Modeling psychotic and cognitive symptoms of affective disorders: Disrupted latent inhibition and reversal learning deficits in highly stress reactive mice
Introduction
Although many treatment strategies are available, major depression (MD) is not a fully treatable disorder (Holsboer and Ising, 2010, Wong and Licinio, 2001). This particularly applies to the symptoms in the cognitive realm that often subside when the affective symptoms of the disease have successfully been treated (Reppermund et al., 2009, Reppermund et al., 2007). Typical antidepressants also lack the capacity to treat the psychotic symptoms of major MD (Holtzheimer & Nemeroff, 2006). It is therefore of great importance to better understand the mechanisms underlying these cognitive deficits and psychotic symptoms and to explore new potential targets for their treatment.
Drugs focusing on the dopaminergic system, such as atypical antipsychotics, have shown great promise in treating depressed patients who do not respond to typical antidepressants (Quintin & Thomas, 2004). Atypical antipsychotics are believed to exert their effect by increasing dopaminergic activity in the prefrontal cortex (PFC) implicating the dopaminergic system in these symptoms (Ichikawa et al., 2002, Kuroki et al., 1999, Rollema et al., 1997). The dopaminergic system subserves an optimal neuronal function in the PFC (Cropley, Fujita, Innis, & Nathan, 2006), which plays a key role in executive functioning tasks (Carpenter et al., 2000, Petrides, 1994, Robbins and Arnsten, 2009). Fittingly, executive functioning tasks are the cognitive tasks that depressed patients and schizophrenic patients display the most deficits in (Austin et al., 2001, Porter et al., 2003, Rabin et al., 2009, Reppermund et al., 2007, Reppermund et al., 2009, Shirayama et al., 2009). Thus, it appears that psychotic MD and schizophrenia (SZ) share certain symptoms and possibly have similar underlying biological underpinnings causing these symptoms. It was therefore our aim to study these symptoms as phenotypic endpoint relevant to both disorders. The focus of this study was the dopaminergic system and the behaviors likely to be subserved by the dopaminergic system in the context of these symptoms.
Dopamine plays a key role in the regulation of latent inhibition (Li). Li is the phenomenon whereby pre-exposure to the to-be conditioned stimulus retards the learning of subsequent pairing of the unconditioned stimulus (US) and the conditioned stimulus (CS) (Lubow, 1973). Disrupted Li is strongly associated with an increased dopaminergic activity in the mesolimbic area (Lubow, 2005, Solomon and Staton, 1982, Weiner, 1990, Young et al., 1993) and is considered to be a model of the inability to ignore irrelevant stimuli associated with schizotypy (Baruch et al., 1988, Guterman et al., 1996, Rascle et al., 2001, Schmidt-Hansen et al., 2009).
In addition to the affective and cognitive symptoms, dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is commonly observed in patients suffering from MD (de Kloet et al., 2005, Holsboer, 2000, Holsboer and Ising, 2010, Ising et al., 2005), but has also been reported in patients suffering from SZ (Gallagher et al., 2007, Muck-Seler et al., 2004, Ritsner et al., 2007, Ryan et al., 2004). An animal model of affective disorders, the “stress reactivity” mouse model, was therefore established using a selective breeding approach to generate mice with high, intermediate or low stress reactivity (Touma et al., 2008). Briefly, a founder population of CD-1 mice was subjected to a standardized stressor (15-min restraint), and the increase of plasma corticosterone concentrations in response to this stressor was determined. Males and females with very high stress reactivity (HR) were then mated, as were males and females with very low stress reactivity (LR). Their offspring were tested for their stress reactivity in the same manner and so forth for each generation to come (for details see (Touma et al., 2008)). An intermediate reactivity (IR) line was additionally established to serve as a control group with the same inbreeding status as the other two lines. The IR mice present a corticosterone response similar to the mean of the founder population of CD-1 mice (Touma et al., 2008). In this study, these three mouse lines have been utilized to investigate the effect of a hyperactive vs. hypoactive HPA axis reactivity on the dopaminergic system as well as behaviors subserved by the dopaminergic system that are relevant to the psychotic and cognitive deficits observed in MD and SZ. Ultimately, we aim to provide a mouse model for cognitive deficits and psychotic symptoms that could be utilized in the search for better treatment options for these symptoms.
To this end, mice from the stress reactivity model were subjected to a reversal learning task, and Li was assessed in a conditioned taste aversion paradigm. The brains of these animals were subsequently analyzed via in situ hybridization to measure dopamine 1 receptor (D1R), dopamine receptor 2 (D2R) and dopamine transporter (DAT) mRNA levels in relevant brain areas.
