One electron, two electrons

“In molecular orbital theory, the fact that most molecules contain electron pair bonds is explained as a consequence of the Pauli principle, according to which in the stable state of any system, any given orbital can be occupied by 2 (and only 2) electrons with opposite spins. This fact greatly favors the stability of even-electron as compared with odd-electron molecules." (R.S. Mulliken, 1978)

Most of the stuff in the material world that we encounter has even-electron configurations, which is accounted for by the familiar Pauli principle. Molecules with odd electrons are more rare. Just how frequently do we encounter odd electron molecules? In frozen sugar solutions, it was approximated that there is one unpaired spin for every 10E4 molecules of irradiated sugar in solution.

Why is the odd-electron configuration so rare? To begin with, theories that account for unpaired electrons are much less developed than theories that describe the types of matter that contain ordinary electron pairs. Most molecules have even numbers of electrons that fill the available molecular energy levels in pairs, and therefore a lot of theories just assume the Pauli exclusion principle. In the case of unpaired electrons, we may need to be prepared to find a new type of physical law.

Second, the existence of odd-electron configurations is often associated with a pronounced color in the system. For example, aniline is colorless when pure but turns brown when oxygen is bubbled through it, and becomes colorless again on sweeping out the oxygen. There are many colorimetric methods for estimating the concentration of unpaired electrons. The human visual system detects the presence of free radicals as color.

Another reason that unpaired electrons differ from electrons in pairs is that unpaired electrons are more delocalized in space. Whereas paired electrons stay in the neighborhood of one nucleus, unpaired electrons are contained in orbitals that may extend over several adjacent atoms. In the cell where biopolymers are intimate contact with each other, it is quite conceivable that unpaired electron migration may take place over large distances involving a number of aggregated biopolymers.

Diphenylpicrylhydrazyl (DPPH) is a stable free radical that is often employed as an EPR standard, and its EPR spectra is shown below. There is an unpaired electron in an orbital in DPPH which embraces at least 30 other nuclei possessing magnetic moments, causing the splitting pattern.

From ESR free radical signals

The wave function of the unpaired electron in DPPH extends throughout a region which encompasses most of its structure, which means that no definite atomic orbital such as an s- or p-orbital may be assigned to it. The electron may be considered to be highly mobile within the structure, and capable of mediating conduction within it. The unpaired electron in DPPH whose ESR signal is shown above is a very different species from the paired electrons in DPPH, which are found in the inner shells.

"In the case of DPPH, the unpaired electron is in an anti-bonding orbital and one would expect electron conductivity with a low value of delta e (1.5 eV); the direction of the orbitals of the unpaired electron coincides with the direction of the c axis, where there is the greatest overlapping of orbitals - this also corresponds to the increased electrical conductivity in this direction." (A. Buchachenko, 1965)

The existence of an unpaired electron in a system like DPPH strongly perturbs the molecular orbitals of nearby electrons, which brings us to the fourth reason why unpaired electrons are so interesting.

Unpaired electrons are associated with an abnormally high chemical reactivity, that can permit the initiation of otherwise forbidden chemical reactions. Not only are free radicals highly reactive, but certain types of chemical reactivity including oxidation, irradiation, UV photolysis, and charge-transfer reactions are directly related to the spin density of a molecule's unpaired electron or electrons. For example, the stability of charge-transfer complexes are undoubtedly connected with the unpaired electron delocalized through the pi-system.

Compare the reactivity of molecules with unpaired electrons in the outer shells with the noble gases like Argon and Xenon that are chemically inert. Electron pairs fill the outer shells of Argon, which has almost no chemical properties at all, and explains why it was named Argon, "the lazy one."

II.

Sugar is an example of a "united molecule", with electron pairs that are held strongly in place, and will remain strongly held in place until some light energy comes along. The light energy can promote an electron to the outer and anti-bonding orbitals. Normally, the anti-bonding orbitals of sugar are devoid of electrons in the ground state, and may be occupied only in excited states.

The molecular organization of organisms is actually very different from the organization of simple sugar. Unlike sugar, the anti-bonding orbitals of the ground state of biological proteins are occupied by an electron transport chain, a life-contributing force in the organism. In the molecular description of sugar, the incoming light energy is said to "disrupt" the electronic configuration of sugar; as long as sugar is kept away from light or chemical energy then sugar will have a completed set of electrons which makes it sugar. In contrast, the configuration of the animal body relies upon electronic "disruption" for its existence. In the organism, it is less easy to distinguish which electrons belong to organism, and which electrons belong to the excited state.

