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Chapter 2: A Review of Related Literature and Research

Introduction:

“Histamine was synthesized in 1907 and later isolated from mammalian tissues” (Katzung, 1998, p. 261). It has multiple roles in the body, including neuromodulation and neurotransmission, allergic and inflammatory mediator, and gastric acid secretion stimulator. Common food sources of histamine are red wine and strawberries (Firshein, 1996). The organic chemical name for histamine is 2-(4-imidazoyl)ethylamine. It is formed from decarboxylation of the amino acid histidine, via the action of the enzyme histidine decarboxylase. The body’s usual mode of histamine detoxification is methylation by the amino acid methionine (Pfeiffer, 1987). Excessive amounts of histamine released into the bloodstream can dangerously raise pulse and lower blood pressure to the point of shock and sometimes death. The mechanism of this phenomenon is described below.

Mast cells contain granules filled with histamine, and this is where most tissue histamine resides. Histamine that is bound to mast cells (or functionally related cells called basophils) is inactive. Exposure to an antigen (allergen) causes the antigen-specific IgE antibody to connect with mast cells (the primary immune response). Reexposure to the same antigen results in antibody signaling to mast cells to release histamine (the secondary immune response) (Weinstein, 1987). Histamine’s actions include vascular permeability and bronchoconstriction (Abbas, Lichtman, & Pober, 2000), which can lead to both asthma and dangerous drops in blood pressure. Excess mast cells, known as mastocytosis, can cause a variety of behavioral disturbances, including “diminished attention and memory, and the affective changes of anger, irritability, and, to a lesser extent, depression” (Rogers, et. al., 1986, p. 437).

Brain histamine neurons originate in the tuberomammillary nucleus (TM), which is located within the hypothalamus. These neurons project throughout the nervous system, including the olfactory system and spinal cord (Wada, Inagaki, Itowi, & Yamatodani, 1991). Histaminergic neurons stimulate the cerebral cortex either directly or indirectly via activation of serotonergic neurons (Blandina et al., 2004). Some histaminergic neurons store neuroactive substances such as galanin, GABA, substance P, glutamate decarboxylase, and adenosine deaminase (Blandina et al., 2004). Brain histamine increases wakefulness, locomotor activity, sexual behavior, and release of adrenocorticotropic hormone (ACTH), and decreases slow-wave sleep, feeding, and growth hormone production (Wada, Inagaki, Yamatodani, & Watanabe, 1991).

In order to better understand histamine’s role in neurotransmission, an introduction/review of neurotransmitters, their receptors, and the signal transduction pathways downstream of the receptors will be presented. A neurotransmitter is a chemical which effects communication between two nerve cells called neurons. It is synthesized inside the neuron (histamine being an exception), travels to the end of the neuron (axon), is released into the extracellular space between two neurons (synapse), and then binds to a specific receptor on the ‘receiving’ neuron, usually the dendrite. After the neurotransmitter activates the receptor, it soon comes off the receptor and is taken up again by the original releasing axon, termed ‘reuptake’. The neurotransmitter’s action is specific and local, or paracrine. This is in contrast to hormones that are released in the other organs of the body, which generally disperse to all tissues, and affect all cells that have the hormone’s receptor (endocrine). However, some neurotransmitters are also hormones; as mentioned previously, histamine is one of them.

There are three classical types of neurotransmitters: peptides, which are small protein fragments, acetylcholine, and amino acids/amino acid derivatives. There are many different peptide neurotransmitters, and some of them interact with histamine, vitamin C, or both. Some examples of the above interactions will be described later. Acetylcholine acts very similar to an amino acid/amino acid derivative neurotransmitter, but is much more hydrophobic and is lipid (fat) related. Acetylcholine can be either inhibitory or excitatory to neurotransmission, depending on the receptor it binds to. Acetylcholine plays a major role in both memory and learning. Amino acids that can act as neurotransmitters are glycine, gamma-amino butyric acid (GABA), glutamate, and aspartate. Glycine and GABA are both neutrally-charged amino acids, and are inhibitory neurotransmitters; that is, they generally inhibit neurotransmission in the entire downstream neuron. Glutamate and aspartate are both acidic amino acid, and both are strong excitatory neurotransmitters, although they do have one inhibitory receptor, discussed below.

