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Pick Your Model Wisely: Understanding the Negative Symptoms of Schizophrenia in Rodent Models Samantha E. Yohn*,†,‡ and P. Jeffrey Conn†,‡,§ †
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States § Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
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ABSTRACT: While the negative symptoms comprise one of the cardinal symptom domains of schizophrenia, there are numerous deficits that are included in this category of symptoms. Therefore, when modeling negative symptoms preclinically, it is important to consider which symptom is being modeled by a specific assay and to try to gain an understanding of the translational value of the findings. It is hoped that enhancing the translational value of animal models will allow for better treatment outcomes for the negative symptoms of schizophrenia in the future. KEYWORDS: Motivation, negative symptoms, schizophrenia
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to be a core symptom of SZ, falling within the cluster of features that encapsulates the negative symptomatology. However, anhedonia itself can be further split into two subdivisions based on temporal components: anticipatory (i.e., motivation and goal directed behavior) and consummatory (i.e., in the moment feelings).5 Interestingly, anhedonia reported by SZ patients depends on the time frame in which the question is asked. For example, SZ patients do not have any issues reporting “in the moment feelings” but display deficits in accurately recalling previously pleasurable activities or predicting pleasure from future events.6 These findings suggest that despite impairments in outward emotional expression, SZ patients do not have deficits in the internal experience of pleasurable emotions. That is, they do not appear to have a hedonic deficit, as implied by the terminology used in commonly accepted definitions and rating scales for negative symptoms that gives the impression of a global reduction in the capacity to experience pleasure.7 The term anhedonia does not adequately capture the complex and multifaceted rewardrelated deficits observed in SZ. Additionally, it has also been argued that the extension of the term anhedonia to aspects of reinforced behavior is detrimental because it references to two different psychological processes that are mediated by dissociable, although overlapping, neural circuits.8 Preclinical models may help to elucidate the underlying neurocircuitry and novel treatment outcomes for the negative symptoms of SZ. It is important, however, that preclinical models have face validity for symptoms they are intended to model. If you were to do a quick literature search on animal models of negative symptoms of SZ, you would come across several papers that regard anhedonia (i.e., diminished experience of pleasure) as an optimal preclinical model. Anhedonia, in this sense, is often measured by a sucrose preference test following antagonism of the N-methyl-D-
he negative symptoms of schizophrenia (SZ) are defined as the absence or diminution of normal behaviors and functions1 that include, but are not limited to, reductions in emotional expressivity, spontaneous speech, sociability, and initiation of goal-directed behavior. While the negative symptoms account for much of the long-term morbidity and poor functional outcome of patients with SZ, they represent a major therapeutic challenge for the field. First, this is because currently approved antipsychotics are ineffective in reducing negative symptoms and may induce or exacerbate these symptoms in SZ patients. Thus, for some patients, the cost of positive symptom management comes at the expense of negative symptoms. Second, research on the negative symptom domain often assumes that these symptoms constitute a single syndrome or therapeutic target, and therefore they are broadly defined and lumped together by current rating or self-report scales. There is now a push to separate the specific negative symptoms experienced, with the hope that this will improve treatment outcomes and symptom management. This push is based in part on studies of factor analyses, which have isolated two separate but related subdomains of negative symptoms: diminished expression (e.g., affective flattening) and amotivation (e.g., avolition or apathy).2 Although amotivation is one of the cardinal symptoms of SZ, it is important to note that there are numerous deficits in reward and motivational processing that have been observed in SZ patients that fall under this category. These include, but are not limited to, deficits in reward learning, neural responses to reward, value representations, effort-related decision making, and willingness to expend effort. Deficits in these reward processes are often inappropriately labeled under the umbrella term of anhedonia.3 Whereas there are many factors that could lead to motivational deficits in SZ, the preponderance of studies indicate that SZ patients do not differ from healthy controls in motivation due to anhedonia. Anhedonia, in this sense, refers to the inability or diminished capacity to experience pleasure and is thought to reflect deficits in brain reward system function.4 Anhedonia has long been suggested © XXXX American Chemical Society
Received: October 15, 2018 Accepted: October 16, 2018
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DOI: 10.1021/acschemneuro.8b00553 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
replicated by several groups8(Figure 1A). Interestingly, a lot less research has investigated atypical antipsychotics on PR
