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Objective: This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia.
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/7748391 Importance of Animal Models in Schizophrenia Research Article in Australian and New Zealand Journal of Psychiatry · August 2005 Impact Factor: 3.41 · DOI: 10.1111/j.1440-1614.2005.01626.x · Source: PubMed CITATIONS 63 READS 221 4 authors, including: Maarten van den Buuse La Trobe University 233 PUBLICATIONS 4,092 CITATIONS SEE PROFILE Snezana Kusljic University of Melbourne 30 PUBLICATIONS 260 CITATIONS SEE PROFILE Available from: Maarten van den Buuse Retrieved on: 16 April 2016 Importance of animal models in schizophrenia research M. van den Buuse, B. Garner, A. Gogos, S. Kusljic Objective: This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia. Method and Results: Several aspects of animal models are addressed, including an- imal experimentation ethics and theoretical considerations of different aspects of valid- ity of animal models. A more speciﬁc discussion is included on two of the most widely used behavioural models, psychotropic drug-induced locomotor hyperactivity and pre- pulse inhibition, followed by comments on the difﬁculty of modelling negative symptoms of schizophrenia. Furthermore, we emphasize the impact of new developments in molecular biology and the generation of genetically modiﬁed mice, which have generated the concept of behavioural phenotyping. Conclusions: Complex psychiatric illnesses, such as schizophrenia, cannot be exactly reproduced in species such as rats and mice. Nevertheless, by providing new informa- tion on the role of neurotransmitter systems and genes in behavioural function, animal ‘models’ can be an important tool in unravelling mechanisms involved in the symptoms and development of such illnesses, alongside approaches such as post-mortem studies, cognitive and psychophysiological studies, imaging and epidemiology. Key words: amphetamine, animal models, genetically modiﬁed animals, motor activity, prepulse inhibition, schizophrenia. Australian and New Zealand Journal of Psychiatry 2005; 39:550–557 As neuroscientists involved in fundamental research, we are often asked how our animal behavioural work can advance knowledge about complex human mental illnesses such as schizophrenia. There appears to be a misconception that an animal model can and should re- produce the human disease in all its aspects. Rats and mice are obviously very different from humans and the simplerbraincorticalstructureofrodentswouldmake it impossible to display the same kind of complex symp- toms as humans. This paper will emphasize, however, that animal research isvery important for our understand- ing of human psychiatric illness. We will focus here on M. van den Buuse (Correspondence), B. Garner, A. Gogos, S. Kusljic Behavioural Neuroscience Laboratory, The Mental Health Research Institute of Victoria, 155 Oak Street, Parkville, Victoria 3052, Australia. Email: email@example.com Received 19 March 2004; revised 11 October 2004; accepted 29 January 2005. schizophrenia, but the same principles also apply to other psychiatric illnesses. We will describe a number of ani- mal behavioural models with relevance to schizophrenia and illustrate their usefulness with recent results from our own studies. Animal experimentation ethics When using experimental animals in behavioural re- search, ethical considerations as well as scientific con- siderations should be extremely important. There is con- cern in the general public and media about the use of animals, particularly primates, for scientific research. It is the responsibility of the scientists to explain exactly why animals are needed, what they are used for and how the results may benefit human clinical practice. If using animals for research, the scientist should use as few ani- mals as possible, use the best possible methods and pay M. VAN DEN BUUSE, B. GARNER, A. GOGOS, S. KUSLJIC 551 special attention to minimizing pain or discomfort in the animals. Animal research in Australia is done within the guidelines of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes . Although these guidelines have provided a workable environment, even without such guidelines, ethically responsible use of experimental animals should be of the utmost impor- tance for any researcher. In addition, it is clear that ani- mals that endure pain or distress may provide erroneous data, particularly where subtle changes in behaviour are studied. Animal models Geyer and Markou discussed the validity of animal models of psychiatric disorders . They state that ‘The primary purpose of animal models