The amino acid derivative neurotransmitters are dopamine, norepinephrine, serotonin, and histamine. Both dopamine and norepinephrine are formed from a common pathway: phenylalanine -> tyrosine -> l-dopa -> dopamine -> norepinephrine -> epinephrine. The first two molecules, phenylalanine and tyrosine, are both bona fide amino acids, and the last four molecules are amino acid derivatives. Dopamine is an inhibitory neurotransmitter; it often achieves this by activating downstream pathways that ultimately become inhibitory. Two major roles that dopamine plays are regulation of the hypothalamus, and maintenance of fine motor control; Parkinson’s disease is the result of excessive loss of dopamine-receiving neurons. Excessive dopamine levels can result in psychosis, and all of the classic antipsychotic drugs inhibit dopamine neurotransmission. Dopamine is often known as the pleasure hormone, since drugs like heroin, cocaine, nicotine, and marijuana act to release dopamine into synapses.

Norepinephrine can be either excitatory or inhibitory, again depending on the receptor it binds to. It plays major roles in attention and arousal. Epinephrine does not play a significant neurotransmitter role in the brain. Serotonin, otherwise known as 5-hydroxytryptamine, is formed by the pathway tryptophan -> 5-hydroxytryptophan -> 5-hydroxytryptamine. As in the dopamine/norepinephrine pathway, the first molecule in the pathway, tryptophan, is a true amino acid. Serotonin is similar to norepinephrine in that it can be either excitatory or inhibitory. Serotonin appears to be involved in diverse biochemical and behavioral functions, including neuroendocrine control, sleep, appetite, and temperature regulation. Its complex relationship with neuroendocrine systems has led many experts to call serotonin the ‘key neurotransmitter,’ or the ‘master hormone.’ However, as discussed in detail below, histamine may equal or exceed serotonin in neuroendocrine influence.

As mentioned previously, histamine is formed directly from the amino acid histidine. Histamine is unique among the amino-acid derived neurotransmitters in that it is not released from an axon, and is not taken up by the releasing axon after its neurotransmission is completed. It is always excitatory, and ironically that excitation may eventually lead to major depression, as will be discussed later. Histamine shares many physiological roles with serotonin, including all four of the roles mentioned above (neuroendocrine control, sleep, appetite, and temperature regulation). Interestingly, serotonin is often released along with histamine during allergic reactions. Like norepinephrine, histamine plays a role in arousal, and like acetylcholine, it also plays a role in learning and memory. Histamine also is implicated in psychosis just as dopamine is, although it is low histamine levels that usually are the culprit, whereas high dopamine levels appear to cause psychosis. Since histamine is always excitatory, it is functionally related to the amino acid neurotransmitters glutamate and aspartate. In short, histamine plays diverse biochemical roles that are shared by almost all other neurotransmitters, and in turn influences many roles of the other neurotransmitters.

Neurotransmitter receptors are located on the receiving end of the neurotransmitter signal (usually the dendrite cell), and are embedded in the outside fatty layer of the cell, termed the plasma membrane. Often there are multiple types of receptors for each neurotransmitter. There are two types of GABA receptors, termed GABAA and GABAB; both are inhibitory. There is only one glycine receptor, and as mentioned earlier it is inhibitory. There are at least four main receptors for both glutamate and aspartate; interestingly the two amino acids share all four receptors, three of which are termed ionotropic and one metabotropic. The ionotropic receptors are called N-Methyl-D-aspartate (NMDA), AMPA, and Kianate. The three ionotropic receptors are all excitatory. The metabotropic receptor group has three subgroups; two are inhibitory and one is excitatory.

There are three types of acetylcholine receptors. Two of them are termed cholinergic muscarinic receptors, and are given the abbreviations M1 and M2. M1 receptors are excitatory, and M2 receptors are inhibitory. The third type of acetylcholine receptor is called the cholinergic nicotinic receptor, and is excitatory. There are two dopamine neurotransmitter receptors, termed D1 and D2; both are inhibitory. The neurotransmitter receptors for norepinephrine are the most complicated of all, besides possibly the glutamate/aspartate receptors. The two major types of norepinephrine receptors in the brain, alpha (a) and beta (b). These are both further divided into a1 and a2 receptors, and b1 and b2 receptors. The a1 and b1 receptors are both excitatory, and the a2 and b2 receptors are both inhibitory.

There are four main types of 5-hydroxytryptamine (5-HT, or serotonin) neurotransmitter receptors. Several others exist but are not well-characterized, or have redundant functions with the four main receptor types. The 5-HT1A receptor is the most abundant in the central nervous system (CNS), and it is the only inhibitory neurotransmitter of the four. The 5-HT2A, 5-HT3, and 5-HT4 receptors are all excitatory. As for histamine, there are four receptors, termed H1, H2, H3, & H4. The H1, H2, and H4 receptors are excitatory. The H3 receptor is inhibitory in that it inhibits release of histamine itself.