aspartate (NMDA) receptor. In this assay, the amount of sucrose consumed is regarded as either an anhedonic (i.e., less pleasurable) or nonanhedonic (i.e., pleasurable) response. With the wealth of clinical literature indicating that SZ patients do not experience deficits in consummatory behaviorthat is, they can still enjoy a piece of chocolate the same as a healthy controlthe question now becomes what is this assay actually measuring? Like with any preclinical model, you cannot ask the mouse the next day to rate on a scale how much it enjoyed its experience. Therefore, the main questions from preclinical models should be: (i) what is this assay intended to measure, (ii) what can we learn from the results, and (iii) what is the translatability? Ultimately, the answers to these questions are critical in establishing an understanding of whether the selected assay is indeed a valid model of a clinical symptom. Based upon evidence from clinical studies, it is unlikely that the sucrose preference assay is a valid procedure for modeling “anhedonia” or subsequent negative symptoms observed in SZ because patients do not have decreased hedonic capacity. This model is not a direct one-to-one comparison with that seen within the SZ patient population; therefore, the results of this assay should not be overanalyzed. Clinical reports often point to anticipatory deficits rather than consummatory deficits. Dissecting anticipatory, that is motivational, components from the broad term of anhedonia will improve our understanding of the neural substrates of negative symptoms and will aid in the development of effective treatment strategies. In recent years, clinical literature has focused less on the self-reported anticipation of pleasure or experience of reward and more on how patients respond and obtain a reward.9 SZ patients with a high preponderance of negative symptoms display inappropriate evaluation of rewards, goal-directed actions, and compromised decision making. Interestingly, separating negative symptoms into these constructs allows these deficits to be appropriately tested clinically in patient populations and healthy controls as well as preclinically. This separation will allow us to accurately answer the questions that were posed above. An example of a task that is highly translatable between species is the traditional progressive ratio (PR) schedule. In the PR schedule, SZ patients or healthy controls are required to exert increasing amounts of work to obtain a monetary reward, and motivation is measured as the point at which they stop responding, termed the breakpoint. Several clinical studies have shown that patients with SZ have significantly reduced PR breakpoints compared with healthy controls.10 However, the issue with the interpretation of these studies is that all patients are medicated by first-, second-, or a combination of first- and second-generation antipsychotics. So while patients have deficits in motivated behavior, the question now becomes are these deficits observed because of the medication, disease, or a factor of both? Clinical studies have shown that the administration of either typical or atypical antipsychotics to healthy controls, with no prior reported history of mental illness, will induce negative symptoms as assessed by a broad rating scale. Further testing in a preclinical PR task, where rodents work for food reward, can be used to assess whether these agents induce motivational impairments. Similar to what is reported clinically, the administration of typical antipsychotics induces an impairment in PR responding, which may comprise a major side effect of the medication. The reduction in motivation observed with typical antipsychotics, such as haloperidol (HAL), has been extensively validated and
Figure 1. Comparison of Haloperidol and Risperidone on Progressive ratio (PR) Responding. Administration of both the typical antipsychotic haloperidol (HAL) (A) and the atypical antipsychotic risperidone (RIS) (B) reduces the total number of pokes in a traditional PR schedule. Administration of the highest dose of risperidone (0.03 mg/kg) reduces the consumption of the freely available reinforcer (C) and increases core body temperature (D) compared with vehicle-treated animals ((A−C) *p < 0.05, **p < 0.01, ***p < 0.001, significantly different from vehicle-conditions, repeated measures ANOVA) ((D) **p < 0.01 significantly different from vehicle-conditions at 90 minute time point, two-way factorial ANOVA; unpublished data collected by S.E. Yohn and J. Galbraith).
performance. We recently have tried to test the atypical antipsychotic risperidone (RIS) on motivated behavior, but the interpretation of the results are convoluted (Figure 1B−D). Although it would appear that following RIS administration, animals have a reduction in responding, this is not the case. Further examination on the pattern of responding using control assays revealed that total food intake is suppressed and core body temperature is increased, suggesting that reductions in PR responding are not solely due to a motivational deficit. Interestingly, while both RIS and HAL display antipsychoticlike efficacy in amphetamine-induced hyperlocomotion (AHL), an animal model of the positive symptoms, they have marked differences on deficits observed in motivated behavior. These findings might hint at the underlying neurocircuitry involved in the exacerbation of motivational dysfunctions in SZ patients and suggest that while RIS can induce negative symptoms clinically, motivational deficits may not be one of them. In addition, these findings lend themselves to the argument that different classes of antipsychotics may be efficacious for treating one symptom domain while inducing deficits in another and, therefore, are not created equally. Although the appetite-suppressing effects of RIS make it difficult to evaluate in the PR assay, there are other assays of negative symptoms, again depending on the component of interest that can be used to test RIS. Associability is a core behavioral feature that contributes to poor psychosocial function and can be tested in rodents using a social interaction paradigm. Obviously, social interaction is not synonymous with work-related motivational deficits. It is therefore B
DOI: 10.1021/acschemneuro.8b00553 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience important that one does not overgeneralize the findings of this data to encompass the broad term of negative symptoms but rather a specific symptom profile of negative symptoms. For example, when reporting results with RIS, it may be important to specify whether there is a deficit in associability rather than a “global” induction of negative symptoms. The separation of distinct subcategories of negative symptoms will allow for a better understanding of underlying pathophysiology and appropriate treatment outcomes.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare the following competing financial interest(s): P.J.C. is an inventor on patents that protect different classes of metabotropic glutamate allosteric modulators.
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ACKNOWLEDGMENTS Much thanks to Jordan Galbraith for her assistance with this project. REFERENCES
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DOI: 10.1021/acschemneuro.8b00553 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
