Animal Models of CNS Disorders

7/29/2019 Animal Models of CNS Disorders

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Accepted Manuscript

Title: Animal Models of CNS Disorders

Author: Paul McGonigle

PII: S0006-2952(13)00387-0DOI: http://dx.doi.org/doi:10.1016/j.bcp.2013.06.016

Reference: BCP 11671

To appear in: BCP

Received date: 18-6-2013

Accepted date: 18-6-2013

Please cite this article as: McGonigle P, Animal Models of CNS Disorders,Biochemical

Pharmacology (2013), http://dx.doi.org/10.1016/j.bcp.2013.06.016

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BCP

Redefining Pharmacology

Article #7d

6/16/13

Animal Models of CNS Disorders

Paul McGonigle

Department of Pharmacology and Physiology

Drexel University College of Medicine

245 North 15th

Street, Philadelphia, PA 19102-1192

Running Title: Animal models of CNS disorders

Key words:

Word count (abstract and text): 6578

98 R f ( d t 2561)

McGonigle CNS Models FINAL 061713.docx
http://ees.elsevier.com/bcp/viewRCResults.aspx?pdf=1&docID=14187&rev=0&fileID=312318&msid={B4FC665A-DCEB-4E31-A2A7-2CE9BCFF81ED}


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Abstract

There is intense interest in the development and application of animal models of CNS disorders to

explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the

therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic

parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and

heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the

clinical endpoints and the paucity of information regarding underlying molecular mechanisms.

Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders

including anxiety, depression, schizophrenia, and Parkinsons Disease. Recently, however, they have

been increasing criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical

profiles. These failures have resulted from a number of factors including inherent limitations of the

models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS

disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most

commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical

factors that affect the variability and reproducibility of these models. It also addresses how progress in

molecular genetics and the development of transgenic animals has fundamentally changed the approach

to neurodegenerative disorder research. To date, transgenic animal models \ have not been the panacea

for drug discovery that many had hoped for. However continual refinement of these models is leading to


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1. Introduction

Animal models are essential research tools that are used to: explore the underlying pathology and

molecular mechanisms of disorders; evaluate the potential efficacy of therapeutic interventions; and

provide an initial estimate of the safety margin and human dosing parameters of a drug candidate. There

are numerous limitations and caveats to the use of such models, not the least of which is the inherent

challenge associated with attempting to model complex and still poorly understood human disorders in a

lower species This task is particularly difficult for CNS disorders due to the paucity of information about

the genetic and epigenetic origins and molecular mechanisms responsible for these disorders, the

heterogeneous nature of many of these conditions and the subjective and sometimes contradictory

endpoints that are used to describe their symptoms and severity. For example, the DSM IV criteria fordepression include: large increases or decreases in appetite, insomnia or excessive sleeping and

agitation or slowness of movement. The reader is left to ponder the challenge of trying to replicate such

symptom clusters in an animal. A more basic technical challenge when using animal models of CNS

disorders to assess mechanism of action, therapeutic potential or safety margin of candidate or tool

compounds is surmounting the blood-brain barrier (BBB). This involves successfully penetrating the BBB

to gain access to the intended target(s) and avoiding active transport out of the CNS by P-glycoprotein


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different symptom clusters, or endophenotypes, to lead to the same diagnosis [1]. A key criterion that is

often used when assessing the utility of an animal model is validity. The most common types of validity

that are considered are face validitywhich requires similar symptom manifestation to the clinical

condition, construct validitywhich requires the model to have similar underlying biology andpredictive

validitywhich requires responsiveness to clinically effective therapeutic agents.