Neurotransmitters constitute the first message in brain communication. However, the neurotransmitter message that is conveyed to the specific receptor on the cell membrane needs to continue inside the cell. The process by which this occurs is called ‘signal transduction’, and there are two different ways for signal transduction to be achieved. During the discussion above of the glutamate/aspartate receptors, there was mention of the terms ionotropic and metabotropic. All neurotransmitter receptors share a similar signaling mechanism with either the ionotropic or metabotropic receptors. The ionotropic receptors form ion channels between the extracellular and intracellular fluid, and are permeable to specific ions, such as potassium (K+), chloride (Cl-), and calcium (Ca2+). The metabotropic receptors convey their signal to the brain cell in much more complicated ways, using a variety of small organic molecules, proteins, and sometimes fatty acids. Some receptors are both ion channels and metabolic signalers.

Ion channel neurotransmitter receptors can be either excitatory or inhibitory. K+ channels that are excitatory achieve this by lowering the conductance for potassium across the plasma membrane, and vice versa (inhibitory K+ channels raise its conductance). Excitatory K+ channel receptors include M1, metabotropic subgroup I, 5­-HT2A, 5-HT4, a1, b1, and both H1 and H2. Inhibitory K+ channel receptors include M2, D2, GABAB, 5-HT1A, and a2. Ca2+ channels are excitatory if they are postsynaptic (the classical dendritic receptor location), and inhibitory if they are presynaptic (axon). Excitatory Ca2+ channel receptors often allow for other positively charged ions (cations) to enter the channel. Excitatory Ca2+ channel receptors include cholinergic nicotinic, NMDA, AMPA, and 5-HT3. Inhibitory Ca2+ channel receptors are D2, GABAB, metabotropic subgroups II and III, and a2. Cl- channels raise Cl- conductance and are always inhibitory; they include GABAA and glycine. Sodium (Na+) channel receptors are inhibitory and raise Na+ conductance; the receptor in the brain for this is b2.

As can be seen above, there is a significant amount of redundancy in the functions of ion channel receptors. Metabolic receptors are no exception as well. There are two major signal transduction pathways in the brain: the inositol triphosphate/diacylglycerol (IP3/DAG) pathway, and the cyclic adenosine monophosphate (cAMP) pathway. There are several pathways that branch off from these two main pathways, and there is also significant communication, or crosstalk, between the two major pathways. The IP3/DAG pathway is always excitatory. The excitatory receptors that are upstream of IP3 and DAG are M1, metabotropic subgroup I, 5-HT2A, a1, H1, and H4. Functionally, the cAMP pathway is more complicated. It can be either excitatory or inhibitory, and to complicate matters further, raising or lowering cAMP levels can be either excitatory or inhibitory. The excitatory receptors that raise cAMP levels are b1 and H2. Inhibitory receptors that raise cAMP levels are D1 and b2. Inhibitory receptors that lower cAMP levels include M2, D2, metabotropic subgroups II and III, 5-HT1A, and a2.

There are dozens of different small molecules and proteins that are involved in both major signal transduction pathways, and only the main, well-defined molecules and proteins will be mentioned. Structurally, the cAMP pathway is relatively straightforward. The model cAMP pathway is the norepinephrine b1 receptor pathway. Norepinephrine binds to the b1 receptor—although in an inhibitory model it would bind to the b2 receptor (cAMP would still be raised). The b1 receptor then activates a modulatory protein termed ‘Gs’ (Chen, et. al., 1999) for G-stimulatory; the b2 receptor communicates with a ‘Gi’ inhibitory protein. The Gs-protein then activates an enzyme called adenylyl cyclase (Menkes, Rasenick, Wheeler, and Bitensky, 1983). Adenylyl cyclase then produces cAMP, and raises its level inside the cell. Elevated cAMP then activates a very important enzyme, protein kinase A (PKA), which then modifies a variety of other proteins (substrates) (Walaas & Greengard, 1991). PKA modifies downstream proteins by a mechanism known as phosphorylation, where the enzyme transfers a high-energy phosphate group to the downstream (substrate) protein. Importantly, PKA activity is reduced in depression (Shelton, Mainer, & Sulser, 1996).

One of the substrate proteins that PKA phosphorylates is the aptly termed cAMP response element binding protein (CREB); this is achieved after PKA translocates into the cell’s nucleus (Hagiwara, et. al., 1993). In this cAMP pathway model, CREB then binds to a specific DNA sequence upstream of a gene called brain-derived neurotrophic factor (BDNF), and increases expression of BDNF mRNA (Zafra et al., 1992). The central dogma of molecular biology states that DNA is transcribed into messenger RNA (mRNA), which is then translated (expressed) into protein (Lewin, 1994). In other words, CREB binds upstream of the BDNF gene, signaling an enzyme complex to transcribe the BDNF DNA into mRNA, and that mRNA is then translated into the mature BDNF protein.