is to enhance our un- derstanding of a human phenomenon’  and recognize that it is very difficult to reproduce a disease as complex as schizophrenia in an animal. Other possibilities are then to only use animals to study the effect of new treatments. Thisisessentiallyaratherrestrictedandcircularbioassay approach. For example, amphetamine-induced locomo- tor hyperactivity in rats has been widely used to test new compounds for antipsychotic activity. However, as will be discussed in more detail later, amphetamine-induced hyperactivity in rodents is mediated by enhanced subcor- tical dopamine release. Compounds such as haloperidol, may reduce this activity by blocking dopamine receptors, but compounds with weak dopamine receptor affinity, such as clozapine and other atypical antipsychotics, will have little effect. Modern advances in receptor binding technology and computer modelling in chemistry have largely superseded the use of animals purely as bioassay systems. Althoughitmaybeimpossibletomodeltheentirecom- plex symptomatic spectrum of a psychiatric illness in an animal, selected symptoms may be successfully mim- icked and have validity. Behavioural models should at minimum have predictive validity and be reliable [3– 5]. Predictive validity refers to the predictive value that observations made in animals will have for the human condition. Reliability refers to the accuracy with which both the experimental and clinical observations are made [3,4]. These concepts are particularly relevant for as- say models, such as those used in the development of new antipsychotic drugs. However, face validity relates to phenomenological similarity between the behaviour exhibited by the animal and the specific symptoms of the human condition . Therefore, it would be unrealistic to expect similar behaviours in rodents as in humans and it is more important to search for relevant equivalents based upon the brain areas and transmitter systems assumed to be involved. Construct validity is then more relevant, as it refers to similarity in the underlying mechanisms that are involvedinparticularbehaviours,eventhoughtheprecise expression of behaviours may differ between humans and experimentalanimals.Anextensionofcontrastvalidityis aetiologicalvalidity,whichreferstothedegreeofsimilar- ity of aetiology between behavioural changes in humans and the experimental animal model studied. For com- plex human illnesses, such as schizophrenia, aetiological validity is difficult to assess, because so little is known about the aetiology of the illness. However, the animal model can be used to test hypotheses about the possi- ble aetiology of the illness. Any animal model, where either the entire illness, aspects of it, or treatments for it are modelled, should be discussed as to their predictive validity, face validity, construct validity or aetiological validity. Two of the most widely used animal models of psy- chosis have been the measurement of the extent of locomotor hyperactivity induced by amphetamine or phencyclidine treatment in rats . Prepulse inhibition (PPI) has been widely used to assess sensory informa- tion processing problems (sensorimotor gating) that may underlie some symptoms of the illness. However, other aspects of schizophrenia, such as negative symptoms, ap- pear to be very difficult to model in rodents . Psychotropic drug-induced hyperactivity For more than 25 years, the effect of psychotropic drugs, such as amphetamine, on locomotor activity in rodents has been used to model positive symptoms of schizophrenia, particularly psychosis. Early studies in rats showed that prior depletion of dopamine in the ven- tral striatum (nucleus accumbens) could completely pre- vent amphetamine-induced hyperactivity, suggesting the importance of subcortical dopamine release in the ef- fects of amphetamine and similar drugs [6,7]. It was only recently that similar conclusions were drawn in human research. Using imaging techniques in normal human subjects, Drevets et al. found that amphetamine, at a dose very similar to that used in rats, caused a much greater dopamine release in the ventral striatum than in the dorsal striatum [8,9]. Furthermore, the euphoric ef- fect of amphetamine treatment correlated with its neu- rochemical effect in the ventral striatum, but not in the dorsal striatum . These observations are relevant for schizophrenia. Amphetamine-induced dopamine release in the striatum was found to be markedly increased in patients with schizophrenia compared to controls  and this enhancement was seen at onset of illness and in 552 ANIMAL MODELS IN SCHIZOPHRENIA RESEARCH never-before treated patients during psychotic episodes and relapse, but