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Figure 6 The progression of 5-HT neurons from aplysia to humans. In the aplysia nervous system there are only a few neurons which contain serotonin, and these neurons are large, with extensive connections. In the rodent brain, the 5-HT neurons are arranged in large grouping along the midline of the mes-cencephalon. The axons from these neurons ascend towards the forebrain in large bundles using mainly the ancient medial fore-brain bundle. In primates, the distribution of serotonergic neurons in the mescencepahlon is into smaller clusters of neurons. In addition, many of the axons from these neurons are now mye-linated. This new arrangement facilitated more precise and rapid delivery of sero-tonin to forebrain targets (Azmitia, 1987).

Figure 6 The progression of 5-HT neurons from aplysia to humans. In the aplysia nervous system there are only a few neurons which contain serotonin, and these neurons are large, with extensive connections. In the rodent brain, the 5-HT neurons are arranged in large grouping along the midline of the mes-cencephalon. The axons from these neurons ascend towards the forebrain in large bundles using mainly the ancient medial fore-brain bundle. In primates, the distribution of serotonergic neurons in the mescencepahlon is into smaller clusters of neurons. In addition, many of the axons from these neurons are now mye-linated. This new arrangement facilitated more precise and rapid delivery of sero-tonin to forebrain targets (Azmitia, 1987).

function in the human eye in rod cells used for night vision, are present in cyanobacteria (Ruiz-Gonzalez and Mar)n, 2004) . Cyanobacteria diverged about 2.5 billion years ago. The active site for solar capture in this receptor protein is tryptophan (Chabre and Breton, 1979; Hoersch et al., 2008). The rhodopsin receptor and the 5-HT1A receptor show substantial homology (Nowak et al., 2006). In plants (Arabidopsis thaliana), a gene sequence was identified with a region of a putative receptor that is similar to sequences of serotonin receptors and other receptors of the so-called rhodopsin receptor family using a G-protein linked mechanism (Josefsson and Rask, 1997). From the gene diversity for serotonin receptors, the 5-HT1A receptor is estimated to have evolved 750 million to 1 billion years ago, before the muscarinic, dopaminergic and adrenergic receptor systems (Peroutka and Howell, 1994). This age estimate would indicate that the receptor existed before the evolution of the most primitive animal form, sponges (Porifera), which evolved some 600 million years ago. If rhodopsin is considered the prototype of the 5-HT1A receptor, the emergence of serotonin receptors occurred 3.5 to 2.5 million years ago in cyanobacteria.

Life began in sea water, where Na+ and Cl~ ions are highly concentrated. Cells evolved a mechanism to exclude these ions in order to maintain a stable membrane potential, and 'neurotransmitters' evolved the ability to regulate these specific ion channels to rapidly manipulate the membrane potential. Second messengers, e.g., G proteins, c-AMP, and phospholipase C systems, appeared early in evolution and occur in all phyla that have been investigated. With the possible exception of the Porifera and Cnidaria, all the classical 'neurotransmitter' receptor subtypes identified in mammals occur throughout the animal phyla (see Walker et al., 1996). Many of the serotonin receptors are seen in the embryonic stage - for example, H3-5-HT binding is seen in the blastula and gastrula of sea urchins (Brown and Shaver, 1989) . A gene from the sea urchin encoding the serotonin receptor (5-HT-hpr) was identified and showed sequence homology with the aply-sia 5-HT2 receptor (Katow et al., 2004). Cells expressing the 5-HT receptor appeared near the tip of the archenteron in 33-h post-fertilization larvae. The serotonergic receptor cells developed 7 cellular tracts by 48 hours, and extended short fibers to the larval body surface through the ectoderm. These serotonergic receptor cells are a mesencephalic cell lineage, which appear to transmit serotonin signals to ectodermal cells at the start of gastrulation in sea urchins. In humans, the 5-HT1A receptors are at their highest levels before birth (Bar-Peled et al., 1991). In rats, the receptors for serotonin are not only present in the fetus, but can also be modified by injections of agonist (Whitaker-Azmitia et al., 1987) . All the invertebrate receptors so far cloned show homologies with mammalian receptors. This indicates that many of the basic serotonin receptor subtypes evolved during early geological periods and appeared at early ontogenic times. As the saying goes, 'Ontogeny recapitulates Phylogeny ' .