BDNF then initiates several positive functions, including supporting the survival and maturation (differentiation) of brain neurons (Hyman et al., 1994), especially serotonin (5-HT) neurons (Mamounas, Blue, Siuciak, & Altar, 1995). The above effect is an example of positive feedback, where the end of the pathway helps to perpetuate the beginning of the pathway. Conversely, stress can significantly lower BDNF levels (Smith, Makino, Kvetnansky, & Post, 1995). In conclusion, the norepinephrine / cAMP / PKA pathway generally assumes a very positive role in mental health, the exception being when it is overstimulated in manic patients (Young et al., 1993). As mentioned earlier, the histamine H2 receptor is coupled to the cAMP pathway, and activation of the receptor raises cAMP levels.

The IP3/DAG pathway is significantly more complicated than the cAMP pathway. This is because there is not one main pathway, but two. Some would argue that it is a misnomer to call IP3/DAG a ‘pathway’, since the single pathway from the membrane receptor splits into two separate pathways very early on; one becoming the IP3 pathway, and the other becoming the DAG pathway. The model system for this hybrid pathway is the 5-HT2A receptor pathway. 5-hydroxytryptamine (5-HT, serotonin) binds to its 2A receptor, activating another G-protein, termed Gq that is different than the one in the norepinephrine receptor pathway. Gq then activates the enzyme phospholipase C (PLC). It is this enzyme that initiates the divergence of the serotonin signal by splitting the lipid-sugar phosphatidylinositol 4,5-bisphosphate (PIP2) into the aforementioned 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (De Chaffoy de Courcelles et al., 1985).

The DAG signal activates the enzyme protein kinase C (PKC) (Nishizuka, 1986). PKC performs a wide variety of functions. It plays a role in long-term changes in brain gene expression, neuronal excitation, and neurotransmitter release (Stabel & Parker, 1991). One of the more important PKC functions is to phosphorylate microtubule-associated protein 2 (MAP2) (Hoshi et al., 1988). Interestingly, PKA also appears to phosphorylate MAP2 (Sloboda, Rudolph, Rosenbaum, & Greengard, 1975). This is one of the ways that the cAMP and IP3/DAG pathways interact with each other.

However, an even more important interaction is that phosphorylated MAP2 inhibits microtubule assembly (Jameson et al., 1980). Microtubules form much of the cytoskeletal framework of the cell. Microtubules are formed by polymerization (multimerization) of tubulin dimers (two attached tubulin proteins). Tubulin dimers then stimulate adenylyl cyclase, the enzyme that is in the cAMP pathway (Hatta, Ozawa, Saito, & Ohshika, 1995). Thus, the DAG pathway feeds, or shunts, into the cAMP pathway. Many psychiatric and neurological researchers were perplexed for several years that antidepressants affecting either norepinephrine or serotonin reuptake both had very similar biochemical results. The discovery of the DAG shunt into the cAMP pathway elegantly resolves this former theoretical paradox.

The IP3 pathway is less straightforward than the DAG pathway. After being formed, IP3 then binds to an intracellular receptor that releases calcium ion (Ca2+). Ca2+ has many important actions within the cell. In this model, Ca2+ activates two main proteins, calmodulin (CaM), and calcineurin. These two downstream proteins of IP3 do not always have positive effects on well-being, as is normally the case for the cAMP and DAG pathway proteins. CaM activates a group of enzymes known as calmodulin kinases (CaM K’s). CaM K’s can interact with the cAMP pathway by influencing CREB-mediated transcription. As discussed earlier, CREB-mediated transcription has a positive effect on brain function. Some CaM K’s activate CREB (Anderson et al., 1998); other CaM K’s inhibit CREB (Hook & Means, 2001). Like the CaM K’s, calcineurin may activate or inhibit CREB (Schwaninger et al., 1995; Bito, Deisseroth, & Tsien, 1996). Histamine H1 receptors are linked to the IP3/Ca2+ pathway, and the DAG/PKC pathway (Wada, Inagaki, Yamatodani, & Watanabe, 1991).

One of the main ways that the brain communicates with the rest of the body is via the hypothalamic-pituitary-adrenal (HPA) axis. Within this axis of activity, the nervous system (brain) regulates the body’s endocrine (hormone) system, and vice-versa. The immune system also interacts with the HPA axis to a certain extent. This axis is the major regulator of virtually all bodily activity. Many different types of stress can raise the levels of one of the most important HPA axis hormones, the peptide corticotropin-releasing hormone (CRH) (Koob, 1999). CRH then stimulates secretion of adrenocorticotropic hormone (ACTH). ACTH then stimulates secretion of a class of steroid hormones called glucocorticoids (Axelrod & Reisine, 1984), of which cortisol is the most important. Later, after the stressor is gone, there is a negative feedback loop that returns the HPA axis to normal activity. However, when the HPA axis is overstimulated for prolonged periods due to chronic stress, the negative feedback loop fails (Johnson et al., 1992). Glucocorticoids can have both positive and negative effects. They have anti-inflammatory actions (Lewin, 1994), but they can also suppress proper immune function. As will be mentioned later, histamine plays a role in HPA axis stimulation.