There are unpaired electrons in the human body

There is very good reason to believe, if we accept the Pauli exclusion principle (and we should), that most types of matter around us contain electron pairs. Yet the behavioural activities of lifeforms (beetles, whales) depend on the existence of unpaired electrons for many processes including the all-important process of respiration. It is interesting to compare the bonding of atoms in the worlds of the living and the inanimate. There seems to be an important difference between matter with electron pairs and the matter of our dear selves: organic lifeforms, that twitch, grow, and reproduce. That difference is the high concentration of unpaired electrons in biological systems. EPR experiments on mammalian tissues have shown that liver and brain tissue are the richest source of unpaired electrons in nature. Living things such as seeds and green leaves have relatively higher concentrations of free radicals compared to dead wood or stone. Reconstituted enzyme systems, like polymerase chain reactions, have a higher concentration of unpaired electrons than distilled water in a test tube. Thus the essential nature of odd-electron transfer reactions is central to the electronic and molecular organization of life. There are many oxidation-reduction reactions in biology that wouldn't be possible without single-electron transfer reactions. Szent-Gyorgyi was interested in charge-transfer reactions.

“In photosynthetic chromatophores, or chloroplasts, as well as in phosphorylating mitochondria, single electrons are transferred in a series of reactions from substance to substance. It seems possible that a similar transfer of electrons plays a wider role in the various activities of the cells or the maintenance of their living state. It is still an open question how such a transfer of electrons takes place. Our attention has been occupied, in this context, in an increasing degree by “charge transfer.” (Szent-Gyorgyi, 1961)

The concentration of free radicals depends on age. Early stages of animal development take place in the midst of a very high concentration of free radical generation, propagation, and termination processes. Then the adult lifeforms (lightning bugs, human beings) live within the burnt-out shells of this initial polymerization process. In the mature form of the animal, the establishment of an equilibrium between the free radicals in a human being and its environment may be related to its alpha EEG rhythms.

The potential differences that are recorded from muscle or cortex verify the existence of unpaired electrons, or electricity, in the mammalian form. Brain oscillations are derived from these unpaired electrons, until brain death when a flat line EEG is recorded. An example of this is shown in the figure below. Crude cobra venom or rattlesnake venom in doses of 0.5 mg/kg led to a complete EEG silence within 1 minute.

From 94Nunez EEG

If the EEG is related to free radical content of the brain, then the death state may be associated with a time when the free radical concentration of the nervous system reaches equilibrium with the spins in the world exterior. At that point, does the Pauli exclusion principle fully apply in its description of the molecular configuration of a dead body? If each 1/2 spin finds -1/2 spin, then in death, the electrons can fully belong to the organism as a giant "united molecule."

Free radical content and cancer

The stability of the animal body differs from the stability of simple sugar, because organisms move, shed cells and grow new ones in its place. Yet for the form of the organism to be somewhat stable, it must have more bonding than anti-bonding electrons, thus most biological tissues do have even numbers of electrons that fill the available molecular energy levels in pairs according to the Pauli exclusion principle. The balance between odd electrons and paired electrons is critical for the health of tissues. As studied by Mallard and Kent in 1964, healthy liver has a higher concentration of free radicals than cancerous liver tissue, suggesting that tissues can become cancerous by acquiring an excess of bonding electrons in the outer shells. Since many cancers are deadly, we may conclude that a certain concentration of unpaired electrons in outer shells is essential for life.

Summary

The entire richness and diversity of the material world is formed by union of only a hundred kinds of atomic particles. For the most part, assemblies of atoms must adopt a configuration with electrons in pairs. Electrons in pairs remain in the confines of the molecule and cannot drift throughout its structure, thus many solids in the external world are electrical insulators. In contrast, the animal body is a highly ordered crystalline array of proteins, starches, and lipids that are associated with unpaired electrons that range over long distances, the function of which is not completely understood.

Biological entities, with their composition of even and odd electrons, are expected to have semi-conducting properties, that is, properties of electrical conductivity between that of a conductor and an insulator. Szent-Gyorgyi was one of first people to point out the connection between the theory of semi-conductors and biological lifeforms. Lightning bugs are like diodes that conduct electricity when a small current is applied across it. It is likely that all living entities have semi-conducting properties, among them the ability to emit light. Besides the light within the creatures of this planet, hardly any light but sunlight occurs in nature: occasional fires, lightning, and starlight.





References

Hart, E. J., Anbar, M. The hydrated electron. Wiley-Interscience: New York, 1970.

Buchachenko, A. L. Stable radicals. Consultants Bureau
Enterprises: New York, 1965.

BOL-148

BOL-148 is the 2-brom derivative of LSD. There is a bromine in place of hydrogen at position 2.