not during periods of remission . Taken together, these studies suggest that enhanced sub- cortical dopamine release is a prominent feature of psychosis in patients with schizophrenia, a compara- ble enhancement of dopamine release can be obtained with amphetamine treatment, and that such an effect of amphetamine is similar in humans and experimental rodents. This comparison of the effects of amphetamine also emphasizes that, when studying animal behaviour, one has to look for behavioural effects that are relevant for thatspecies:inhumans,amphetaminemayinduceeupho- riaandpsychosisinadditiontohyperactivity,whereasthe same treatment in rodents induces mostly locomotor hy- peractivity[6–9].Althoughitisdifficulttoreliablyassess other effects of amphetamine in rats and mice, locomotor activity can be easily quantitated by several means. Tech- niques range from human observations and rating scales, which are labour-intensive and prone to subjectivity and human error, to automated photocell set-ups, which allow objective measurements and high throughput. We have used the amphetamine-induced locomotor hy- peractivity model to study the role of central serotonergic projections in the brain in the modulation of dopaminer- gic activity. Interest in the possible role of serotonin in thepathophysiologyofschizophreniahasoriginatedfrom the observation that many atypical antipsychotics dis- play significant serotonin receptor subtype binding affin- ity. Furthermore, neurochemical measurements in post- mortemsampleshaverevealedmarkedchangesinindices of serotonergic activity in patients with schizophrenia. For example, affinity of the serotonin transporter was significantly reduced in the ventral hippocampus, whereas the density of 5-HT2A receptors was reduced in the frontal cortex . We assessed the effect of selective serotonin deple- tion in the brain of rats on locomotor hyperactivity in- duced by amphetamine or phencyclidine in these ani- mals . Microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the midbrain dorsal raphe nucleus (DRN) caused marked depletion of serotonin in the striatum and hypothalamus, but not hippocampus, whereas this microinjection into the median raphe nu- cleus (MRN) depleted serotonin in the hypothalamus and hippocampus, but not striatum . Studies in humans could never induce similarly selective depletions of sero- tonin. Current strategies, such as dietary amino acid de- pletion  induce serotonin depletion throughout the brain, a global effect that makes it difficult to ascribe function to any brain regions or serotonergic projection system in particular. In our studies, rats with lesions of the DRN showed no changes in the extent of locomotor Figure 1. Effect of lesions of the median raphe nucleus (MRN) or dorsal raphe nucleus (DRN) on the change in locomotor activity induced by treatment with amphetamine (0.5mgkg−1) or phencyclidine (PCP, 2.5mgkg−1). Lesions were induced by microinjection of 5,7-dihydroxytryptamine into either one of the raphe nuclei 2 weeks before the behavioural experiments. In MRN-lesioned rats, the effect of PCP was markedlly enhanced, supporting a role of brain serotonergic projections from this nucleus in symptoms of schizophrenia. For further details see . hyperactivity induced by either amphetamine or phen- cyclidine. However, in rats with selective MRN lesions, locomotor hyperactivity to phencyclidine, but not am- phetamine, was significantly enhanced (Fig. 1) . Fur- ther studies determined that serotonin depletion in the dorsal hippocampus, to which the MRN projects, also leads to marked enhancement of the locomotor hyperac- tivity response to phencyclidine treatment . Although these effects were studied relatively early af- ter the lesions (2–3 weeks), we are now studying the effect of chronic interventions on the neurodevelopment of behaviour. For example, the effect of neonatal stress, combined with later stress or treatment with stress hor- mones, may provide a way to study the synergistic effects of early and late developmental insults on the pathophys- iology of schizophrenia . Such studies are of great importance in order to test the ‘two-hit’ hypothesis of schizophrenia[18,19]andwouldbeverydifficulttocarry out in humans. Prepulse inhibition (PPI) Another example of behavioural observations with close similarity between humans and experimental animals, is PPI. As extensively reviewed by Geyer, PPI M. VAN DEN BUUSE, B. GARNER, A. GOGOS, S. KUSLJIC 553 Figure 2. Comparable prepulse inhibition (PPI) of acoustic startle in male C57BL6/129J mice, Sprague–Dawley rats and Dunkin–Hartley guinea pigs. PP2 to PP16 refers to prepulse intensity levels of 2–16 dB above