Substance P exerts its various behavioural effects mainly via interactions with neurokinin-1 receptors (NK1). Recently, the NK1 receptor has attracted considerable interest for its possible role in a variety of psychiatric disorders including depression and anxiety. Although few studies have focused on the localization of NK1 receptors in specific regions of the human brain, in particular striatum and cortex, a detailed knowledge of its distribution in the human CNS is still lacking. Thus, the anatomical localization of the NK1 mRNA and binding sites in the human post-mortem brain was studied, focusing on regions related to the pathophysiology of mood disorders.

In situ hybridization experiments with a riboprobe specific for the human NK1 receptor were performed. High levels of NK1 mRNA were found in the locus coeruleus and striatum, while moderate hybridization signals were observed in the cortex, hippocampus and different amygdaloid nuclei. Very low levels of NK1 mRNA were detected in the cerebellum and thalamus.

[3H-SP] autoradiography showed a good correlation between receptor binding sites and NK1 mRNA expression throughout the brain, with the highest levels of binding in the locus coeruleus (130.6 ± 15 fmol/mg) and striatum (caudate 20.2 ± 0.57 fmol/mg; putamen 19.2 ± 1.2 fmol/mg), and intermediate levels of binding in hippocampus (dentate gyrus 12.3 ± 3.08 fmol/mg, CA region 2.2 ± 0.85 fmol/mg), lateral amygdala (4.2 ± 0.46 fmol/mg) and temporal cortex (3.7 ± 0.25 fmol/mg).

Since a long and a short isoforms of the NK1 receptor have been isolated, it was interesting to assess whether there was a differential distribution of the two splice variants in the human CNS and in peripheral tissues. In the CNS, a quantitative PCR analysis (TaqMan) showed the presence of both the long and the short NK1 isoforms in all the regions studied, with an overall prevalence of the long isoform throughout the human brain. In contrast, in peripheral tissues the truncated form was the splice variant more represented.

These results indicate that the NK1 receptor is present in human brain regions associated with cognitive, limbic and motor functions and do not suggest a tissue-specific role of the long and short isoforms in the CNS.