Section snippets
Subjects
A total of 48 male mice were used in these experiments. The mice originated from the 11th generation of the stress reactivity mouse model. This mouse model consists of three CD-1-derived mouse lines, selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity, respectively (Touma et al., 2008). Stress reactivity was determined by the method described below. From each breeding line, HR, IR, and LR, 16 male mice were selected according to their plasma corticosterone increase
Stress reactivity test
The differences in the restraint stress-induced corticosterone increase were highly significant between the three breeding lines (KWH-test: HR: N = 16, IR: N = 16, LR: N = 16, H = 41.80, df = 2, p < 0.001; post-hoc MWU-tests: all U = 0, all p < 0.001), with HR mice having the highest increase (mean ± SEM: 400 ± 12.5 ng/ml), LR mice the lowest (mean ± SEM: 52.3 ± 3.0 ng/ml) and IR mice being intermediate (mean ± SEM: 176.7 ± 3.5 ng/ml). These findings are in accordance with previous generations of the stress reactivity mouse
Discussion
The aim of the present study was to examine if mice with increased stress reactivity display behaviors associated with cognitive and psychotic features of major depression and schizophrenia. Furthermore, the dopaminergic system of these mice was investigated in brain areas relevant to these behaviors. The experiments reported here demonstrate that mice selected for high stress reactivity have deficits in reversal learning and disrupted Li, along with congruent alterations in the expression of
References (66)
- et al.
Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system
Neuroscience
(1990) - et al.
Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats
Psychoneuroendocrinology
(2007) - et al.
The effects of chronic mild stress on male Sprague-Dawley and Long Evans Rats: I. Biochemical and physiological analyses
Behavioural Brain Research
(2002) - et al.
Network interactions in schizophrenia – Therapeutic implications
Brain Research Reviews
(2000) - et al.
Working memory and executive function: Evidence from neuroimaging
Current Opinion in Neurobiology
(2000) - et al.
The neuropsychology of ventral prefrontal cortex: Decision-making and reversal learning
Brain and Cognition
(2004) - et al.
Molecular imaging of the dopaminergic system and its association with human cognitive function
Biological Psychiatry
(2006) - et al.
Dopamine D2 receptor mechanisms in the expression of conditioned fear
Pharmacology, Biochemistry and Behavior
(2006) - et al.
Early maternal deprivation and prepulse inhibition: The role of the postdeprivation environment
Pharmacology, Biochemistry and Behavior
(2002) - et al.
Neural circuits subserving behavioral flexibility and their relevance to schizophrenia
Behavioural Brain Research
(2009)
Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder
Schizophrenia Research
Latent inhibition in drug naive schizophrenics: Relationship to duration of illness and dopamine D2 binding using SPET
Schizophrenia Research
Latent inhibition effects reflected in event-related brain potentials in healthy controls and schizophrenics
Schizophrenia Research
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinical improvement
Journal of Affective Disorders
Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression. Implications for pathophysiology of DST nonsuppression
Biological Psychiatry
Advances in the treatment of depression
NeuroRx
Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: Role of 5-HT1A receptor agonism
Brain Research
The combined dexamethasone/CRH test as a potential surrogate marker in depression
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Visual search in schizophrenia: Latent inhibition and novel pop-out effects
Schizophrenia Research
Involvement of dopaminergic mechanisms in the nucleus accumbens core and shell subregions in the expression of fear conditioning
Neuroscience Letters
Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women
Psychiatry Research
Frontal lobes and behaviour
Current Opinion in Neurobiology
Efficacy of atypical antipsychotics in depressive syndromes
Encephale
Correlation of prepulse inhibition and Wisconsin Card Sorting Test in schizophrenia and controls: Effects of smoking status
Schizophrenia Research
Clinical features of latent inhibition in schizophrenia
Schizophrenia Research
Persistent cognitive impairment in depression: The role of psychopathology and altered hypothalamic–pituitary–adrenocortical (HPA) system regulation
Biological Psychiatry
State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients
European Neuropsychopharmacology
Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation
European Journal of Pharmacology
Evidence of basal pituitary–adrenal overactivity in first episode, drug naive patients with schizophrenia
Psychoneuroendocrinology
Mice selected for high versus low stress reactivity: A new animal model for affective disorders
Psychoneuroendocrinology
The switching model of latent inhibition: An update of neural substrates
Behavioural Brain Research
Latent inhibition of conditioned dopamine release in rat nucleus accumbens
Neuroscience
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