Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
Dialogues in clinical neuroscience 08/2010; 12(3):359-82.
Source: PubMed


All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed.

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Available from: Darrick T Balu, Nov 06, 2014
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    • "N-methyl-D-aspartate receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia (Coyle et al., 2010). This hypothesis has been developed partially by the observation that NMDAR antagonists, such as phencyclidine and ketamine , reproduce all of the schizophrenia symptom domains in healthy human subjects including hallucinations, negative symptoms and cognitive symptoms (Itil et al., 1967; Javitt, 2009). "
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    ABSTRACT: NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR-/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR-/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (Arc) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15mg/kg; 5days) treated adult wild-type mice. We found that in contrast to SR-/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR-/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR-/- mice more accurately reflect NMDAR hypofunction in schizophrenia. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Jan 2015 · Schizophrenia Research
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    • "Hence, cognitive symptoms undermine the patient's intellectual capability to lead a normal independent life (e.g., to earn a living), whereas the other negative symptoms concerning affect and motivation diminish the desire or drive to pursue a normal productive life (e.g., neglect with regard to basic personal hygiene). Both aspects impose major hurdles for rehabilitation and a return to functional independence but, unfortunately, both are often difficult to diagnose and are the most resistant to current medication (Coyle et al. 2010). "
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    ABSTRACT: Schizophrenia is a chronic debilitating brain disorder characterized by a complex set of perceptual and behavioural symptoms that severely disrupt and undermine the patient's psychological well-being and quality of life. Since the exact disease mechanisms remain essentially unknown, holistic animal models are indispensable tools for any serious investigation into the neurobiology of schizophrenia, including the search for remedies, prevention of the disease and possible biological markers. This review provides some practical advice to those confronted with the task of evaluating their animal models for relevance to schizophrenia, a task that inevitably involves behavioural tests with animals. To a novice, this challenge not only is a technical one but also entails attention to interpretative issues concerning validity and translational power. Here, we attempt to offer some guidance to help overcome these obstacles by drawing on our experience of diverse animal models of schizophrenia based on genetics, strain difference, brain lesions, pharmacological induction and early life developmental manipulations. The review pays equal emphasis to the general (theoretical) considerations of experimental design and the illustration of the problems related to critical test parameters and the data analysis of selected exemplar behavioural tests. Finally, the individual differences of behavioural expression in relevant tests observed in wild-type animals might offer an alternative approach in order to explore the mechanism of schizophrenia-related behavioural dysfunction at the molecular, cellular and structural levels, all of which are of more immediate relevance to cell and tissue research.
    Full-text · Article · Apr 2013 · Cell and Tissue Research
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    • "That means that neurons from two or more sources integrate information for cognitive performance (Salinas and Sejnowski, 2001; Stephan et al., 2008). Our results support previous findings of disrupted synaptic plasticity of the thalamocortical connection (Krystal et al., 2003; Negyessy and Goldman-Rakic, 2005) resulting in cortical dysconnectivity in schizophrenia (Balu and Coyle, 2012; Byne et al., 2009; Goff and Coyle, 2001; Lewis and Lieberman, 2000; Pakkenberg et al., 2009; Sodhi et al., 2011; Watis et al., 2008). We consider that our indications of lower connection strengths with the nonlinear modulation of the thalamocortical connection during the HSCT suggest that altered glutamatergic transmission of the MD thalamus could underlie the reduced gating of the task. "
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    ABSTRACT: Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.
    Full-text · Article · Feb 2013 · NeuroImage
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