Neurotensin and its high affinity receptor (NTSR1) localise within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems and it is now clear that
neurotensin can selectively modulate dopaminergic neurotransmission. This has led to the hypothesis that altered
neurotensin function contributes to the pathogenesis of
schizophrenia and other
psychoses. This hypothesis has been supported circumstantially by a number of lines of evidence. (1) Central administration of
neurotensin produces effects similar to those produced by the peripheral administration of atypical
antipsychotics. (2) Observations of low levels of
neurotensin in the CSF of schizophrenics. (3) Reduced numbers of
neurotensin receptors in the brains of schizophrenics. Given the above link between
neurotensin and
dopamine, and the evidence implicating altered
neurotensin function in
psychosis, we 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 between
schizophrenia and the gene encoding the
neurotensin high affinity receptor (NTSR1). However, caution is required because the associated marker, a tetranucleotide repeat, is located 3 kb away from the 3' end of the gene and there is no evidence that it is functional. Therefore, as a follow-up to our earlier work on
neurotensin, we have now sought to test the hypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs) are associated with
schizophrenia. However, while we found 14 novel sequence variants in 28 probands with
psychosis, none resulted in an
amino acid change, and neither direct nor indirect association studies suggested these are involved in susceptibility to
schizophrenia.