The neurokinin-3 (NK3) and the neurokinin-1 (NK1) receptors are differentially targeted to mesocortical and mesolimbic projection neurons and to neuronal nuclei in the rat ventral tegmental area.

Endogenous tachykinins released into the ventral tegmental area (VTA) activate both the neurokinin-1 (NK1) and neurokinin-3 (NK3) receptors, the latter of which is thought to be involved in the pathophysiology of schizophrenia (Spooren et al., 2005). This is suggested, in part, by the clinical efficacy of two non-peptidic NK3 receptor antagonists (osanetant and talnetant) on the positive symptoms in schizophrenic patients (Meltzer et al., 2004; Spooren et al., 2005). The underlying mechanism for this antipsychotic effect is largely unknown, but may reflect blockade of NK3 receptor-dependent activation of dopaminergic transmission in either 1) the mesocortical pathway from the ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC), or, 2) the mesolimbic pathway from the VTA to the nucleus accumbens (Acb) (Oades and Halliday, 1987; Gerfen and Wilson, 1996; Tzschentke, 2001). Both the mPFC and Acb receive a major input from dopaminergic, and a more minor input from GABAergic projection neurons in the VTA (Koob and Swerdlow, 1988; Carr and Sesack, 2000a). A specific involvement of the mesocortical dopaminergic pathway is suggested by the major role of the mPFC in normal cognitive functions and in the cognitive abnormalities in schizophrenia (Bannon and Roth, 1983; Koob and Swerdlow, 1988; Abi-Dargham and Moore, 2003). The mesolimbic dopaminergic pathway to the Acb, however, potentially modulates corticostriatal transmission affected by the motivated behaviors that are also impaired in schizophrenia (Wightman and Robinson, 2002; Wise, 2002). NK3 receptors are present in VTA dopaminergic and non-dopaminergic neurons (Chen et al., 1998; Lessard et al., 2007). Microinjection of the selective NK3 receptor agonist senktide in the VTA also increases dopamine release locally and in both the Acb and mPFC (Overton et al., 1992; Bannon et al., 1995; Marco et al., 1998; Seabrook et al., 1995). The enhanced dopamine release is consistent with the coupling of NK3 receptors to stimulatory Gq proteins, and with the abnormal activity of VTA dopaminergic neurons in schizophrenia (Regoli et al., 1994; Farde, 1997). Presently however, the subcellular location and comparative distribution of the NK1 or NK3 receptors in either the mPFC or Acb projection neurons of the VTA is not known. We have shown previously that dopaminergic and non-dopaminergic somatodendritic profiles of the rat VTA contained twice as less NK1 immunogold particles, as compared to NK3 immunogold particle density (Lessard and Pickel, 2005; Lessard et al., 2007). Despite this sparse distribution, NK1 receptor activation in the VTA is known to evoke significant cardiovascular and behavioral changes in awake rats (Deschamps and Couture, 2005) that may be mediated, in part, through altered output of neurons that project to the mPFC or Acb. In the present study, we sought to compare cellular and subcellular distributions of NK3 and NK1 receptors in neurons of the VTA that were identified by retrograde transport of Fluorogold (FG) from either the Acb or mPFC of rat brain. Electron and confocal microscopy showed pathway-specific differences in abundance of these neurokinin receptors in mesolimbic and mesocortical projection neurons. Moreover, only the NK3 receptors were targeted to the nucleus in neurons of the rat VTA or NK3-transfected human HEK-293T cells. The cellular and subcellular location of NK3 and NK1 receptors within the subpopulations of VTA neurons is critical for understanding their normal function and the unique antipsychotic effect of NK3 receptor antagonists.