In general, animal models of CNS disorders have good predictive validity for compounds working

through established mechanisms assuming the compounds have appropriate pharmacokinetic

properties. In many cases, these models were established or refined to detect the therapeutic potential of

prototypical orfirst in class molecules. For example, the Forced Swim Test (FST) gained acceptance

based on its ability to detect the activity of tricyclic antidepressants and needed to be refined to detect the

activity of Selective Serotonin Reuptake Inhibitors (SSRIs) [2,3]. CNS models exhibit varying degrees of

face validity and one of the better examples is the test for pre-pulse inhibition (PPI) [4]. Schizophrenic

patients exhibit deficits in PPI that can be mimicked by treatment with PCP or amphetamine in rodents.

Very few CNS models exhibit construct validity but one good example is the Huntingtons disease (HD)

transgenic mouse [5]. HD is caused by a variable triplet repeat in the coding region of the huntingtin gene

resulting in the expression of aberrant huntingtin protein. The R6/2 knock-in transgenic mouse model

produces aberrant huntingtin protein and exhibits a rich phenotype that includes deficits in motor, mood

and cognition and reduced time of survival [5,6]. Interestingly, transcriptional profiling studies reveal a


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While considerable progress has been made on this front, it is important to remember that a

mouse is not a small rat and there are often critical procedural differences between the rat and mouse

versions of these tests. The following sections describe some of the most popular models for common

psychiatric and neurological disorders, their utility and limitations as well as some future trends. Table 1

provides a list of critical factors for different general categories of models and Table 2 provides a

summary of models and recommended reviews for the disorders covered in this review.

2.1. Depression

Most animal models of depression involve an acute or chronic exposure to a stressor to elicit one

or more symptoms of the disorder. One of the most popular and widely used models of depression is the

rodent FST which is based on the observation that a rat placed in an inescapable cylinder of water will

eventually adopt an immobile posture after initial attempts to escape [2,13]. This behavior is interpretedas a form of learned helplessness or behavioral despair and the time spent trying to escape can be

increased by administration of antidepressants. Modification of the assay to recognize both swimming

and climbing as escape behaviors was necessary for the assay to detect the antidepressant potential of

the SSRIs [3]. The assay is quick and relatively easy to use, reliable across laboratories and is able to

detect a broad range of antidepressants including the dissociative anesthetic, ketamine. There are

distinct differences in the rat and mouse versions of the test, it is quite sensitive to the choice of mouse


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antidepressants including tricyclics, monoamine oxidase inhibitors, monoamine reuptake inhibitors,

atypicals as well as some newer classes such as NMDA receptor inhibitors or mGluR allosteric

modulators that are currently in clinical trials [16]. Moreover, neither anxiolytics nor antipsychotics are

active in these assays [16].

The choice of models that require chronic administration of antidepressants to obtain efficacy is

relatively limited. The most widely used and validated of these are the olfactory bulbectomy and chronic

mild stress (CMS) models [15,17]. Both models involve procedures that result in sustained changes in

behavior that can be reversed by chronic but not acute treatment with antidepressants. In the olfactory

bulbectomy model, surgical removal of the olfactory bulbs results in the development of locomotor

hyperactivity that can be reversed by chronic but not acute treatment with antidepressants [15,17]. The

rat version of this model has been extensively validated with a broad range of antidepressants but it hasseveral caveats, including that antidepressants require several weeks to exhibit efficacy in the clinic but

only days in the model, hyperactivity is not a common symptom of depression and the neuroanatomical

basis for the response is poorly understood. The CMS model involves the repeated but unpredictable

presentation of mild stressors such as temporary food and water deprivation, small temperature changes

and housing changes over a period of 3-4 weeks [15,18,19]. This results in the appearance of several

behaviors that are considered symptoms of depression, such as sustained decreases in sucrose


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such as exploration of the environment with a naturally aversive stimulus such as a brightly lit space to

create conflict or anxiety. For example, in the elevated plus maze (EPM), the animal has a natural

tendency to spend more time in the two enclosed arms rather than the two elevated open arms with no

sides. Treatment with anxiolytic drugs, e.g., the benzodiazepines, increases the number of entries and

time spent in the open arms [21]. While this test controls for some potential confounds, such as changes

in locomotor activity, it is very sensitive to housing, environmental conditions such as ambient light, noise

and odor as well as different strains of mice [22]. Other popular tests in this category include the elevated

zero maze, the light-dark box, the open field, ultrasonic vocalizations and defensive burying [20]. The

defensive burying test, which measures the animals tendency to bury a n aversive object, such as a

shock probe or marbles, is noteworthy because it is the only test in this category that reliably detects the

anxiolytic potential of SSRIs.

