The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
PKA pathway is the theoretical explanation for the action of many antidepressants, especially those that block reuptake of norepinephrine. However, the raise in cAMP may be negated by H2 receptor activation of GABA receptors, which then inhibit all serotonergic neuron firing (Lakoski & Aghajanian, 1983). As mentioned previously, serotonin and its receptors play a key role in maintaining mental health. H2 receptor activation inhibits neuronal firing in general (Jacobs, Yamatodani, & Timmerman, 2000) via GABA activation. Although H2 receptors raise cAMP levels, the end result of H2 receptor activation is inhibition of other neurotransmission.
An important function of histamine is to activate acid-producing cells in the stomach. Histamine-2 receptor (H2 receptor) antagonists are commonly used as stomach antacids. H2 receptors are also found in the brain. Histamine H2 receptor antagonists can slow the progression of Alzheimer’s disease (Lipnik-Stangelj, Juric, & Carman-Krzan, 1998). This suggests that in the brain, histamine-mediated activation of H2 receptors may cause brain damage. All H2 receptor antagonists can cause CNS reactions. The specific CNS reactions include: “delirium, psychosis, confusion, disorientation, hallucinations, hostility, mental status changes, irritability, obtundation, or agitation” (Cantu & Korek, 1991, p. 1027). In particular, the H2 antagonist Cimetidine (Tagamet) can have serious CNS side effects, including epileptic phenomena, delusions, and coma (Van Sweden & Kamphuisen, 1984). In animal studies, H2 antagonists can also cause fear (Santos, Huston, & Bandao, 2001).
The histamine H3 receptor negatively regulates H1 and H2 receptors by inhibiting histamine release (Bongers, Leurs, Robertson, & Raber, 2004). Additional evidence supporting histamine’s anxiety-generating effects is provided by the finding that blocking H3 receptors increases anxiety in animals (Bongers, Leurs, Robertson, & Raber, 2004). However, H3 blockers can also have antidepressant effects (Ito, 2000). Sometimes antidepressants may increase anxiety, and the H3 receptor could play a major role in this unfortunate pharmacological side effect. The H3 receptor has been implicated in diverse mental dysfunctions, including migraine, attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease (Leurs, Bakker, Timmerman, & de Esch, 2005). Unlike the other three histamine receptors, H3 receptors may couple to multiple signal transduction pathways (Passani et al., 2004). As mentioned previously, histamine suppresses food intake. Paradoxically, H3 receptor knockout mice often become obese (Takahashi, Suwa, Ishikawa, & Kotani, 2002). The H4 receptor has only recently been discovered. One of its main roles appears to be mast cell activation (Hofstra, Desai, Thurmond, & Fung-Leung, 2003).
Increased histamine levels in guinea pigs results in increased vitamin C utilization and, presumably, synthesis (Nandi, Subramanian, Majumder, & Chatterjee, 1974). An interesting experiment was also conducted in rats by an Indian research group in the 1970’s. When “1 mg of histamine was injected into the rats, the increase in the urinary histamine was about four-fold but it was brought back almost to the normal value after administration of ascorbic acid” (Subramanian, Nandi, Majumber, & Chatterjee, 1974, p. 639). In humans, supplementing with 2000mg/day of vitamin C will drop histamine levels by an average of 40% (Johnston, Retrum, & Srilakshmi, 1992). One of the behavioral results of lowing histamine levels is increased appetite. As mentioned earlier, histamine plays a role in feeding behavior, specifically the suppression of food intake, and stimulates drinking in animals (Sakata & Yoshimatsu, 1995). Interestingly, vitamin C appears to play a positive role in feeding behavior, since low vitamin C levels in the brain result in diminished appetite (Wilson, 1982).
As mentioned in the introduction section of this chapter, prostaglandins influence brain activity, as well as immune activity. Vitamin C plays a role in prostaglandin metabolism, including breakdown of dihomo-gamma linolenic acid (DGLA) into side metabolites. DGLA normally gets converted into the inflammatory metabolite arachidonic acid (AA) (Horrobin, 1996). Thus, vitamin C plays a role as an anti-inflammatory mediator. Vitamin C and prostaglandin E1 (PGE1) may share similar roles in regulating collagen synthesis, infection, and cholesterol and insulin levels (Horrobin, 1996). Although histamine plays a major role in the Th2 immune response, it is actually recognized as an immunosuppressive agent. Two grams daily of vitamin C enhanced migration of a certain immune cell called a neutrophil, and this migration was inversely correlated with blood histamine levels. This suggests that vitamin C can enhance immune function via histamine detoxification