the 70 dB background noise used in the experiments. % inhibition refers to the percentage inhibition of the startle response by prepulses 100msec before the 115dB acoustic pulses [24,48,51,52]. There were 6–12 animals per group. is an operational measure of sensorimotor gating, essen- tially a shielding mechanism against sensory information overload or ‘inundation’ [3,17,20–22]. Prepulse inhibi- tion of the acoustic startle uses a very simple behavioural response to study this gating mechanism. Startle is medi- ated by a simple neuronal circuit in the brainstem, the ac- tivityofwhichismodulatedbyseverallimbicandcortical regions.Thelatterbrainregionsincludemedialprefrontal cortex, nucleus accumbens, hippocampus and amygdala. Prepulse inhibition is similar between different species (Fig. 2) and most rat strains (Fig. 3). Treatment with dopaminergic drugs, such as apomorphine or am- phetamine, has been reported to cause a disruption of PPI similar to that seen in patients with schizophrenia or other psychiatric disorders [17,20,23]. It should be noted, however, that in rats as well as mice, differences have been observed in the sensitivity to the disruption of PPI by drugs such as apomorphine and amphetamine [20,23–26]. Strain-relateddifferences inbaselinePPIand sensitivity to drug treatments become particularly impor- tant in studies using genetically modified mice, where the background strain of mice could determine or contribute to the extent of any deficiency in PPI [23,27]. Severalserotonergictreatmentsalsocausedisruptionof PPI[20,23].Recently,weobservedthatselectiveseroton- ergic lesions of the MRN, but not DRN, cause a marked reduction of PPI . This indicates that such lesions have effects in more than one model of the aspects of schizophrenia. Figure 3. Comparison of acoustic startle amplitude (top panel) and prepulse inhibition (PPI) of acoustic startle (bottom panel) of seven rat strains. Startle amplitude was calculated as the average amplitude of 20 startle trials during a PPI session; PPI is expressed as the average percentage inhibition obtained from a range of prepulse intensities (see Fig. 2). For further methods and details, see [17,24–26]. Although marked differences were found between rat strains with respect to startle amplitudes, PPI tended to be similar, except in Hooded–Wistar rats (HW) that displayed significantly impaired responses . F344, Fischer 344 rats; FH, Fawn–Hooded rats; HW, Hooded–Wistar rats; SD, Sprague–Dawley rats; SHR, spontaneously hypertensive rats; WKY, Wistar–Kyoto rats. In other studies, we observed that administration of the serotonin-1A receptor agonist 8-hydroxy-di-propyl- aminotetralin (8-OH-DPAT) also disrupts PPI and that this effect could be modulated by sex steroids. In male rats, castration prevented the effect of 8-OH-DPAT on PPI, whereas testosterone treatment restored it . In- terestingly, in female rats, ovariectomy did not alter the effect of 8-OH-DPAT on PPI; however, treatment of ovariectomized rats with either a high dose of oestro- gen or a combination of a low dose of oestrogen with progesterone, prevented the disruption . These find- ings show that sex steroids potently, and in a sex-specific way,modulatetheeffectofserotoninreceptorstimulation 554 ANIMAL MODELS IN SCHIZOPHRENIA RESEARCH on PPI, with the effect of testosterone being essentially permissive in male rats and oestrogen and progesterone being protective in female rats. Such an effect of sex steroids could be important for our understanding of how hormones could be involved in sex differences in the first occurrence and symptomatology of schizophrenia . It has been shown by Kulkarni et al. that addition of oe- strogen treatment could accelerate and enhance the effect of antipsychotic treatment in acutely psychotic women [31,32]. Our findings in rats may help to explain the mechanism of this interaction. Negative symptoms of schizophrenia Ellenbroek and Cools recently reviewed the published work on animal models for the negative symptoms of schizophrenia . They suggested that ‘few of the nega- tive symptoms lend themselves to modelling in animals’. For example, alogia and affective flattening are partic- ularly difficult to measure reliably in rats and mice . Only social withdrawal is relatively easy to measure in such animals and in monkeys. In rats, social interaction can be quantified and this process has, in some studies, been automated to facilitate reliability of measurements andincreasethroughput[33,34].Ratsthataretreatedwith phencyclidineshowasyndromeofstereotypedbehaviour and reduced social interaction when observed in a test environment with another untreated rat . Treatment with antipsychotic