Vitamin C has a very interesting history. Over two hundred years ago it was realized that certain fruits could help prevent a connective tissue wasting disease known as scurvy in ocean-bound sailors. However, the antiscorbutric factor in the fruits (such as lemons and limes), was not identified until the 20th Century. It was then that Vitamin C was isolated in 1928 from adrenal gland by the Nobel prize-winning chemist Albert Szent-Gyorgy, and named ascorbic acid (Grunewald, 1993). It was subsequently isolated from fruit (lemons) in 1932 (Haas, 1992), and shortly thereafter was synthesized in 1933 (Jacob, 1996). Vitamin C is mainly found in fruits and vegetables (Haas, 1992). “The best-known sources of vitamin C are the citrus fruits – oranges, lemons, limes, tangerines, and grapefruits” (Haas, 1992, p. 142). The best vegetable vitamin C sources are black currants and raw red peppers (Reavley, 1998). Vitamin C has been the best selling nutritional supplement for decades; in 1993 its sales were $117 million (Firshein, 1996). It is best used in powdered form (Vayda, 1994). Calcium ascorbate, sodium ascorbate, and ester-C are better tolerated than ascorbic acid (Vayda, 1994), presumably due to their non-acidic chemistry (ascorbic acid sometimes irritates the stomach).

Vitamin C has a molecular weight of 176.1. Its chemical formula is C6H6O8. The chemical name is 2,3-enediol-l-gulonic acid (Koenig, 1996). Vitamin C is an organic chemical known as a ketolactone, and has two dissociable hydrogen atoms. “At physiological pH ascorbate is nearly totally in its anionic form” (Levine & Morita, 1985, p. 5). This molecule that has one dissociated hydrogen atom and one weakly attached hydrogen atom is called ascorbate. Vitamin C analogues that have 100% biological activity include l-dehydroascorbic acid, l-ascorbic acid-6-palmitate, and l-ascorbic acid-5, 6-diacetate (Koenig & Elmadfa, 1996).

Dehydroascorbate differs from ascorbate in that it lacks the two ionizable hydroxyl groups (Rose, 1988). A hydroxyl group contains one oxygen and one hydrogen atom. When both hydrogens have dissociated from their connecting oxygen atoms, the molecule rearranges and the oxygen atoms each gain a double bond with the rest of the dehydroascorbate molecule. Technically, dehydroascorbate is not an acid, since it cannot release any hydrogen atoms into solution. It is relatively hydrophobic compared to ascorbate, and thus can be transported across the fatty cell membranes. Dehydroascorbate has antiscorbutric properties, but not antioxidant properties (Jacob, 1996). When vitamin C is oxidized to dehydroascorbate, it is transported to neighboring cells, and then reduced back to ascorbic acid (Nualart, et. al., 2003).

The main role of vitamin C is to manufacture collagen (Reavley, 1998), via the hydroxylation of the amino acid proline (Grunewald, 1993). It helps produce the oxygen-carrying molecule hemoglobin and also aids in iron absorption (Reader’s Digest Association, 1999). Vitamin C oxidizes lysine to hydroxytrimethyllysine to synthesize the non-essential amino acid carnitine (Goodman et al., 1996). It helps form bones, cartilage, teeth, and strengthens capillaries (Hoffer & Walker, 1978), and this is mainly due to its collagen synthesis role (Hediger, 2002). Vitamin C converts folic acid to folinic acid (Goodman et al., 1996), and hydroxylates the neurotransmitter dopamine to form norepinephrine (Goodman et al., 1996).

Known enzymes dependent on vitamin C for optimal activity include: 4-hydroxyphenyl pyruvate dioxygenase, g-butyro betaine, 2-oxoglutarate 4-dioxygenase, proline hydroxylase, lysine hydroxlyase, procollagen-proline 2-oxoglutarate 3-dioxygenase, trimethyllysine 2-oxoglutarate dioxygenase, dopamine b-monooxygenase, and peptidyl glycine a-amidating monooxygenase (Levine & Hartzell, 1987). Also, many genes are affected (modulated) by ascorbic acid. Genes that are modulated by ascorbic acid include: procollagen, acetylcholine receptor a, pro-atrial natriuretic factor, cytochrome P450’s CYP2A1 and CYP2B1, alkaline phosphatase, osteocalcin, osteopontin, lipid-binding protein, lipoprotein lipase, myosin light-chain 2, and myogenin (Hitomi & Tsukagoshi, 1996).

