Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice

Department of Genetics, University of North Carolina, Genomic Medicine Building, CB#7264, Chapel Hill, NC 27599-7264, USA.
Mammalian Genome (Impact Factor: 3.07). 12/2011; 23(5-6):322-35. DOI: 10.1007/s00335-011-9385-8
Source: PubMed


Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.

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Available from: Fernando Pardo-Manuel de Villena, Mar 10, 2014
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    • "Mice chronically treated with haloperidol demonstrate, in a strain-specific manner, many of the motor side effects seen in humans, including vacuous chewing movements (akin to TD), reduced locomotion (hypokinesia) and muscular rigidity (Parkinsonism ) (Fujiwara, 1992; Waddington et al., 1983; Ethier et al., 2004). In recent studies we examined susceptibility to haloperidolinduced motor side effects across a panel of 27 inbred mouse strains, finding that broad-sense heritability for each of these responses exceeded 70% (Crowley et al., 2010), and mapped quantitative trait loci regulating drug response (Crowley et al., 2011). To examine whether brain HPP+ levels correlate with EPS susceptibility, we chose two strains that were very sensitive to haloperidol-induced motor side effects (C57BL/6J and NZO/HILtJ) and two resistant strains (BALB/cByJ and PWK/PhJ) from Crowley et al. (Crowley et al., 2010). "
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    ABSTRACT: The typical antipsychotic haloperidol is a highly effective treatment for schizophrenia but its use is limited by a number of serious, and often irreversible, motor side effects. These adverse drug reactions, termed extrapyramidal syndromes (EPS), result from an unknown pathophysiological mechanism. One theory relates to the observation that the haloperidol metabolite HPP+ (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium) is structurally similar to MPP+ (1-methyl-4-phenylpyridinium), a neurotoxin responsible for an irreversible neurodegenerative condition similar to Parkinson's disease. To determine whether HPP+ contributes to haloperidol-induced EPS, we measured brain HPP+ and haloperidol levels in strains of mice at high (C57BL/6J and NZO/HILtJ) and low (BALB/cByJ and PWK/PhJ) liability to haloperidol-induced EPS following chronic treatment (7-10 adult male mice per strain). Brain levels of HPP+ and the ratio of HPP+ to haloperidol were not significantly different between the haloperidol-sensitive and haloperidol-resistant strain groups (P=0.50). Within each group, however, strain differences were seen (P<0.01), indicating that genetic variation regulating steady-state HPP+ levels exists. Since the HPP+ levels that we observed in mouse brain overlap the range of those detected in post-mortem human brains following chronic haloperidol treatment, the findings from this study are physiologically relevant to humans. The results suggest that strain differences in steady-state HPP+ levels do not explain sensitivity to haloperidol-induced EPS in the mice we studied.
    Full-text · Article · Oct 2013 · NeuroToxicology
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    • "It is important to note that a direct antipsychotic drug-gene interaction should be taken into close consideration, even if a direct intervention on genes (belonging to the glutamate/NMDA receptor family) has been shown only for haloperidol [116, 117]. Since modulation of progenitor cell proliferation as well as neurogenesis resulting in NMDA receptor modulation has been described [118], these findings set one possible agenda by which a direct antipsychotic drug-gene interaction can become neurogenic. "
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    ABSTRACT: Schizophrenia is a complex psychiatric disorder. Although a number of different hypotheses have been developed to explain its aetiopathogenesis, we are far from understanding it. There is clinical and experimental evidence indicating that neurodevelopmental factors play a major role. Disturbances in neurodevelopment might result in alterations of neuroanatomy and neurochemistry, leading to the typical symptoms observed in schizophrenia. The present paper will critically address the neurodevelopmental models underlying schizophrenia by discussing the effects of typical and atypical antipsychotics in animal models. We will specifically discuss the vitamin D deficiency model, the poly I:C model, the ketamine model, and the postnatal ventral hippocampal lesion model, all of which reflect core neurodevelopmental issues underlying schizophrenia onset.
    Full-text · Article · Oct 2012 · Neural Plasticity
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    • "While attempts have been made to implicate specific genes in susceptibility to tardive dyskinesia (e.g. [58] [59] [60]), gaps persist in our understanding of the neurobiological phenotype and mechanisms underlying such associations. Selection of a rat strain shown to be high in both levels of, and variability in, this behavior optimized the chances of identifying neurochemical variables that were correlated with the behavior. "
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    ABSTRACT: The widely accepted rat vacuous chewing movement model for tardive dyskinesia could be more fully mined through greater focus on individual variability in vulnerability to this neuroleptic-induced behavior. We have examined parallels between behavioral and neurobiological variability within a cohort in order to evaluate the role that neurobiological factors might play in determining susceptibility to tardive dyskinesia. Inter-observer reliability and individual consistency across time, in both spontaneous and neuroleptic-induced vacuous chewing movements, were empirically demonstrated. While this behavior increased across 8 months of observation in both vehicle controls and haloperidol-treated rats, pre-treatment baselines were predictive of final levels across individuals only in the vehicle control group, not the haloperidol-treated group. Haloperidol-induced elevations in neostriatal D2 and GAD(67) mRNA were not correlated with individual variability in haloperidol-induced vacuous chewing movements. Ambient noise during the observations was found to exacerbate chronic haloperidol-induced, but not spontaneous vacuous chewing movements. Significant correlations were found among the haloperidol-treated rats between nigral and tegmental GAD(67) and tegmental α7 mRNA levels, measured by in situ hybridization histochemistry, and vacuous chewing movements, specifically in the noisy conditions. Variability in these secondary responses to primary striatal dopamine and GABA perturbations may play a role in determining vulnerability to vacuous chewing movements, and by analogy, tardive dyskinesia. Both the differential predictive value of baseline vacuous chewing movements and the differential effect of noise, between controls and haloperidol-treated rats, add to evidence that haloperidol-induced vacuous chewing movements are regulated, in part, by different mechanisms than those mediating spontaneous vacuous chewing movements.
    Full-text · Article · Apr 2012 · Behavioural brain research
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