The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
favor signaling through either one or the other pathway. There is some evidence to support this theory. In one study, modified DAG and metabolic products of IP3 were measured after pathway stimulation with different neurotransmitters. Serotonin had balanced DAG and IP3 metabolite responses, while histamine had a weak DAG response, but a strong IP3 metabolite response (Sarri, Picatoste, & Claro, 1995). As discussed earlier, there is much evidence to suggest that the DAG pathway promotes mental health, while the IP3 pathway may cause mental illness. Both of the above pathways are activated by H1 receptors.
It is possible that the Ca2+ (IP3/DAG) and cAMP/PKA pathways can antagonize each other (Jacobs, Yamatodani, & Timmerman, 2000). In fact, there is much evidence to suggest a direct antagonism between the cAMP and IP3 pathways (DAG feeds into the cAMP pathway, thus it should not be included in cAMP pathway antagonism). As mentioned in the previous section, serotonin activates the IP3 pathway via binding to its 5-HT2A receptor. Serotonin-stimulated Ca2+ release was significantly higher in severe depression, termed melancholia (Kusumi, Koyama, & Yamashita, 1991), although the serotonin signal shunting into the cAMP pathway is the presumed mechanism of SSRI antidepressant actions. Histamine stimulates formation of IP3 (Bielkiewicz-Vollrath, Carpenter, Schulz, & Cook, 1987). As discussed in the previous section, CaM is a protein downstream of IP3. CaM activates the enzyme phosphodiesterase, which degrades cAMP (Cheung, 1970), harming that critical pathway. Conversely, activation of PKA inhibits many CaMK’s (Matsushita & Nairn, 1999); as mentioned before CaMK’s are immediately downstream of CaM in the IP3 pathway. In addition, some antidepressants have been shown to inhibit CaM (Silver, Sigg, & Moyer, 1986).
As mentioned above, calcineurin is in the IP3 pathway. Calcineurin may cause anxiety by inhibiting release of the major inhibitory neurotransmitter, GABA (Klee, Ren, & Wang, 1998). Calcineurin also negatively regulates the cAMP pathway protein CREB, presumably by increasing its degradation (Bito, Deisseroth, & Tsien, 1996). One study showed that calcineurin activates CREB, but that was in pancreatic islet cells, not in the CNS (Schwaninger et al., 1995). Other studies have shown that calcineurin generally inhibits PKA activity by inactivating PKA’s downstream protein targets (substrates) (Shenolikar & Nairn, 1991; Greengard et al., 1998). Calcineurin inhibits an important form of synaptic plasticity known as long-term potentiation (LTP), which then often leads to long-term depression (LTD) (Winder et al., 1998). Calcineurin and the cAMP pathway enzyme PKA antagonize each other in the regulation of several downstream proteins besides CREB (Tong, Shepherd, & Jahr, 1995; Raman, Tong, & Jahr, 1996; Traynelis & Wahl, 1997). Perhaps most importantly, calcineurin is activated during allergic reactions (Abbas, Lichtman, & Pober, 2000).
The H1 receptor stimulates the IP3/DAG pathway, and is also the receptor that is involved in allergic reactions (Repka-Ramirez & Baraniuk, 2002). In the CNS, H1 receptor activation can inhibit learning and memory (Knoche et al., 2003). Histamine injected into rats resulted initially in hypoactivity, followed by hyperactivity; these effects were abolished by addition of an H1 blocker (antagonist) (Chiavegatto, Nasello, & Bernardi, 1998). H1 antagonists also inhibited histamine-induced increase in spontaneous motor activity in rats (Kalivas, 1982). Mutant mice that have had their H1 receptors knocked out showed blunted responses of aggression towards animal intruders compared with normal mice (Yanai et al., 1998a). This suggests that the H1 receptor is involved in aggressive behavior. H1 knockout mice also had a marked increase in serotonin levels (Yanai et al., 1998b). This effect could simply be the serotonin system compensating for the lack of stimulatory H1 receptors. On the other hand, the above effect could suggest that strong activation of H1 receptors results in low serotonin levels, and possibly subsequent anxiety and/or depression.
Humans possessing a certain mutation in the H2 receptor “have been found to have an increased susceptibility to schizophrenia” (Brown, Stevens, & Haas, 2001, p. 647). In addition, it appears that histamine-induced depression may be mediated via H2 receptors, although H2 receptor activation raises cAMP levels. In animal models, administration of histamine often exerts a depressant effect, which can be reversed by H2 receptor blockade but not H1 receptor blockade (Cantu & Korek, 1991). Histamine H2 receptor activation inhibits normal immune responses that are regulated by vitamin C (Johnston, 1996). As noted above, H2 receptor activation raises cAMP levels, and activates the PKA pathway (Jacobs, Yamatodani, & Timmerman, 2000). Activation of the