The vast majority of animals can synthesize vitamin C. D-glucose is the starting molecule. Glucose is metabolized through the pentose phosphate cycle, shunting over to aldonolactonase and l-gulono-gamma-lactone oxidase to produce ascorbic acid (Nishikimi & Yagi, 1996). Primates (including humans), guinea pigs, and some bats and birds do not have the enzyme gulonolactone oxidase, and thus cannot synthesize vitamin C (Banhegyi et al., 1997). The prevailing theory of why the above animals lost the ability to synthesize vitamin C is that all of these animals lived in an ascorbate-rich plant environment for millions of years, and thus lost the gene to synthesize vitamin C due to its uselessness (Cameron & Pauling, 1993). Genetic analysis indicates that the ability to synthesize vitamin C was lost in primates roughly 45-50 million years ago (Nishikimi & Yagi, 1996). Interestingly, this happened very early in the evolution and divergence of primates, long before any primate resembling a human appeared.

A conservative estimate for bodily vitamin C is “a total pool size of about 1500 mg” (Kallner, 1987, p. 422); a more liberal estimate is 5000 mg (Ginter, 1980). Adults lose 3-4% of their total vitamin C daily (Goodman et al., 1996). “An 8-ounce glass of fresh-squeezed orange juice supplies 124 mg of vitamin C” (Reader’s Digest Association, 1999, p. 379). In a non-stressed person, about 200 milligrams per day is needed to maintain vitamin C levels (Lieberman & Bruning, 1997). Absorption of up to 180 mg of vitamin C is 80-90% efficient (Koenig & Elmadfa, 1996). Regular vitamin C supplementation raises blood concentrations of the vitamin by an average of 25-30%. Both dietary and supplemental vitamin C appears to have identical biological effects in maintaining blood levels (Boeing & Rausch, 1996). Vitamin C supplementation of 2000 mg/day raises plasma levels by 57% (Johnston, 1996).

The vitamin C concentration in the brains of different mammals is directly proportional to neuron density (Rice, 2000). In the brain, extracellular vitamin C concentration rises rapidly after behavioral activation (Katsuki, 1996). Vitamin C is transported into non-CNS cells via a sodium-dependent co-transport mechanism (Rose, 1998). Vitamin C in the ascorbic acid form cannot enter the brain; it first must be oxidized to dehydroascorbate to cross the blood-brain barrier (Agus et al., 1997), where it is then reduced back to ascorbate. Oxidized vitamin C is usually regenerated by a very small peptide called glutathione (Banhegyi et al., 1997), and vitamin C can also regenerate oxidized glutathione (Jacob, 1996), depending on which antioxidant molecule is needed most at the time. The enzyme thioredoxin reductase can also recycle vitamin C (May, 2002), as can the antioxidant alpha-Lipoic acid (Xu & Wells, 1996).

Literature Review:

Histamine plays both a varied and powerful role in the brain. Histamine alone can inhibit release of all major neurotransmitters: serotonin, glutamate, acetylcholine, GABA, dopamine, and norepinephrine (Brown, Stevens, & Haas, 2001). Even low levels of histamine can inhibit neuronal firing of all serotonergic receptor subtypes (Lakoski & Aghajanian, 1983). Interestingly, histamine can also release norepinephrine from brain tissue (Bugajski, 1984), in addition to inhibiting its release, as mentioned above. Excess norephinephrine release may lead to anxiety disorders or mania.  Histamine administration in rats decreased blood dopamine concentration (Willems et al., 1999). In contrast, histamine administration into anesthetized rat brain raised extracellular dopamine levels (Galosi et al., 2001). Elevated dopamine levels are thought to be associated with psychosis, since classical antipsychotics block dopamine receptors (Victor & Ropper, 2001).  Histamine can enhance glutamate signaling (Galosi et al., 2001); excess glutamate signaling can be neurotoxic.

Histamine itself is a very toxic molecule. Even low doses of histamine can kill endothelial cells in culture (Fernandez-Novoa, & Cacabelos, 2001). High histamine levels, known as histaminemia, “causes separation of vascular endothelial cells” (Clemetson, 1999, p. 1). This can lead to heart disease and death. In humans, histamine increases heart rate and lowers blood 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’ 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 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 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 (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 pathway. Studies have shown that Ca2+ release is increased in major depression (Kusumi, Koyama, & Yamashita, 1991). The protein calcineurin is downstream of the release of Ca2+. As mentioned above, calcineurin is involved in neurotransmitter depression. Histamine and calcineurin are both involved in mental illness and allergic reactions (Abbas, Lichtman, & Pober, 2000); therefore histamine’s activation of calcineurin may play a key role in both of these morbid outcomes.

