Abstract
The 5-HT2A-serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT2A-serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT2A-serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.
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Acknowledgements
We are grateful to Dr Richard Mailman for supplying aripiprazole. This work was supported in part by NIMH RO1MH57635 and KO2MH01366 and the NIMH Psychoactive Drug Screening Program to BLR. MAD was supported in part by a supplement to RO1MH57635 with DJS and VS supported by NRSA and AHA predoctoral fellowships, respectively.
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Davies, M., Setola, V., Strachan, R. et al. Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J 6, 42–51 (2006). https://doi.org/10.1038/sj.tpj.6500342
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DOI: https://doi.org/10.1038/sj.tpj.6500342
Keywords
- 5-HT2A
- serotonin receptors
- T25N
- I197V
- A447V
- H452Y
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