Conflict tests combine a motivated behavior, such as eating or drinking, with an aversive stimulus

like a mild shock. This is typified by the Vogel Punished Drinking assay, in which water deprived rats are

given access to water but drinking behavior is punished by a mild shock [23]. Anxiolytics such as

benzodiazepines, produce an increase in water consumption. Other tests in this category include the

Geller-Seifter test, Four-plate test, Novelty-suppressed feeding and Novelty-induced hypophagia [20].

The Vogel and Geller-Seifter tests are thought to have a low incidence of false positives when assessing


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2.3. Schizophrenia

Animal models of schizophrenia can be fit into three general induction categories: pharmacological,

developmental and genetic. Three distinct clusters of symptoms have been identified in schizophrenic

patients: positive symptoms such as hallucinations and delusions, negative symptoms such as emotional

withdrawal and anhedonia and cognitive dysfunction including impaired working memory and attention.

Patients often present with heterogeneous combinations of symptoms making diagnosis, treatment and

modeling extremely difficult. The most successful and widely used models of schizophrenia involve acute

or chronic treatment with amphetamine or phencyclidine (PCP) which produce increases in locomotor

activity and deficits in PPI of startle [26]. These models are based on the observation that both drugs can

produce hallucinations and delusions when administered in man and PCP can produce a sustained

relapse in patients with schizophrenia following a single exposure [27]. All currently marketed

antipsychotics are active in these models but the general consensus is that they only address the positive

symptoms and have limited effects on the other symptom clusters. Schizophrenia is considered to be a

neurodevelopmental disorder that is typically manifest after puberty. Treatment of pregnant rats with

methylazoxymethanol (MAM), a mitotic inhibitor that targets neuroblast proliferation produces long-lasting

anatomical and behavioral deficits in the offspring that resemble many aspects of schizophrenia. These

deficits include reduction in the size of neocortical and limbic structures, enhanced locomotor response to

amphetamine, increased dopamine release in the nucleus accumbens and impaired PPI [27,28]. Another


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MAM model is very sensitive to the timing of MAM administration and the behavioral effects in the social

isolation model are relatively fragile and can be reversed by handling. The mortality reported for the

neonatal ventral hippocampal lesion model is about 15% and up to 30% exhibit hippocampal damage that

fails to meet criteria. Clearly these models are not suitable for routine screening of drug candidates but

can be used to explore the pathology and molecular mechanisms underlying this disorder.

There is compelling evidence that schizophrenia is a genetic disorder with heritability around 80%

but there is no single genetic mutation that is responsible for this heterogeneous disorder [31,32]. Rather,

several candidate genes have been associated with increased risk of schizophrenia. These genes are

primarily involved in neuronal plasticity, dopaminergic or glutamatergic function and synaptogenesis and

there is a significant effort underway to create transgenic animal models based on manipulation of these

genes. Genes of interest include DISC-1 (disrupted-in-schizophrenia 1), NRG1 (neuregulin-1), and

Reelin which are all involved in synaptogenesis and synaptic plasticity and dysbindin which is involved in

exocytosis and receptor trafficking [27]. Additional studies involving 18 GWAS studies and over 1 million

SNPs have implicated a wide variety of genes including a number involved in T-cell related immune

function [31]. Transgenic mice with constitutive knockout, inducible knockout, reduced expression or

mutations of these genes have been created and each exhibit unique and complex phenotypes that

include characteristics associated with schizophrenia [33,34]. Further study is required however before


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cognitive tests and there are several excellent reviews on this topic [36,37,38]. This is an ongoing effort

that will no doubt affect the development of animal models of schizophrenia for the foreseeable future.

