterations in behavioral performance between Bpnt2fl/fl and Bpnt2fl/fl Nestin-Cre mice on any of the assays performed (Fig. 4A–G).