Additional evidence for the potential morbidity of the IP3 pathway is that H1 receptor activation can inhibit learning and memory (Knoche et al., 2003), cause hyperactivity (Chiavegatto, Nasello, & Bernardi, 1998), and cause aggression (Yanai et al., 1998). An H2 receptor mutation can result in schizophrenia (Brown, Stevens, & Haas, 2001). Some antihistamines can reduce anxiety by antagonizing the H1 receptor (Lader & Scotto, 1998), while H2 antagonists can have antidepressant effects (Cantu & Korek, 1991). Both H1 and H2 antagonists can cause a wide variety of physical and mental side effects.

Increased histamine levels result in increased vitamin C utilization (Nandi, Subramanian, Majumder, & Chatterjee, 1974); this strongly suggests that vitamin C regulates histamine levels via its antihistamine effect. Vitamin C is a very efficient histamine detoxifier (Clemetson, 1999). “After two weeks of 2,000 mg vitamin C per day, the blood histamine level fell about 40% below the baseline value” (Johnston, Retrum, & Srilakshmi, 1992, p. 989). Vitamin C raises the level of cAMP (Tisdale, 1975), a key molecule in the mental health-enhancing cAMP pathway. Perhaps just as importantly, cAMP inhibits histamine release (Cathcart, 1986). Conversely, low cAMP levels can increase histamine release (Mohsenin & Dubois, 1987).

 

Chapter 4: Results and Findings

Introduction:

In Chapters 1 and 2 this dissertation established a theoretical framework in which vitamin C attenuates histamine-mediated mental illness. In Chapter 4, data will be presented that exemplifies the multitude of positive effects on the body by vitamin C, including positive effects on mental illness. It has been known for some time that vitamin C is a key nutrient for proper brain function (Mark & Mark, 1989). Vitamin C’s positive role in mental health is illustrated by its potential to reduce anxiety when large doses are used (Balch & Balch, 1997). It also has a mild antidepressant effect (Brody, 2002). Conversely, vitamin C deficiency consistently produces behavioral abnormalities and fatigue, in addition to the classic skin lesions seen in scurvy (Petrie & Ban, 1985; Kallner, 1987). When vitamin C levels are low, the CNS and brain attempt to maintain a normal tissue level by depleting other tissues of vitamin C (Rose, 1988). This finding begs the question of how low or high vitamin C levels can affect mental health, if the CNS and brain constantly strive to maintain homeostasis of this vitamin. An explanation of this theoretical question is found in the Conclusions and Implications section of Chapter 5.

Analysis of Data: N/A

Findings:

Vitamin C induces myelin formation, membrane enzyme activity, hormone synthesis, acetylcholine and norepinephrine release, and also influences neurotransmitter binding, neurotransmitter receptor distribution, and neurotransmitter density (Rebec & Pierce, 1994). At physiological pH (7.4), “ascorbic acid causes a concentration-dependent increase in the affinity of 5-hydroxytryptamine (5-HT) for 5-HT3 binding sites” (serotonin receptor 3 sites) (Katsuki, 1996, p. 299). Vitamin C also modulates dopamine levels. High brain dopamine levels are associated with psychosis. This can be achieved with chronic use of the stimulant amphetamine. Traditional antipsychotic drugs lower dopamine levels, and are called neuroleptics. Vitamin C experimentally has a neuroleptic-like action, in that it inhibits amphetamine-induced locomotion, presumably via inhibition of dopamine-stimulated neurotransmission (Rebec & Pierce, 1994). When the potentially neurotoxic neurotransmitter glutamate is injected into animal brain, there is a dramatic increase in extracellular vitamin C release (Katsuki, 1996).

There are a number of ways in which vitamin C improves mental health. Vitamin C increases secretion of the hormone oxytocin, which heightens arousal and well-being (Brody, 2002). “Ascorbate promotes myelin formation” (Rice, 2000, p. 214), which is critical for proper nerve function. Vitamin C supplementation inhibits stress-induced cortisol release, and reduces stress-related mortality (Brody, Preut, Schommer, & Schurmeyer, 2002). Intake of vitamin C at 4 g/day significantly reduced cortisol levels, and increased levels of the androgen steroid hormone dihydroepiandosterone (DHEA) (Komindr, Nichoalds, & Kitabchi, 1987).

