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

Abstract

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, Nkx6-1), glutamate receptors (Grin1, Grin2a), and an indirect target of haloperidol (Drd1a) that has not been as well studied as the direct target, Drd2.

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

“…Previous work (Crowley et al, 2012a; Crowley et al, 2012b) indicated that 3.0 mg/kg/day haloperidol delivered via continuous 60-day slow release subcutaneous pellets (Innovative Research of America, Sarasota, FL) yielded plasma haloperidol concentrations in mice in the 10– 50 nM range with lower variation as compared to minipumps, repeated injections or oral administration. Furthermore, this dose and delivery method has been previously demonstrated to produce vacuous chewing movements in C57BL/6J mice that peaked around four weeks and persisted for over one year, long after drug administration ended (Crowley et al, 2012a).…”

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury

“…In a previous study (Crowley et al 2012b), only 3 of 27 inbred strains manifested a substantial amount of toxicity after haloperidol treatment, and the latency in A/J mice was substantially larger (36% and 59%) than that of the other two strains (NZW and NZO). Therefore, it was possible that A/J mice uniquely had an additional pharmacogenetic factor that increased its susceptibility to HIT.…”

“…We recently analyzed a murine genetic model of haloperidol-induced toxicity (HIT) (Zheng et al 2015) in which the Parkinsonian-like symptoms developing in haloperidol-treated mice resemble those observed in drug-treated human patients (Crowley et al 2012a). The 27 inbred strains evaluated in this genetic model exhibit substantial variability in susceptibility to HIT (Crowley et al 2012b). For example, C57BL/6 mice are completely resistant, while A/J mice are highly susceptible to the Parkinsonian hypokinesia associated with HIT.…”

Therapeutic Perspective on Tardive Syndrome with Special Reference to Deep Brain Stimulation

“…Since the early 1970s, rats that were exposed to dopamine receptor blocking agents for consecutive weeks manifested different patterns of purposeless, chewing activity, which is termed “vacuous chewing movements”(22–25, 30–34). VCM are also observed in mouse models of TDS (55, 56). The VCM induced by haloperidol was further exacerbated by knocking out Nur77 (57).…”