18 All three tachykinins are represented in the corpus striatum.21 Colocalization of substance P with other neurotransmitters in the brain In the human brain, 5-HT and SP coexist in a substantial proportion of the cell population of the dorsal raphe nucleus, the current target for antidepressant drug treatment.22,23 Almost 50% of the serotonergic neurons in the dorsal raphe nucleus, projecting to the forebrain, and 25% of the serotonergic neurons in the median raphe nucleus express SP mRNA.23 SP and 5-HT are colocalized in cat ventral medullary neurons24 and in serotonergic neuronal afferents to the hypoglossal Inhibitors,research,lifescience,medical nucleus of the rat.25 Moreover,

SP is coexpressed with the serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 in rat striatum.26 It is remarkable that the expression of SP Inhibitors,research,lifescience,medical in the striatum, substantia nigra, and amygdala is reduced after chronic treatment with the antidepressant drugs imipramine, desipramine, clomipramine, amoxapine, and mianserin. Imipramine and desipramine also reduce the amount of SP in the hippocampus, while its reduction in the septum is only induced by mianserin.27 The colocalization of SP and NE is demonstrated by the existence of SP-containing axon terminals in the locus cerulcus.28 Direct application of SP to the locus ceruleus has an excitatory effect via the neurokinin Inhibitors,research,lifescience,medical NK1 receptor.29-31 SP is also colocalized with dopaminergic

neurons in the nucleus accumbens.32 SP is under the stimulatory control of dopaminergic Inhibitors,research,lifescience,medical neurons, projecting

to the substantia nigra pars compacta and to the internal segment of the globus pallidus.33 Blockade of dopaminergic transmission by reserpine decreases the levels of SP mRNA, since Inhibitors,research,lifescience,medical it is under the stimulatory control of dopamine.34 Chronic treatment with amphetamine was found to be without effect on dopamine receptor levels in the striatum, but markedly increased the SP mRNA levels.34 Some studies suggest that the pain-suppression system involving the activation of mesolimbic dopaminergic neurons is naturally triggered by exposure to stress, through the endogenous release of opioids and SP in the midbrain.35 SP is also Electron transport chain coexpressed with a wide variety of other neuropeptides and neurotransmitters, and even with neuronal nitric oxide synthase.36 Neurokinin receptors Three distinct neurokinin receptors are known: NK1, NK2, and NK3. SP is the most potent tachykinin for the NK1 receptor, whereas NKA exhibits the highest DAPT secretase cell line affinity for the NK2 receptor and NKB for the NK3 receptor.37 Recently, the NK4 receptor, which was initially claimed to be an atypical opioid receptor, was shown to respond potently to NKB in the rat,38 but its detection in human tissue has not been possible to date.39 However, it must be pointed out that all mammalian tachykinins have limited selectivity for a particular neurokinin receptor.