Many recently completed clinical studies of cognitive impairment associated with schizophrenia followed

the MATRICS guidelines but in general were underpowered or too short to detect modest effects. Larger

ongoing studies that are following these guidelines are more likely to provide useful insight into the

predictive validity of the recommended preclinical tests [39,40].

3. Neurodegenerative diseases

3.1. Alzheimers Disease

Over the last 15 years, there has been a tremendous effort focused on the development and

characterization of animal models for AD. This has been fueled by the anticipated tidal wave in

prevalence of this disease based on the rapid growth and increased longevity of an aging population, and

the recognition that there are presently no disease-modifying therapies for this disease. Moreover,

progress in human genetics has identified multiple genes linked to specific forms of the disease, at last

count in excess of 130 [41].

Animal models of AD fall into 3 general categories, pharmacological, lesioned and transgenic.

The first two categories are based on the observation that cholinergic transmission is impaired in AD and

cholinergic neurons preferentially degenerate as the disease progresses. The most commonly used


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pathology that is characteristic of this disease [45,46]. Consequently, recent efforts have been devoted

primarily to the development of transgenic models of AD.

Mutations in three genes, amyloid precursor protein (APP), presenilin-1 (PSEN1) and presenilin-2

(PSEN2) cause autosomal dominant AD and mutated forms of these genes are the basis of the majority

of current transgenic models. These autosomal dominant forms make up only a small fraction of AD

cases, but their pathology and symptoms are thought to be similar to the more prevalent sporadic form of

AD. Mutations in each of these genes alter the processing ofamyloid (A) by APP and result in

increased levels of the toxic A42 form [47]. Several distinct mutations have been identified in the APP

gene and are named for the geographic location of their discovery. Thus, the Swedish mutation

increases Aproduction, the London and Indiana mutations increase the proportion of A42 and the

Arctic mutation increases fibrillogenesis. The most widely used mouse models of AD involve transgenic

expression of mutated human APP [47]. Several APP lines exist and they all develop amyloid pathology,

exhibit synaptic toxicity and memory deficits but do not exhibit degeneration or loss of neurons. The lines

differ in terms of the promoters used, which drive levels and spatial patterns of expression, the isoforms

(APP695, APP751, or APP770), the mutation or combination of mutations which influences the severity

and onset of the phenotype and the background strain which can modulate the phenotype [47]. One of

the earliest transgenic lines, the Tg2576 as well as most currently used mouse lines use the Swedish


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rodents and primates both exhibit accumulation of A, cognitive impairment and development of

neurodegeneration but are technically challenging to use on a routine basis [51].

None of the models described so far produce the neurofibrillary tau pathology that is

characteristic of AD. No mutations of tau have been directly linked to AD but some have been shown to

cause frontotemporal dementia (FTD). To produce lines that exhibit both the plaque and neurofibrillary

tangle pathology of AD, lines containing mutant tau have been crossed with lines containing mutant hAPP

and/or PS1. The most notable of these is the 3xTg line which combines hAPP with the Swedish mutation

with single mutation forms of tau and PS1. This line develops plaque pathology before tangle pathology

just as observed in humans [52]. It is anticipated that lines of transgenic rodents will be further refined in

an effort to more faithfully recapitulate the pathology and behavioral phenotype of AD. Along these lines,

a transgenic rat line has been produced using hAPP with the Swedish mutation, and PS1 with the delta 9mutation in the Fischer 344 strain. The animals exhibit both amyloid plaque and tau neurofibrillary tangle

pathology, cognitive deficits, neurodegeneration and neuronal loss [12]. This model seems to have a

high level of fidelity with regard to current concepts of AD pathology and will provide the opportunity to

evaluate the behavioral phenotype using some of the more robust rat tests for cognition and mood. One

important caveat is that although mild cognitive deficits are detectable at 6 months in this model, robust

pathology and cognitive deficits are not observed until 15 months [34]. Despite considerable progress in


