The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
loop that may contribute to HPA axis dysfunction.
Certain peptides that stimulate release of the HPA axis hormone CRF can cause a variety of behavioral abnormalities in animals. The abnormalities include startled reactions, aversion, enhanced sensitization, decreased food intake, stress-induced immobilization, and inhibition of exploration (Koob, 1999). Histamine can produce virtually identical behavioral abnormalities, thus strengthening the hypothesis that histamine is a major stimulator of CRF release. ACTH is also released by stimulation of either H1 or H2 receptors (Knigge & Warberg, 1991).
As mentioned previously, histamine release raises Ca2+ levels via the IP3 pathway. It appears that many mentally ill patients have elevated intracellular Ca2+ responses (Kusumi & Koyama, 1998). There is evidence that there is an increase in released calcium during aging (Kurian, Chandler, Patel, & Crews, 1992), which may explain some age-related dementias. Some doctors believe that depression can result from hypofunction of cAMP-mediated cellular responses and relative dominance of the IP3/DAG pathways, while the converse is true for mania (Wachtel, 1990). The correlation of low cAMP levels with depression and high cAMP levels with mania has been speculated upon since 1970 (Abdulla & Hamadah, 1970). The enzyme phosphodiesterase regulates cAMP by degradation. Importantly, the phosphodiesterase inhibitor Rolipram possesses antidepressant activity (Wachtel, 1982). Thus, histamine could be involved in either depression or mania, depending on which receptor pathway it has a greater influence on.
The discussion that follows provides a model example for receptor regulation by the cell. Low serotonin levels cause the brain to adapt by increasing the number of serotonin receptors, termed ‘up-regulation’. Many, if not all, of the downstream small molecules and proteins in the pathway are also up-regulated, including the density of serotonin receptors (Arora & Meltzer, 1989). The problem is that any variation in serotonin levels will be amplified by the now up-regulated pathway. Theoretically, this can lead to mood swings, bipolar disorder, anxiety, and possibly major depression (Aprison, Takahashi, & Tachiki, 1978), presumably due to ‘burnout’ of the overworked pathway. The selective serotonin reuptake inhibitors (SSRI’s—Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro) are thought to attenuate depression by normalizing the up-regulated serotonin pathway. They block reuptake of serotonin in the axon, thus keeping more of it in the synapse. More serotonin in the synapse means that more binds to the serotonin receptor. The previously up-regulated receptor is then down-regulated to roughly normal levels, and the pathway downstream of the receptor also becomes down-regulated, and thus normalized. The same effect is seen with the norepinephrine reuptake inhibitor Effexor on the cAMP pathway. Since histamine can inhibit serotonin receptor function, it may directly cause mental illness by the above mechanism of pathway up-regulation.
There is much evidence that the cAMP pathway is important in maintaining synaptic plasticity (mental health). Long-term antidepressant use results in PKA activation (Popoli, Brunello, Perez, & Racagni, 2000). Several different kinds of serotonin and norepinephrine-reuptake inhibitors (antidepressants) increase the level of CREB mRNA (Nibuya, Nestler, & Duman, 1996). The non-pharmaceutical antidepressant S-adenosylmethionine (SAMe) stimulated cAMP to bind to PKA, and also increased MAP2 activation via phosphorylation (Zanotti et al., 1998). As previously mentioned, the H2 receptor activates the cAMP pathway.
Histamine excites neuronal firing via H1 receptors, while H2 receptor activation inhibits neuronal firing (Jacobs, Yamatodani, & Timmerman, 2000). As mentioned above, the H1 receptor pathway is IP3/DAG. The IP3/DAG pathway signaling molecule PIP2 is significantly higher in mania (Brown, Mallinger, Renbaum, 1993). The DAG pathway enzyme PKC is elevated in mania compared to normal subjects (Friedman et al., 1993). Administration of antidepressants in vitro decreases Ca2+ release into the intracellular cytosol (Ca2+ activation) (Shimizu et al., 1994), and also may inhibit protein kinases in the Ca2+ pathway (Silver, Sigg, & Moyer, 1986). However, activation of some Ca2+-dependent protein kinases (ex. CaM KII) increased BDNF expression levels (Ghosh, Carnahan, & Greenberg, 1994).
The above findings underscore the theory that the IP3/DAG pathway can be both positive and detrimental to synaptic plasticity, which is the cellular correlate to mental health. One theory is that low levels of released intracellular Ca2+ lead to synaptic depression, while large Ca2+ increases have the opposite effect (Lisman, 1994). Another explanation as to how the IP3/DAG pathway can be unbalanced is that some neurotransmitters may