Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice

Abstract

Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg/kg/day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs, the mouse analog of TD) and other movement phenotypes derived from open field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90, and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field, and EPS. Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ~0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

“…However, basal differences, prior to treatment, between the two strains are independent of the drug and could explain the different susceptibility to EPS. This susceptibility could be common to different AP drugs, since the two strains have been phenotyped in response to haloperidol [24] and risperidone [9] As already mentioned, it is known that DRD2s are occupied by risperidone, blocking the indirect pathway. However, this antipsychotic drug is also characterized by a very high affinity for 5-HT2A receptors.…”

“…To address this issue, we analyzed the different populations of striatal Research Amalia Lafuente neurons and evaluated their mTOR-mediated response to risperidone in two mice strains with well-known different susceptibility to developing EPS [9,24].…”

“…In fact, dopamine receptors encoded in the Drd1a and Drd2 genes have been identified for association with haloperidol-induced tardive dyskinesia in mice [24,36].…”

“…These strains were selected from previous studies according to their EPS profile, one with susceptibility to developing EPS (A/J) and another with resistance (DBA/2J) [9,24]. To this end, we studied the phosphorylation pattern of ribosomal protein S6 (rpS6), which is phosphorylated at Ser235/236 and Ser244/247 residues by rps6 kinase, a major downstream effector of mTOR [25].…”

Animal models for predicting the efficacy and side effects of antipsychotic drugs

“…61 Finally, not all animals exposed to long-term antipsychotic treatment develop VCMs; their incidence is higher with advancing age and symptoms is exacerbated by stress, which is also consistent with clinical observations in humans. 62,63 Usually, animals are treated with slow-releasing preparations of antipsychotic drugs, haloperidol and fluphenazine decanoates being most commonly used, at a dose of 1 mg/day during periods ranging from 4 to 36 weeks. 64,65 For the experimental evaluation, the animals are placed individually in cages with mirrors under the floor, to facilitate visualization of the mouth.…”