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Huntingtons Disease (HD) is an autosomal dominant neurodegenerative disorder that is associated with

numerous motor, cognitive, behavioral and psychological impairments. The mutation consists of an

expansion within the poly-CAG repeat region in exon 1 of the huntingtin gene that results in production of

aberrant huntingtin protein with an expanded stretch of polyglutamine near the N-terminus [53,54]. The

physiological function of huntingtin remains unknown but a longer stretch of polyglutamine repeats is

associated with an earlier age of onset and more severe symptoms. Prior to the identification of the

mutation in 1993 [53], HD was modeled by injection of kainic or quinolinic acid into the striatum [55].

These neurotoxins destroy discrete populations of neurons, with quinolinic acid lesions exhibiting greater

fidelity to the human pathology and resulted in animals with behavioral and neurochemical abnormalities.

Quinolinic acid lesions in the monkey have been used to create a primate model that exhibits many of the

neuropathological, neurochemical and clinical features of HD [56,57]. The transgenic mouse models of

HD can be grouped into three general categories: mice that express the N-terminal fragment of the

human huntingtin gene containing the polyglutatamine mutations; knock-in mice with additional CAG

repeats inserted into the existing CAG expansion in the murine gene; and mice that express the full-

length human huntingtin gene along with the murine form [55,58]. The R6/2 line was the first transgenic

model of HD and it is the most thoroughly characterized and widely used. It expresses an N-terminal

fragment of huntingtin with approximately 144-150 CAG repeats and exhibits a progressive behavioral

and neuropathological phenotype that closely resembles human HD [59]. Motor deficits are observed as


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[60,61]. The current focus of work in this area is likely to be on the evaluation of potential therapeutics in

existing transgenic models.

3.3. Parkinsons Disease

Parkinsons Disease (PD) is the second most common age-related neurodegenerative disease

after AD and is characterized by resting tremor, slowness of movement, postural instability and freezing.

It is caused by a progressive degeneration of dopaminergic neurons that are primarily located in the

substantia nigra pars compacta but the molecular basis of the disorder remains unknown [62,63]. The

two categories of PD models are toxin-based models and transgenic mice. The first animal model of PD

involved the central administration the toxin, 6-hydroxydopamine (6-OHDA) into dopaminergic cell or

terminal regions. 6-OHDA is preferentially transported into dopaminergic neurons by the dopamine

transporter where it accumulates and produces toxic reactive oxygen species (ROS) that ultimately kill the

neuron. The toxin does not cross the blood-brain barrier and unilateral administration results in

asymmetric circling behavior that is particularly suitable for the evaluation of therapeutic interventions

[62,64,65]. 6-OHDA does not produce the same cellular pathology that is observed in PD and does not

appear to work via the same molecular mechanism. The current gold standard animal model of PD is

the MPTP primate model [62]. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)is a neurotoxin that

was inadvertently produced during the synthesis of an analog of Demerol for recreational use. Ingestion


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[62]. Unfortunately, the translational utility of these models for new mechanistic approaches focused on

neuroprotection in PD has been disappointing [66].