Tremendous diversity has occurred in receptors in mammals. There are hundreds of serotonin receptor clones, and the human brain has at least 20 separate neuronal transcripts of 5-HT receptors (Moroz et al., 2006). Serotonin is specifically bound to at least 16 specific receptor proteins in the human brain which regulate ion channels, c-AMP levels and kinase activity in neurons. The 5-HT receptors are found in every cell of the body. Why so many, and why such a large distribution? It can be speculated that the difficulty in making and obtaining tryptophan in animals results in low serotonin availability. The function of a receptor is to alert a cell that a chemical is present in the environment, without removing or altering the chemical. Thus, if a chemical is in short supply, the appearance of receptor molecules permits its actions to be transmitted throughout the organism. In order for this to be maximally effective, an efficient mechanism for the distribution of serotonin is required. Animals have specific tryptophan and serotonin binding proteins in their blood to help transport these molecules to specific target areas, such as the brain. Glial cells at the junction of the blood-brain barrier have special transport proteins for concentrating tryptophan and delivering it to the serotonin neurons (Bachmann, 2002; O'Kane and Hawkins, 2003). Serotonergic neurons developed long, unmyelinated axons that can take up tryptophan and utilize enzymes required for serotonin synthesis throughout the brain and gut. In summary, loss of tryptophan has promoted a highly branched, unmyelinated neural network, and a plethora of specific receptors to maximize serotonin's actions.

5-HT function

Plants do not have neurons or muscles, but they are nevertheless capable of limited movement by rotating their leaves towards the light and sending their roots deep into the soil to capture H2O and nitrogen. In multicellu-lar plant organisms, growth and mitosis are modulated by tryptophan-derived molecules, including serotonin. Furthermore, with the increase in organistic complexity, these molecules, in particular auxin, evolved homeo-static functions for effectively capturing and transporting solar energy and integrating plant rhythms and organism physiology. The plants developed effective transport systems for delivering tryptophan-based molecules from one region to another (e.g., leaf to root), depending on need (Mauseth, 2008). These two methods of producing movement, mitosis and maturation of plant cells, are similar to that seen in unicellular organisms and fungi (Eckert et al., 1999). Auxin and other tryptophan regulate the rapid tracking of leaves toward the shifting source of light. The movements of both leaves and roots depend on compounds similar to serotonin, such as auxin (I vanchenko et al., 2008). The turning of the leaf to its source of energy depends on the rearrangement of the cell's cytoskeleton inside the leaf cells. In the root, the emersion into the soil is produced by regulating cell division and maturation. Serotonin, auxin and melatonin are involved in ion signaling in the dedifferentiation and differentiation of plant cells (Jones et al., 2007). Auxin is the single most important trophic factor in plants (Perrot-Rechenmann et al., 2002). Serotonin and melatonin have diurnal and seasonal rhythms in their synthesis and function in plants based on availability of solar energy. Thus, many of the transport and receptor mechanisms for serotonin and related molecules are established prior to the appearance of neurons. The actions of serotonin on the cell cytoskeleton and differentiation forecast the actions of serotonin in neuronal development and adult neuroplasticity in mammals (Azmitia, 1999).

