British Journal of DOI:10.1111/j.1476-5381.2011.01386.x www.brjpharmacol.org BJP Pharmacology Themed Issue: Translational Neuropharmacology – Using Appropriate Animal Models to Guide Clinical Drug Development Correspondence Professor Kevin Fone, School of Biomedical Sciences, Medical School, Queen’s Medical Centre, REVIEWbph_1386 1162..1194 The University of Nottingham, Nottingham NG7 2UH, UK. E-mail: Animal models of [email protected] ---------------------------------------------------------------- Keywords schizophrenia schizophrenia; animal model; antipsychotics; isolation rearing; ventral hippocampal lesion; CA Jones, DJG Watson and KCF Fone reelin; DISC-1; neuregulin; dysbindin; phencyclidine School of Biomedical Sciences, Medical School, Queen’s Medical Centre, The University of ---------------------------------------------------------------- Nottingham, Nottingham, UK Received 23 November 2010 Revised 9 March 2011 Accepted 12 March 2011 Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble ‘positive-like’ symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 Abbreviations 5-HT6, 5-hydroxytryptamine6 receptor; BDNF, brain-derived neurotrophic factor; D2, dopamine D2 receptor; DISC-1, disrupted-in-schizophrenia 1; DTNBP1, dystobrevin-binding protein 1; EGF, epidermal growth factor; GAD65, glutamic acid decarboxylase enzyme 65 kDa isoform; GAD67, glutamic acid decarboxylase enzyme 67 kDa isoform; GAT-1, GABA transporter 1; GD, gestational day; GLAST, glutamate–aspartate transporter; Ig, immunoglobulin; LPS, lipopolysaccharide; MAM, methylazoxymethanol; NAA, N-acetylaspartic acid; nAcc, nucleus accumbens; NAAG, N-acetylaspartylglutamate; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; NRG1, neuregulin 1; PCP, phencyclidine; PFc, prefrontal cortex; PND, postnatal day; PPI, prepulse inhibition of acoustic startle; vHip, ventral hippocampal; VTA, ventral tegmental area Introduction (including auditory and visual hallucinations, delusions, con- ceptual disorganization and thought disorder), negative Schizophrenia is a chronic debilitating neuropsychiatric dis- (emotional blunting, social withdrawal, anhedonia, avoli- order affecting approximately 1% of the population world- tion, poverty of thought and content of speech) and cogni- wide. Symptoms cluster into three categories: positive tive dysfunction (including impaired executive function, 1162 British Journal of Pharmacology (2011) 164 1162–1194 © 2011 The Authors British Journal of Pharmacology © 2011 The British Pharmacological Society Animal models of schizophrenia BJP working memory and attention) (Andreasen, 1995). Patients phrenia which have to be treated to meet therapeutic needs, present with extremely heterogeneous symptom combina- and recommended a specific neuropsychological test battery tions, making diagnosis and treatment problematic. Many to characterize these domains. A development of this initia- patients undergo prolonged periods of remission interspersed tive is the evaluation of the clinical relevance and predictive with relapses of psychotic episodes. Disease onset is typically value of existing preclinical cognitive tasks and agreement for post adolescence (16–25 years), with a higher incidence of the need to develop a preclinical cognitive test battery to aid psychotic symptoms in males and a bimodal later onset drug development (Hagan and Jones, 2005; Nuechterlein (40–60 years) in females. Although the aetiology of schizo- et al., 2005). Floresco et al. (2005) suggested using two phrenia remains contentious, it is a multifactorial neurode- approaches in experimental animals: lesions or drugs to velopmental disorder influenced by both genetic and manipulate specific systems altered in schizophrenia and environmental factors (Lewis and Lieberman, 2000; van Os developing models with cognitive deficits that resemble those et al., 2010), such that monozygotic siblings of affected indi- seen in the disorder, to improve translational reliability of viduals show a 50–80% risk of developing the disorder. data obtained. Young et al. (2009) extensively reviewed exist- The first drugs, found by serendipity rather than design in ing animal cognitive paradigms and critically appraised their the 1950s, to treat the psychotic symptoms of schizophrenia translational relevance to the seven human cognitive (haloperidol and chlorpromazine, called classical neurolep- domains identified as being affected in schizophrenia. tics) are also known as the first-generation antipsychotics. However, such cognitive paradigms need to be examined, not The second-generation or atypical antipsychotics, so called just in normal healthy animals, but in credible validated because of their different clinical profile (including clozapine, models of the disorder which will be reviewed in this paper. olanzepine, risperidone and aripiprazole) developed from the Animal models of complex heterogeneous psychiatric dis- 1970s have less tendency to produce unwanted extrapyrami- orders are clearly very valuable preclinical tools with which to dal side effects and hyperprolactinaemia (Remington, 2003). investigate the neurobiological basis of the disorder. They offer While first-generation antipsychotics are classified according a more rapid platform to monitor disease progression than in to chemical structure, the second-generation antipsychotics humans, and the opportunity to perform invasive monitoring are characterized according to their pharmacology. These of structural and molecular changes that underlie the cause of drugs were developed to treat the positive (psychotic) symp- the disease and test novel therapeutics not possible in patients. toms and not the negative or cognitive impairments. However, a perplexing problem is how to assess some of the However, multi-site, double-blind studies comparing several core symptoms of psychiatric disorders (like thoughts, and second-generation antipsychotics with a typical antipsy- verbal learning and memory), which are uniquely human chotic, perphenazine, failed to substantiate any major thera- traits (Powell and Miyakawa, 2006). In general, most behav- peutic advantage of the former (Lieberman et al., 2005). The iours can only be indexed rather than directly quantified, and cognitive symptoms of schizophrenia often precede the we are left to monitor performance in tasks designed to have occurrence of psychosis, and their treatment is considered a translational relevance to core symptoms and make inference better predictor of therapeutic outcome (Mintz and Kopelow- about the psychiatric state. A further problem with models of icz, 2007). However, while positive symptoms are currently schizophrenia is that there is no current ‘gold standard’ medi- treated to a varying degree by typical and atypical anti- cation available to treat all the symptoms that can be used as psychotics, the negative, and in particular, the cognitive a definitive positive control in preclinical studies, although impairments, remain resistant to treatment with current drugs like haloperidol and clozapine should reverse behav- antipsychotics even after remission of the psychosis ioural correlates of positive symptoms. Furthermore, many of (Nuechterlein et al., 2004; Keefe et al., 2007; Mintz and the current antipsychotics may have a small therapeutic Kopelowicz, 2007). Consequently, there is an urgent need to window of effect before sedation and other non-specific motor develop novel compounds that demonstrate increased effi- suppressant actions confound interpretation in tasks designed cacy against cognitive dysfunction and