There are relatively rare forms of PD that have been linked to genetic mutations. The two

autosomal dominant genes are -synuclein and leucine rich repeat kinase 2 (LRRK2). -synuclein is an

abundant presynaptic phosphoprotein that is a major structural component of Lewy bodies, a hallmark

pathologic feature of PD and point mutations or duplications are sufficient to cause PD. Several -

synuclein transgenic lines have been created and their phenotype heavily depends on the choice of

promotor [67,68]. None of the models accurately represent PD. While there are some dopamine-

responsive functional abnormalities, there is no progressive loss of dopaminergic neurons. Only

transgenic mice with the prion promotor (mPrP) exhibit the full range of-synuclein pathology that is

observed in humans [68]. LRRK2 is a large multi-domain containing protein that is localized to

membrane structures and mutations linked to PD are concentrated in the GTPase and kinase domains

[69]. Transgenic LRRK2 mice have abnormalities in the nigrostriatal system and behavioral deficits that

are dopamine-responsive. However, they display a very mild phenotype with minimal evidence of

neurodegeneration and are clearly not robust models of PD [70]. There are several autosomal recessive

genes that have been linked to PD and the best characterized of these are parkin, DJ-1 and PINK1.

Knockout mice have been created for each of these genes but none of them exhibit nigrostriatal


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sensory modalities which makes interpretation of an animals behavioral response to pain particularly

difficult. There are acute pain models as well as chronic models of arthritis, cancer and neuropathy-

related pain. Tests that are most commonly used to evaluate different sensory modalities of pain include

the von Frey and Randal-Sellito tests for mechanical sensation; tail flick, hot plate and Hargreaves tests

for heat sensation; and the acetone, cold plate and cold water tests for cold sensation (see [73]). Acute

models of pain include subcutaneous injection of formalin into the plantar tissue of the paw, i.p.

administration of an irritant such as acetone and surgical incisions in multiple parts of the body [74]. In

general, these models are sensitive to analgesics of different classes. In recent years, the major focus in

this field has been on the development and improvement in the assessment of models of chronic pain

[72]. The two most commonly used models of neuropathic pain are the chronic constriction injury (CCI)

and spinal nerve ligation (SNL) models [75,76]. The CCI model utilizes loosely constrictive ligatures

around the sciatic nerve at mid-thigh level to produce long-lasting changes in posture, gait and

spontaneous paw-lifting [77]. The SNL involves tight ligation of spinal nerves L5 and L6 distal to the

dorsal root ganglia to produce increased sensitivity to noxious heat and mechanical stimuli as well as

licking of the affected paw [78]. When directly compared, the SNL model exhibited more pronounced

mechanical hypersensitivity whereas the CCI model was associated with more behavioral signs [79]. It is

important to note that surgical skill, variations in procedures and differences in genetic strains can all

influence the performance of these models [74].


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after a set period of time to make the occlusion transient rather than permanent [90]. The disadvantage

of both of these approaches is that they involve opening the skull and require significant surgical skill [91].

Alternatively, stroke may be produced by a procedure termed thread occlusion in which a thread or

balloon catheter is inserted into a large peripheral artery and advanced to the origin of the MCA [92].

These methods do not require a craniotomy and the thread or catheter can be removed at any time to

permit controlled reperfusion but they also require considerable surgical skill. Unfortunately, the vessel

occlusion approaches do not model the actual mechanism of occlusion since most large infarcts result

from thromboembolism [91,93]. To address this limitation, embolic models have been developed, in

which a suspension of small clot fragments is injected into the common carotid artery [94]. Acute

mortality associated with this approach is low but, not surprisingly, the foci of infarction are widely

distributed and mortality can be as high as 30-40% within 24 hours [91]. There have been numerous

clinical trials with compounds that were efficacious in one or more of these models but to date only tPA

(tissue plasminogen activator) is approved for the treatment of stroke. Some 114 compounds with

neuroprotective activity in preclinical stoke models (average of 25%) have advanced to clinical trials with

no evidence of significant efficacy [95]. It is still not clear whether this is due to limitations of the models or

the clinical trials, but in either case, the predictive validity of these models remains to be determined. It is

certainly possible that greater than 25% neuroprotection is required to obtain efficacy in stroke patients

and that administration of candidates before or concomitantly with the stroke insult in preclinical studies is


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McGonigle CNS Models - Tables-Revised 061713.docx


