The high affinity neurotensin receptor gene (NTSR1): comparative sequencing and association studies in schizophrenia

Neurotensin and its high affinity receptor (NTSR1) localise within dopamine rgic neurones in the mesocortical, mesolimbic and nigrostriatal systems(1-5 ) and it is now clear that neurotensin can selectively modulate dopaminergi c neurotransmission.(2,3,6-11) This has led to the hypothesis that altered neurotensin function contributes to the pathogenesis of schizophrenia and o ther psychoses. This hypothesis has been supported circumstantially by a nu mber of lines of evidence. (1) Central administration of neurotensin produc es effects similar to those produced by the peripheral administration of at ypical antipsychotics.(12-15) (2) Observations of low levels of neurotensin in the CSF of schizophrenics.(16-17) (3) Reduced numbers of neurotensin re ceptors in the brains of schizophrenics.(18,19) Given the above link betwee n neurotensin and dopamine, and the evidence implicating altered neurotensi n function in psychosis, we(20) have postulated that DNA sequence Variation in neurotensin or its receptors might be associated with schizophrenia. In keeping with this hypothesis, an association has recently been reported(21 ) between schizophrenia and the gene encoding the neurotensin high affinity receptor (NTSR1). However, caution is required because the associated mark er, a tetranucleotide repeat, is located 3 kb away from the 3' end of the g ene and there is no evidence that it is functional. Therefore, as a follow- up to our earlier work on neurotensin,(20) we have now sought to test the h ypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs)(22) are associated with schizophrenia. However, while we found 14 novel sequence variants in 28 probands with psychosis, n one resulted in an amino acid change, and neither direct nor indirect assoc iation studies suggested these are involved in susceptibility to schizophre nia.