Serotonin acquired many new functions in animals as the animals developed more complex processes. Serotonin-producing cells served a defense mechanism (stinging) in Cnidaria (coral) and in many Arthropoda (insects) (Horen, 1972; Weiger, 1997). In lower animals, serotonin neurons are primarily sensory neurons (activated by external stimuli), and influence food intake, defense withdrawal, and complex locomotor actions such as swimming (e.g., in sea urchins, Echinodermata) (Yaguchi and Katow, 2003). In the worm ganglia (Annelids), serotonin is first found in interneurons, which permits better regulation of complex behaviors such as swimming (Kristan and Nusbaum, 1982) and possibly learning and memory (Moss et al., 2005 ). In Caenorhabditis elegans (Nematodes), 5-HT is involved in modulating feeding behavior by rapidly altering a chemosensory circuit (Chao et al., 2004). The involvement of serotonin is also directed at neurons. The serotonin released from an apical ganglion interacts with specific neuronal receptors to increase or decrease the firing rate of its target cells involved in sensory and motor processing (Marois and Carew, 1997). Actions of serotonin on sexual activity and reproduction are evident (Boyle and Yoshino, 2005). In addition, serotonin changes cAMP and Ca2 + levels in its target neurons, influences their transcription rate and modifies cell morphology (Pettigrew et al., 2005).

The actions of serotonin thus extend from that of anti-oxidant through morphogenesis and ascend to being involved in complex behaviors such as an organism's position in a social hierarchy. Serotonin in lobsters (Arthropods) regulates socially relevant behaviors such as dominance-type posture, offensive tail flicks, and escape responses (Kravitz, 2000). This action of serotonin may be through the 5-HT1A receptor (Sosa et al., 2004). 5-HT-regulated social and mental behaviors increased in number and complexity as these functions became more advanced and complicated. The many reports of increased social dominance in primates (Edwards and Kravitz, 1997) and improved mood and confidence in social interactions in humans after using drugs which increase serotonin levels are well documented (Kramer, 1993; Young and Leyton, 2002). In these higher animals, 5-HT continues in its role of a homeostatic regulator in adjusting the dynamic interactions of these many functions within the organism, and how the organism interacts with the outside world.


The actions of serotonin in Metazoa begin very early in development. They are seen at both the blastula and gastrula stages, as noted by the appearance of serotonin receptors in the blastula stages. In Mollusca, serotonin is involved in the determination of the animal pole during early blastula stages (Buznikov et al., 2003). Application of para-chlorophenylalanine (PCPA, a tryptophan hydroxylase inhibitor) interferes in morphogenesis by arresting gastrulation, which results in the disintegration of embryos. At lower concentrations of PCPA, retarded morphogenetic movements were observed that resulted in malformations in the anterior parts of the embryos and yolk granule degradation in the notochord (Hâmâlâlnen and Kohonen, 19891. In mammals, the actions of serotonin on the developing fetus are felt from the time of conception due to the circulating serotonin in the plasma of the mother (Côté et al.i 2007). Serotonin neurons are formed very early in gestation in vertebrates (Lidov and Molliver, 1982; Wallace and Lauder, 1983; Okado et al., 1989). Peripheral tissue also expresses cells which contain serotonin. For example, the mast cells (neuroendocrine) of the lung contain serotonin in the fetus (Kushnir-Sukhov et al., 2006). It is logical to assume that if serotonin made a very early phylogenic appearance, then it should also make a very early ontogenic appearance. Plant seeds and animal embryos have the highest levels of serotonin.

By increasing cAMP and P-CREB, serotonin mediates a trophic response that may underlie both maturation and memory formation in aplysia (Glanzman et al., 1990). Thus, in much the same way as serotonin and its derivatives influence the process and organelles of photosynthesis to move in order to track the source of light, in animals serotonin influences the morphology of sensory and motor neurons involved in neuronal networking in order to track the source of relevant stimuli. The changes in neuronal morphology are particularly intriguing, because they affect neuronal connectivity in much the same way as has been proposed for vertebrates. Even a relatively brief removal of serotonin from the brain of vertebrates results in loss of spine, dendritic profiles and synapses (Yan et al., 1997; Okado et al., 2001). This topic of neuroplas-ticity has been extensively reviewed by the current authors (Azmitia, 2001, 2007; Azmitia and Whitaker-Azmitia, 1991, 1997; Jacobs and Azmitia, 1992).