drugs can inhibit these behaviours . There are several learning and memory tests in rodents, focusingondifferentaspectsofmemory.Forexample,the classic Morris water maze determines long-term spatial memory, a behaviour particularly dependent on intact hippocampal function . The Y-maze is a simple test for short-term spatial memory , whereas the T-maze test has been used to assess working memory in rodents .Thesetestscouldbeusedtoassesscognitivechanges in experimentally treated animals, providing an insight into central mechanisms involved in cognitive changes in schizophrenia. New genes and gene products Schizophrenia and other mental illnesses have a strong genetic component  and molecular and genetic stud- ies have revealed several candidate genes that could be involvedinthedevelopmentoftheillness.Animpor- tant role for animal research in psychiatry will be funda- mental in vivo research into the role of such new genes, gene products and basic brain mechanisms, preferably before drug development. Traditionally, this has been at- tempted by combining research on different rat strains with genetic linkage analysis [40,41]. More recently, par- ticularly work on genetically modified mouse models has become the method of choice to provide greater under- standing of the role of genes in brain mechanisms in schizophrenia. Using molecular biological tools, trans- genic mice have had genes added, leading to overexpres- sion of the gene’s products, whereas knockout mice have had genes removed or inactivated, leading to a short- age of the products of that gene. These models have been very valuable to assess gene function and in the future we will see this even more so for genetic modifi- cations that are brain-region-specific and can be induced by external biochemical means at specific ages (for a dis- cussion and references on the technical aspects of such modifications, see ). A recent review on in vivo phar- macology pointed out that ‘molecular biology, combina- torial chemistry and computer modelling cannot predict the integrated response in the whole animal (or human), particularly for novel genes. The human genome project will identify more than 30000 new gene products and a crucial component of the identification and characteriza- tion of these gene products will be whole-animal studies’ . Many of these genes, including ones implicated in schizophrenia , have not been ‘traditionally’ linked to psychiatric illnesses and a challenge for in vivo neuro- scientists will be to identify their role in animal models of psychiatry, using behavioural tests with relevance to the illness of interest. It is important to realize that transgenic or knockout mouse models, with their marked overexpression or dele- tion of gene function, almost never replicate the subtle changesingenefunctionseenincomplexmentalillnesses such as schizophrenia. Moreover, it is unlikely that mu- tation of a single gene can ever fully replicate the multi- genetic mechanisms that are involved in schizophrenia . These genetically modified mice can therefore only be used to obtain global information about the function of the gene on brain function. This new insight then has to be used as the basis for further studies, for example, on the effect of more subtle alterations in the function of this gene, or administration of the gene product or inhibition of its synthesis. One consideration in the use of animal behavioural models in research on new gene products is which be- havioural models to use. Also questions as to whether to study male and female animals, what age to choose and which neurotransmitter systems to focus on, are not sim- ple to answer. As Crawley and Paylor stated: ‘If called by a molecular geneticist to test a knockout for a newly discovered gene expressed in the brain, with no a priori hypothesisaboutthefunctionofthegene,thebehavioural neuroscientist may be tempted not to answer. One M. VAN DEN BUUSE, B. GARNER, A. GOGOS, S. KUSLJIC 555 wonders where to start and how far to go’ . It is important always to test new knockout models in a bat- tery of behavioural tests. The specificity of behavioural responses needs to be assessed: if there are problems with the general health of the animals or neurological complications, this will influence the outcome of many behavioural tests which often rely on movements by the animals. A wide range of tests may also reveal other unexpected negative findings, ‘side-effects’ that could complicate interpretation of the behaviour of primary interest. However, there could be unexpected positive findings, that is, a new role of the targeted gene could come to light . In deciding which tests to use, there are