The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
pressure (Katzung, 1998). This hypotensive action of histamine can result in serious clinical consequences, including shock and death. Symptoms of excessive blood histamine include: gastrointestinal upset, headache, flushing, tachycardia, bronchoconstriction, wheals, and hypotension (Katzung, 1998). Histamine can cause either pain or analgesia, depending on where in the brain it is injected (Glick & Crane, 1978).
There is much evidence of histamine’s involvement in both physical and mental disorders. Asthmatics “may be 100-1000 fold more sensitive to histamine than are normal subjects” (Katzung, 1998, p. 264). Histamine may be involved in the psychiatric illness Attention Deficit Disorder (ADD) (Passani, Bacciottini, Mannaioni, & Blandina, 2000). Hyperactivation of the central histaminergic neuron system may play a major role in age-related memory loss and anxiety (Hasenohrl, Weth, & Huston, 1999). Conversely, low histamine levels appear to decrease anxiety (Peitsaro, Kaslin, Anichtchik, & Panula, 2003). Histamine may be involved in ethanol tolerance; in lay terms, histamine may support alcoholism. Rats that were genetically bred to have low histamine levels were more sensitive to ethanol than normal rats (Lintunen et al., 2002). Theoretically, high histamine levels may result in ethanol tolerance.
There is a significant amount of evidence to support the theory that histamine is directly involved in stress-induced biochemical changes. In non-stressed rats, histamine normally interacts with a & b-adrenergic receptors, and also the cholinergic muscarinic receptor. In stressed rats, histamine only interacts with a-adrenergic receptors, not b-adrenergic receptors (Bugajski, 1984). Many antianxiety drugs work by improving the activity of the major inhibitory neurotransmitter GABA, or by activation of the GABA receptor. Interestingly, GABA inhibits histamine release (Jacobs, Yamatodani, & Timmerman, 2000). Administration of histidine, the amino acid precursor to histamine, induced bizarre ‘mock fighting’ behavior in rats, and it was determined that both H1 receptors and cholinergic muscarinic receptors potentiate this behavior (Pilc, Rogoz, & Skuza, 1982).
Stress can activate histamine release, which in turn acts to release the stress hormones ACTH, CRF, prolactin (PRL), and vasopressin (Brown, Stevens, & Haas, 2001). At rest and during stress, CRF, norepinephrine, and glucocorticoids like cortisol maintain CNS and immune system homeostasis. Excess histamine disrupts this homeostasis by shifting the immune system to a pro-inflammatory state (Chrousos, 2000). CRF release is normally initiated by the neurotransmitters dopamine, serotonin, and norepinephrine (Tuomisto & Mannisto, 1985). Increased histamine levels may act to ‘hijack’ CRF release regulation away from the above neurotransmitters, thus unbalancing the HPA axis and ultimately CNS homeostasis. Indeed, it has been shown that histamine is a potent stimulator of the pituitary and adrenal organs (Bugajski & Gadek, 1983). There is also evidence that histamine plays a major role in physiological responses to chronic stress, by maintaining the brain in an alerted state (Parmentier, et. al., 2002) against a real or imagined challenge.
There are two types of immune responses: Th1 and Th2. Th1 is an immune response that is directed against microbes. Th2 is an immune response that is directed against otherwise harmless proteins termed ‘antigens’. Excess cortisol shifts the immune response toward Th2 (Hurwitz & Morgenstern, 2001). This can initiate a vicious positive-feedback cycle, since allergic reactions can promote and maintain HPA axis over activity, eventually leading to mental depression (Hurwitz & Morgenstern, 2001). HPA axis overactivity in turn leads to an overproduction of cortisol. The above positive-feedback cycle finding is corroborated by the discovery that stress increases cortisol levels, and high cortisol levels are associated with depression (Brody, Preut, Schommer, & Schurmeyer, 2002). One of the possible mechanisms for the above outcome is that high cortisol levels downregulate brain 5-HT receptors (De Kloet, Sybesma, & Reul, 1986), and may also decrease tryptophan availability (Maes, De Ruyter, Hobin, & Suy, 1987), which is essential for serotonin synthesis.
Stress can release neuropeptides that may induce brain mast cell histamine release, causing a Th2 allergic reaction (Abbas, Lichtman, & Pober, 2000). Histamine stimulates the HPA axis without serotonergic or adrenergic receptor activation. A proposed mechanism of the above effect is that histamine interacts with prostaglandins to stimulate the HPA axis (Willems et al., 1999). The hormone corticosterone raises histamine levels in the hypothalamus, and the excess histamine in turn raises plasma corticosterone levels (Mazurkiewicz-Kwilecki, 1983), providing a ‘feed-forward’