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criptTable 1. Critical Factors Affecting Variability and Reproducibility

All Models Transgenic Models Lesion Models

Sex Gene construct Surgical skill

Strain Penetrance Choice of toxin

Age Constitutive/Inducible Dose and speed of delivery

Housing Choice of Promotor Extent of damage

Handling Pathological Phenotype Recovery environment & Time

Environment Behavioral Phenotype Infections

Confounding Behavior Rare or common mutation Post-op anesthetic


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criptTable 2.Summary of animal models of CNS Disorders

Disorder Category Representative

Tests

Rationale Strengths Weaknesses Predictive

Validity

Reviews

Depression Acute Forced Swim

Tail Suspension

Acute stress

produces form ofbehavioral

despair

Fast,

reproducible,widely used

Acute effect not

consistent withdelayed onset of

ADs in clinic

Good for SSRIs,

SNRIs, TCAs andKetamine

[13], [15]

[97], [98]

Chronic Chronic Mild

Stress, Olfactory

Bulbectomy,

Social Defeat

Chronic stress

produces long

lasting

behavioral

changes that

resemble

symptoms of

depression

Multiple

symptoms that

can be reversed

by chronic but

not acute drug

treatment

Time consum-

ing, labor inten-

sive, costly,

limited

reproducibility

across labs

Good for SSRIs,

SNRIs, TCAs, ECS

and Ketamine

[13], [15]

[18], [97]

Anxiety Ethological Elevated Plus

Maze, Light/Dark

Box, Open Field,

Defensive Burying

Conflict between

naturally

occurring

behavior and

naturally

aversive

situation

Fast,

reproducible,

sensitive, widely

used

Very sensitive to

environmental

factors, strain

differences,

False positives

Good for

benzodiazepines,

5-HT1A agonists,

Defensive

Burying also

good for SSRIs

[21]

Conflict Vogel Punished

Drinking, Geller-

Seifter, 4-Plate,

Novelty

Suppressed

Feeding

Conflict between

motivated

behavior and

aversive stimulus

Fewer false

positives

May require

operant

conditioning,

less sensitive to

novel

mechanisms

Good for

benzodiazepines,

4-plate and NSF

detect SSRIs,

SNRIs, TCAs

[20], [23]

Cognitive Fear Conditioning,

Fear Potentiated

Startle

Conditioned to

associate neutral

stimulus with

aversive

properties

Assesses the

learning

component of

fear and anxiety

Time

consuming,

requires

conditioning

Good for

benzodiazepines,

5-HT1A agonists

[9], [20]

[24]


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criptSchizophrenia Pharmacological PCP,

Amphetamine

Compounds

produce

psychotic

symptoms in

man

Fast,

reproducible,

reliable across

labs, good for

positive

symptoms

Acute model, no

developmental

pathology, does

not model

negative

symptoms

Good for typical

and atypical

antipsychotics

[26]

Developmental MAM treatment,

Post-weaning

Isolation, Ventral

Hippocampal

Lesion

Produce

developmental

abnormalities

and post-puberty

deficits

Mimics time

course and some

developmental

aspects of

disorder

Time

consuming, low

throughput, not

suitable for

screening

Not sufficiently

validated

[27], [29]

Genetic DISC1, NRG1,

Dysbindin

Based on genetic

linkage,

associated with

increased

susceptibility

Produce distinct

neurological and

behavioral

phenotype

Mild

phenotypes

Not sufficiently

validated

[4], [27]

[34]

Alzheimers

Disease

Pharmacological Scopolamine Based on

degeneration of

cholinergic

system in AD

Produces

cognitive

impairment,

mimics

degeneration of

cholinergic

neurons

Does not

reproduce

pathology or

progressive

nature of

disorder

Good for

symptomatic

therapies such as

AchE inhibitors

[43]