In mammals, serotonin has evolved a trophic relationship with glial cells. High-affinity receptors have been identified on astrocytes and Schwann cells from rodents and primates (Hertz et al., 1984; Whitaker-Azmitia and Azmitia, 1986i Gaietta et al.i 2003). One function is for astrocytes to provide serotonergic neurons with tryptophan (Pow and Cook, 1997). The serotonin receptors on astrocytes can also release the neurite extension factor S100B, and glucose (Azmitia, 2001). Serotonin application induces glial-derived neurotrophic factor (GDNF) mRNA expression via the activation of fibroblast growth factor receptor 2 (FGFR2) (Tsuchioka et al., 2008). Activation of serotonin receptors also promotes the development of glial cells in the brainstem of rats (Tajuddin et al., 2003).

The recruitment of secondary cells to amplify serotonin's trophic actions emerged in animals. Astrocytes are found in vertebrates, and in C. elegans and drosophila. These supportive cells may have appeared even earlier. Using antibodies against a myelin marker and an astro-cytic marker, evidence for glial cells was found in moths (Arthropoda) and aplysia (Roots, 1981). The emergence of these cells as targets for serotonin is what Brodie and Shore envisioned in 1957 when they termed the serotonin system the ')rophotrophic system', Serotonin has trophic functions (mitosis, apoptosis, differentiation and metabolism), directly and through astrocytes, the other major cellular system in the brain, by receptor-mediated changes in glucose availability and trophic factor release. These actions are considered to be significant in the development and aging of the brain (Azmitia, 1999) . Serotonin can in fact be considered to be important for the development and maturation of the entire organism, since serotonin and its receptors are found throughout the body - see Hansen and Witte, 2008 (gut), Wasserman, 1980 (lung), Raymond et al., 1993 (kidney), Hagmann et al., 1992 (liver) and Nordlind et al., 2008 (skin).

The idea that serotonin functions as a trophic factor in vertebrate brains requires a new concept for how serotonin can be most efficiently distributed from axons. Traditionally, neurotransmitters are transported by the axon to a specific synaptic site where the neurotransmitter is released. This is seen for a proportion of the serotonin axons (Muller et al., 2007). There were major discussions regarding whether serotonin could also function by diffusion from unmyelinated axonal varicosities on to non-synaptic sites (Beaudet and Descarries, 1978), and the controversy was settled by accepting the idea of diffuse release, as well as acknowledging that many of the receptor targets of serotonin are on non-neuronal cells. For example, in the rat brain, serotonin axons course through the lateral and III ventricles along ependymal cells (M0llgard and Wiklund, 1979). Serotonin fibers can be considered to be a 'drip irrigation system' for the brain. As long as the axons are intact, serotonin is efficiently released throughout the brain. In old age and in neuro-degenerative diseases, serotonin axons in the human brain degenerate (Azmitia and Nixon, 2008).

Seasonal affective disorder and suicides Dysfunctions in brain serotonin are implicated in many mental disorders, such as autism, Down's syndrome, anorexia nervosa, anxiety and depression. There are nearly 10,000 papers dealing with serotonin and various diseases ranging from alcohol addiction (Martinez et al., 2008) to herpes zoster (Ohyama et al., 2004) . The relationship between serotonin and depression is cited in over 13,000 papers, with 1750 citations since 2007. Furthermore, a strong correlation exists between brain serotonin levels, depression and suicide, with the first paper in this area written over 40 years ago (Shaw et al., 1967). Those attempting suicide had significantly lower levels of 5-HIAA in the CSF compared to controls (Mann et al., 1996). PET studies indicate that the 5-HT2 A receptor is altered in depressed suicide attempters (Audenaert et al., 2006). A decrease in serotonin has serious consequences on normal brain homeo-stasis, both structural and functional., and influences a person's desire to continue living. It is surprising to learn that sunlight has dramatic actions on the brain serotonin system of humans.

