The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
(Johnston, Martin, & Cai, 1992).
Vitamin C detoxifies histamine by its conversion to hydantoin-5-acetic acid, and then aspartic acid (Clemetson, 1999). In order to achieve this, vitamin C needs copper (Cu2+) as a catalyst to degrade histamine (Sharma & Wilson, 1980). Vitamin C also inhibits phosphodiesterase, the enzyme that degrades cAMP. This results in raised cAMP levels (Tisdale, 1975). Also, vitamin C synergizes with cAMP inducers to stimulate cAMP production (Hitomi & Tsukagoshi, 1996). This effect on cAMP by vitamin C is the second main antihistamine action (besides histamine degradation), because cAMP inhibits histamine release (Cathcart, 1986). Cyclic AMP is also is a potent inhibitor of IgE-stimulated allergic mediator release, including: “histamine, slow reaction substance A (SRS-A), prostaglandins (PGs) and eosinophil chemotactic factor A (ECF-A)” (Sharma & Wilson, 1980, p. 163). Vitamin C also inhibits prostaglandin GF2a (PGF2a) synthesis. PGF2a decreases cAMP levels. Importantly, decreased cAMP levels are associated with histamine release (Mohsenin & Dubois, 1987).
Summary:
Histamine is a multifunctional hormone that in excess has potentially lethal side effects. The lethal side effects come from allergen overstimulation of the immune system, resulting in excess histamine release, which can lower blood pressure to the point of shock (Katzung, 1998). Histamine is intimately involved in both immune system and central nervous system activities. It affects a number of CNS functions, including “the arousal state, brain energy metabolism, locomotor activity, neuro-endocrine, autonomic and vestibular functions, feeding, drinking, sexual behavior, and analgesia” (Wada, Inagaki, Yamatodani, & Watanabe, 1991, p. 415). Histamine is formed by the amino acid histidine, and is unique among amino-acid derived neurotransmitters in that it is degraded in the extracellular space (synapse) instead of being taken up by the releasing neuron (axon). This is important since the level of vitamin C in the brain plays a major role in how fast excess histamine is removed from the synapse before it has morbid downstream effects. Histamine is an excitatory neurotransmitter, and appears to cause anxiety in some people (Hasenohrl, Weth, & Huston, 1999).
The H1 and H2 receptors are the most important of the four types of histamine receptors. The H1 receptor is coupled to the inositol triphosphate (IP3) / diacylglycerol (DAG) pathway, and the H2 receptor is coupled to the cAMP pathway. Although histamine sends an excitatory signal through both receptors, activation of either pathway may result in depression. For the H1 receptor, this is probably due to activation of the protein calcineurin, which is involved in long-term depression (LTD) of neurotransmission (Winder et al., 1998). Depression resulting from H2 receptor activation is likely due to downstream inhibition of neuronal firing (Jacobs, Yamatodani, & Timmerman, 2000). Another theory is that H2 receptor activation leads to inhibition of the serotonergic system (Lakoski & Aghajanian, 1983), which is the target for activation by many antidepressants. A third theory is that histamine indirectly causes depression by inhibiting release of other neurotransmitters (Brown, Stevens, & Haas, 2001).
There is evidence that certain individuals are much more sensitive to histamine than others (Katzung, 1998). Besides anxiety, histamine has also been linked to Attention Deficit Disorder (ADD) (Passani, Bacciottini, Mannioni, & Blandina, 2000), and alcoholism (Lintunen, et. al., 2002). The major inhibitory neurotransmitter in the brain, gamma-amino butyric acid (GABA), inhibits histamine release (Jacobs, Yamatodani, & Timmerman, 2000), suggesting that control of histamine levels in the brain is important. Many antianxiety drugs positively influence the GABAergic system.
Histamine can activate the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroregulatory system in the body. Normally, the neurotransmitters dopamine, serotonin, and norepinephrine control release of a key HPA axis hormone, corticotropin releasing factor (CRF) (Tuomisto & Mannisto, 1985). Since histamine inhibits release of the above neurotransmitters, it may unbalance the HPA axis via overstimulation. Chronic overstimulation of the HPA axis may eventually lead to depression (Hurwitz & Morgenstern, 2001). Histamine also releases another key HPA axis hormone, adrenocorticotropin (ACTH) (Knigge & Warberg, 1991), which is directly downstream of CRF.
It is theorized that the DAG pathway generally plays a positive role in mental health, while the IP3 pathway may play a detrimental role (Wachtel, 1990). Interestingly, histamine has strong IP3 stimulatory activity and a weak DAG stimulatory activity (Sarri, Picatoste, & Claro, 1995). Calcium ion (Ca2+) is released following activation of the IP3