Vitamin C has been shown to protect the brain from drug-induced neurotoxicity (Shankaran, Yamamoto, & Gudelsky, 2001). Seniors with high vitamin C levels have better memory performance (Perrig, Perrig, & Stahelin, 1997). Another study concluded that retirees who supplemented with vitamin C had a lower rate of cognitive impairment (Paleologos, Cumming, & Lazarus, 1998). Vitamin C supplementation of 3 g/day reduced both state and subjective anxiety responses to psychological stressors (Brody, Preut, Schommer, & Schurmeyer, 2002). Vitamin C can reduce behavioral anxiety in animals (Brody, 2002).

Neuronal oxidative damage has been shown to be inhibited by vitamin C (Hediger, 2002). Vitamin C also protects against neuronal cell death by buffering glutamate-generated reactive oxygen species, known as ROS (Rice, 2000). The catecholamine neurotransmitters epinephrine, norepinephrine, and dopamine are easily oxidized, and oxidized catecholamines can be neurotoxic. Vitamin C inhibits metal ion-induced oxidation of catecholamines, and also detoxifies catecholamine degradation products (Gruenwald, 1993). Vitamin C inhibits glutamate-induced fast-firing neurons (Kiyatkin & Rebec, 1998), providing a protective effect against glutamate-mediated neurotoxicity.

Vitamin C inhibits dopamine-stimulated adenylate cyclase, even at low concentrations (it does not alter basal adenylate cyclase activity) (Thomas & Zemp, 1977). Adenylate cyclase produces cAMP. However, vitamin C does not inhibit norepinephrine-stimulated adenylate cyclase (Tolbert, Thomas, Middaugh, & Zemp, 1979). The above difference in adenylate cyclase interactions has important theoretical implications. Since high dopamine levels can cause psychosis, vitamin C inhibition of dopamine-stimulated adenylate cyclase may be the main mechanism of its neuroleptic-like action. By inhibiting dopamine-stimulated adenylate cyclase, vitamin C may be useful in treating dopamine-related disorders such as tardive dyskinesia, schizophrenia, and Huntington’s chorea (Tolbert, Thomas, Middaugh, & Zemp, 1979). Vitamin C also reduces many of the symptoms of the neurological illness Huntington’s disease (Rebec, Barton, Marseilles, & Collins, 2003).

There are a multitude of environmental pollutants that can lower vitamin C levels. Smoking, alcohol, steroids, analgesics, oral contraceptives, antidepressants, and anticoagulants can all reduce tissue and blood levels of vitamin C (Balch & Balch, 1997). Vitamin C deficiency can result in susceptibility to carbon monoxide, lead, and mercury poisioning (Vayda, 1994), since vitamin C plays an active role in detoxifying these chemicals. All three chemicals above are proven brain toxins. Vitamin C deficiency can lead to anemia, soft gums, capillary weakness, tooth decay, skin hemorrhages, loss of appetite, and muscular weakness (Hoffer & Walker, 1978). Not only does excess glucose cause a variety of chronic diseases, it also inhibits cellular uptake and accumulation of vitamin C in neutrophil immune cells (Washko, Rotrosen, & Levine, 1991).

Summary:

There are many reasons to supplement (megadose) with vitamin C in addition to improving and/or preserving mental health. White blood cell levels of vitamin C are only consistently raised with intakes of six grams or more daily (Janson, 2000). Vitamin C helps both cellular and humoral immune responses (Janson, 2000). Epidemiological studies have found that high plasma levels of vitamin C correlate with a death rate reduction of roughly 33% (Boeing & Rausch, 1996). Vitamin C appears to facilitate social interactions, since depletion of vitamin C in rats inhibited social behavior (Rebec & Wang, 2001).

Vitamin C attenuates subjective responses to psychological stress and also “reduces stress-induced cortisol release, and other indices of stress, including mortality following the stressor” (Brody, Preut, Schommer, & Schurmeyer, 2002, p. 320). Vitamin C can also improve mental health in more indirect ways. It is common knowledge that allergies and asthma are both physically and mentally irritating to people. People who doubled their vitamin C intake from 100 to 200 milligrams/day had 30% less bronchitis and/or wheezing (Feinstein, 1996). Vitamin C also partially blocks synthesis of inflammatory prostaglandins and leukotrienes (Feinstein, 1996).

There are a number of various food and vitamin interactions with both vitamin C and pharmaceutical antihistamines that are worth mentioning. Folic acid supplementation can raise histamine-related allergic symptoms (Pfeiffer, 1987). Therefore, people with allergies who supplement with a B-complex vitamin may want to take one which does not include folic acid. High copper can be both destructive to vitamin C and also can produce a pellagra-like mental illness (Pfeiffer, 1987). Again, people who take nutritional supplements, for example a multimineral supplement, may want to avoid supplementing with copper, unles