A seasonal variation in affective disorders was reported several decades ago (Videbech, 1975), and has certainly been noted from the earliest times of recorded history. All Northern hemispheric cultures since the Mesopotamians have developed special holidays to mark the nadir of light on Earth, and celebrations to counter winter's gloom (for example, Makar, Sankranti, Saturnalia, and Dong Zhi) (Count and Count, 2000). Seasonal affective disorder (SAD) consists of recurrent major depressive episodes in the fall/winter with remissions in spring/summer, and is effectively treated with serotonin drugs and/or light therapy (Westrin and Lam, 2007) . Treatment with light therapy or antidepressant medication is associated with equivalent marked improvement in the assessment of psychosocial functioning and life quality. There was no significant difference in measures in 96 SAD patients receiving 8 weeks of treatment with either (1) 10,000-lux light treatment and a placebo capsule, or (2) 100-lux light treatment (placebo light) and 20 mg fluoxetine (Michalak et al. , 2007). Several studies have confirmed that patients respond favorable to light therapy (Yerevanian et al., 1986; Stewart et al., 1991; Rao et al., 1992).

Light therapy has effects on serotonin parameters in humans. It has been shown that blood serotonin increases in healthy subjects and patients with non-seasonal depression after repeated visible light exposure. Blood samples from jugular veins in 101 healthy men showed that turnover of serotonin by the brain was lowest in winter, and directly related to the prevailing duration of bright sunlight (Lambert et al., 2002). The production of serotonin measured by this procedure increased rapidly with exposure to increased luminosity. Serotonin levels were higher on bright days no matter what the time of year, and the amount of serotonin present reflected the hours of sun exposure on a particular day - conditions the day before had no effect. In a group of patients with a history of SAD, significantly lower plasma biopterin and tryptophan levels were measured that increased after light therapy (Hoekstra et al., 2003).

A seasonal rhythm in plasma serotonin transporter in normal subjects was first demonstrated over 25 years ago (Whitaker et al., 1984). There was a significant reduction in the Hamilton Depression Rating Scale (HAMD21) score after therapy vs before treatment, and the Kd for citalopram binding was significantly higher after phototherapy than before treatment (Swiecicki et al., 2005). In agreement with the previous work, binding studies of 5-HTT show that this protein is in a sensitized state during depression in SAD, and normalizes after light therapy and in natural summer remission (Willeit et al., 2008). Phototherapy had a significant influence on both the measured serotonin transport parameters (Bmax and Kd).

This suggests that daily light therapy has a sound basis in biology and makes evolutionary sense.

Blue light is effective at increasing tryptophan absorption during photosynthesis in chloroplasts, and this light is efficient at treating patients suffering from SAD. As mentioned with the plant chloroplast system, it appears in human studies that blue light might be the most effective. Blue light can suppress melatonin levels and aid in circadian phase shift. Light therapy is effective at significantly reducing Hamilton Depression Rating Scale (SAD Version) when a narrow band of blue light (468 nm) is used (Glickman et al., 2006). The UV-A spectrum does not increase the antidepressant response of light therapy, and clinical application of light therapy should use light sources that have the UV spectrum filtered (Lam et al., 1992). Light therapy relieves suicidal ideation in patients with SAD consistent with overall clinical improvement. Emergence of suicidal ideas or behaviors is very uncommon with light therapy (Lam et al., 2000) . It has been proposed that the lighting standards in the home and workplace should be re-evaluated on the basis of new knowledge regarding the neurobiological effects of light (Jacobsen et al., 1987). This might be considered one of the first steps taken by a society to achieve conditions conducive to enhancing serotonin function in the general population, and an acknowledgement of serotonin's special relationship with sunlight that began to emerge at the beginning of life on Earth (Figure 7).


Sunlight has beneficial effects on the serotonin system and the mood and stability of humans. This is consistent with the idea that serotonin is involved in homeostasis in humans (Azmitia, 2001) and contributes to the emergence of mind (Azmitia, 2007). What is surprising is the consistency of serotonin's function throughout evolution. The indole ring of tryptophan was the first and principal






-> Rhodopsin Receptor




Photosynthesis NADH Oxygen

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