important practical issues. In a recent review, Craw- ley listed several different behavioural categories and al- most 40 specific behavioural paradigms that could be used to assess behavioural changes in new genetically modified mouse models (Table 1, see ). More tests means more animals required and larger numbers of ani- mals may cause problems with adequate housing. A wide range of tests requires expertise. All this may make a phenotyping facility a very expensive place to run. One way to meet these issues is for several specialized lab- oratories to collaborate. Another possibility is to estab- lish specialized phenotyping facilities that have a range of ‘standard’ behavioural tests available and collaborate with specialized research groups if less common tests are needed. We have conducted some behavioural screening in a numberof‘knockout’mice.Forexample,becauseseveral studies have shown sex differences in the occurrence of schizophrenia [28,29,45], we studied aromatase knock- out (ArKO) mice. These animals have a mutation in the gene encoding for the enzyme that mediates the conver- sion of the sex steroid testosterone to oestrogen . These mice display all the physiological and endocrine hallmarks of loss of oestrogen production, such as infer- tility and morphological changes in the gonads [46,47]. As such, this knockout does not replicate a known deficit associated with schizophrenia, but the mice were used to better understand the role of oestrogen (or rather the lack of) in behaviour. The mutation did not appear to have any effect of gross motor control, as measured with the rotarod, or anxiety, as measured on the increased plus- maze . However, in these mice, we found an age- dependent reduction of PPI that was present in males, but not in females . This decline in function was sug- gested to be mediated by an age-dependent reduction of dopaminergic activity in these animals, rendering them in a functional hyperdopaminergic state similar to that seen after treatment with dopaminergic drugs such as amphetamine or apomorphine. Consistent with this hy- pothesis, male, but not female ArKO mice also showed Table 1. Behavioural tests widely used in ‘phenotyping’ new genetically modified mouse models (adapted from [44,50]) Category Paradigms Preliminary observations General health and appearance Body weight Body temperature General (home cage) behaviour Neurological reﬂexes Motor coordination Baseline locomotor activity Rotarod performance Learning and memory Morris water maze Radial maze Y-maze T-maze Passive avoidance Active avoidance Feeding 24-h food intake Pain sensitivity Tail-ﬂick Hot-plate Aggression Resident-intruder Reproductive behaviours Sexual behaviours Parental behaviours Anxiety models Elevated plus-maze Light-dark Social interaction Depression models Porsolt swim test Schizophrenia models Locomotor hyperactivity Prepulse inhibition Latent inhibition Drug abuse models Self-administration Place conditioning Withdrawal an age-dependent increase in the locomotor hyperactiv- ity induced by amphetamine . These studies are im- portant for schizophrenia in that they show that loss of oestrogen production may induce accelerated age- and sex-dependent alterations in dopaminergic function that results in changes in behaviour in animal models with relevance to the disease. This work in ArKO mice may shed light on the mechanisms behind sex differences in the occurrence and symptoms of schizophrenia. Several other studies in knockout mouse models have similarly provided new insight into possible pathophysiological mechanisms involved in this illness [23,42,49]. Conclusion Studies in experimental animals can provide poten- tially important new insight into a range of brain mech- anisms with relevance to schizophrenia, such as detailed investigations on the role of certain brain areas in be- haviour, the mechanism of action of psychoactive and antipsychotic drugs, the interaction of classical and 556 ANIMAL MODELS IN SCHIZOPHRENIA RESEARCH ‘novel’neurotransmittersandgenesinbrainfunction,and neurodevelopmental mechanisms. Several of these stud- ies would be very difficult to carry out in humans, both from a technical and an ethical point of view. Clearly, complex psychiatric illnesses, such as schizophrenia, cannot be exactly reproduced in species such as rats and mice. Nevertheless, animal ‘models’ are an impor- tant tool in studying the symptoms and development of suchillnesses,alongsideapproachessuchaspost-mortem studies, psychophysiological studies, imaging and epidemiology. References 1. Preuss TM. 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Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proceedi