Lesion Transection of

Fimbria Fornix,

Electrolytic orchemical lesion of

cholinergic nuclei

Based on

Degeneration of

cholinergicsystem in AD

Produces

cognitive

impairment anddegeneration of

cholinergic

neurons

Does not

reproduce the

pathology orprogressive

nature of the

disorder

Good for

symptomatic

therapies such asAchE inhibitors

[44], [51]

Transgenics Tg2576, hAPP,

PSAPP, 5XFAD,

3XTg, PSAPP rat

Genetic

mutations linked

to rare forms of

AD that exhibit

symptoms of

Recapitulate

multiple aspects

of the pathology,

exhibit cognitive

deficits, show

Majority exhibit

only subset of

pathology,

based on rare

forms

Good for AChE

inhibitors,

disappointing to

date for novel

therapies

[46], [47]

[51]


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criptsporadic AD progression

Huntingtons

Disease

Lesion Kainic Acid,

Quinolinic Acid

Mimic loss of

discrete

populations of

neurons in

caudateputamen

Produce many

behavioral

deficits

associated with

HD

Do not mimic

pathology,

progressive

nature or

reduced survival

Limited

validation

[56], [57]

Transgenics R6/2, HdhQ111,

YAC128

Based on

autosomal

dominant

mutation

responsible for

disorder

Complex

phenotypes,

mimic pathology,

progressive

deficits and

reduced survival

for R6/2

Most faithful

mutations

produce mild

phenotype,

limited

progression,

normal survival

Not sufficiently

validated but

tetrabenazine is

active in YAC128

mice and

patients

[5], [54]

[55], [58]

Parkinsons

Disease

Toxins 6-OHDA, MPTP Based on well-

establisheddegeneration of

dopaminergic

neurons

Robust motor

deficits, MPTPproduces

Parkinsonism

in man and

primates

Some aspects of

disorder notobserved, such

as Lewy Bodies

and Locus

Coeruleus

involvement

Good for

dopaminergicmechanisms, not

for disease-

modifying agents

[62], [63]

[64], [65]

Transgenics -synuclein,

LRRK2, Parkin, DJ-

1, Pink-2

Based on genetic

mutations linked

to rare forms of

disorder

Reproduce some

of the pathology

associated with

the disorder

Mild or no

phenotypes and

no

dopaminergic

degeneration

No information [63], [67]

[70]

Pain Acute Formalin

Injection,

Writhing, Surgical

Incision

Introduction of

irritant or

production of

tissue damage

Fast,

reproducible and

sensitive to

many

mechanisms

Dont model

more common

chronic or

pathological

conditions

Good for several

established

classes e.g.,

opiates and

NSAIDS

[72], [74]

Neuropathic Spinal Nerve

Ligation, Chronic

Constriction

Based on

production of

nerve damage

Chronic

condition with

robust

Can be

technically

challenging,

Good for

established

classes of

[72], [74]

[75], [76]


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Page 29 of 29

Accepted

Manus

criptInjury,

Streptozotocin,

Paclitaxel

using surgical,

chemical or

metabolic

approaches

symptoms,

reproducible

across labs

time consuming,

subject to false

positives

analgesics but

several false

positives recently

Cancer Bone tumors Mimic bone

metastases toproduce pain

Produces robust

symptoms andmimics

physiological

response

Technically

difficult andtime consuming

Good for

establishedclasses, not yet

validated for new

mechanisms

[83], [84]

Stroke Occlusion Ligature, clips,

cauterize

Mimic focal

ischemia by

restricting blood

flow

Produces

ischemic damage

to discrete

regions

Difficult to

control and

reverse

Poor, based on

failure of

multiple stroke

trials

[91]

Emboli Injection of

emboli

Mimic the cause

of major infarcts

Produces

significant

ischemic damage

Difficult to

control, not

transient

Good for tPA, so

far not predictive

for any othermechanisms

[91]

Documents

Animal Models of CNS Disorders