In general, new strategies to reduce neuroleptic-induced extrapyramidal symptoms (EPS) focus on understanding the mechanisms of action of the atypical antipsychotic drugs (e.g. clozapine). The proposed research adopts a different strategy and attempts to understand from the genetic perspective the wide natural variation in drug response. We use neuroleptic-induced catalepsy in the mouse as a model to investigate the mechanisms responsible for the variability in EPS. Our working hypothesis is that the variability in this behavior is at least in part inherited. In addition, we propose that this complex behavior is under the control of multiple genes, rather than one or two major genes. The BXD/Ty recombinant inbred (RI) strains are used as a tool in detecting and mapping the locations of the relevant genes. The chromosomal position of these genes can be estimated by quantitative trait loci (QTL) analysis which seeks to discover significant associations between the phenotype of interest and multiple gene markers which have been previously mapped. For statistical reasons, this analysis is best viewed as an exploratory tool for identifying candidate QTL, which need independent confirmation. B6D2 F2 mice, typed for haloperidol sensitivity, will be used to confirm the candidate QTL. This confirmatory analysis will emphasize PCR based microsatellite genotyping. In preliminary results, one QTL detected by this 'two-step' approach is either near or part of the D2 dopamine receptor gene (Drd2). The question arises as to whether or not the QTL detected by the RI/F2 approach can be extended to the general population. To address this question, it is proposed to screen the confirmed QTL in the neuroleptic responsive (NR/Np) and neuroleptic non-responsive (NNR/Np) selected lines which were derived from a recently created heterogenous stock (HS/Np). Alleles conferring response should be over-represented in the NR/Np line, while those conferring non-response should predominate in the NNR/Np line. Animals from S2, S4 and S8 will be genotyped; these generations cover the period of the most marked segregation of the relevant alleles. In the BXD/Ty series, QTL which account for < 16% of the variance will not be detected. Methods to detect smaller but measurable QTL have been suggested e.g. the use of F1 crosses between RI strains as a means of increasing power. An alternative approach for detecting these smaller QTL is proposed which makes use of the knowledge that haloperidol-induced catalepsy results from blockade of D2 dopamine receptors. Furthermore, it has been demonstrated that the variation in haloperidol response among selected lines, inbred strains and B6D2 F2 hybrids is strongly associated with somatodendritic D2 receptor density. It is proposed to map and confirm, using the RI/F2 approach, QTL for somatodendritic D2 receptor density. The confirmed QTL will then be screened in a large population (N = 150) of F2 hybrids phenotyped for haloperidol response. If successful, this approach will not only detect additional QTL for haloperidol response but for some QTL will also assign functional attributes.
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