From molecules

In spite of its close structural relationship to LSD, BOL-148 has no psychedelic effects. In 15 healthy males, doses of 75-110 ug/kg BOL-148, which 100X exceed an effective dose of LSD, caused no change in pupillary dilation, patellar reflex, or blood pressure (H. Isbell, 1959). BOL-148 did not alter the behavior of 6 individuals with schizophrenia, when given at 10X the dosage of active LSD, although for BOL-148 these doses may have been too low to observe any effect. One mg BOL-148 twice a day for 2 weeks, or 5 mg for 3 days had no evident effect on their psychoses (W.J. Turner, 1958).

Unlike LSD, which is one of the most potent drugs known on the electrical potentials of the brain, BOL-148 is without effect on the EEG. There was no sign of the fast electrical activity or alerting behaviour seen with injections of LSD in cats, even when doses of up to 100 ug/kg of BOL-148 were used intraventricular (P.B. Bradley, 1956). BOL-148 produced no EEG changes in Macaca mulatta, in high dose ranges 110-175 ug/kg (R.R. Monroe, 1961). Saline gave the same response as 1000 ug/kg BOL-148 in cats with permanently implanted EEG electrodes (E. Eidelberg, 1965). In rabbits, 500 ug/kg BOL-148 failed to produce EEG alerting for longer than 15 minutes (A.K. Schweigerdt, 1966).

BOL-148 has a very slight change in the molecular structure of LSD, but it has none of the behavioral effects of LSD. When LSD or BOL-148 were administered intraventricularly to cats, LSD caused behavioral arousal whereas BOL-148 produced mild sedation. In rabbits, BOL-148 had a neutral effect on eyeblink conditioning, whereas LSD enhances this specific type of behavioral learning (J.A. Harvey, 2003). No affective changes in Papio papio were observed after BOL-148 in doses of 2-4 mg/kg (M.D. Fairchild, 1980).

Table 3 below shows the questionnaire responses for LSD and several LSD derivatives. LSD is the most potent drug, and caused the most positive responses on the questionnaire. BOL-148 is on this table, and at doses of 80 ug/kg, or 50 times the active dose LSD, there were few positive responses on the questionnaire. This evidence shows a lack of effect of BOL-148 in human volunteers.

From other human hallucinogens, LSD derivatives

There is some evidence that BOL-148 pre-treatment protects against LSD psychosis. Studies with rabbits have shown that a dose of 1 mg/kg BOL-148 had no direct temperature effect on rabbits, but prevented the pyretogenic actions of LSD (A. Horita, 1958). In humans, BOL-148 does not function as a direct LSD antagonist since intravenous injections of BOL-148 at the height of a LSD trip did not cancel the LSD effects, but pre-treatment with BOL-148 in nonpsychotic humans did produce tolerance to the LSD reaction, though the tolerance-producing effect of BOL-148 for equal weights of LSD is much less, approximately 1/30 that of LSD. A degree of cross-tolerance to LSD can be developed with 2-3 mg of BOL-148 daily for five days or by pre-treatment with 1.0 ug of LSD daily for five days. The attenuation of the LSD reaction observed after pre-treatment with BOL-148 is still less than that which occurs after pre-treatment with LSD, despite the fact that the daily doses of BOL-148 were 20-30 times greater than those used in developing tolerance to LSD. (H. Isbell, 1959)

In an experiment with 10 men, pretreatment with BOL-148 for 5 days (1 mg BOL-148 three times daily) significantly attenuated LSD psychosis caused by 0.5-1.5 ug/kg LSD. As shown in the figure below, blood pressure, pupil size and number of positive responses to questionnaire were reduced during LSD challenge 5 days after BOL-148 pretreatment. (Isbell, H. 1959)

From other human hallucinogens, LSD derivatives

When similarities between LSD and BOL-148 have been indicated, the assays usually involved simplified preparations. For example, LSD and BOL-148 were found to have the same affinity for beta-adrenergic receptors (A. Dolphin, 1978), and were equally effective as MAO and acetylcholinesterase inhibitors in histochemical analysis of rat brain (T.R. Shanthaveerappa, 1963).

There is one report from 1957 suggesting that BOL-148 is a hallucinogen with psychotomotor properties in doses much higher than LSD. Two normal volunteers experienced psychic effects when BOL-148 was administered intravenously to total doses of 18 and 22 mg.

"In man small doses of bromo-LSD are said to produce none of the bizarre psychic effects noted with LSD but this is not the case when bromo-LSD is administered intravenously in large doses. Thus, when constant intravenous infusions of bromo-LSD were given to normal subjects, both experienced psychic changes, which became more severe as the infusion continued and persisted for 3 to 4 hours after the infusion was stopped. No hallucinations were noted but there were feelings initially of drowsiness, depression, anxiety, and apprehension followed by feelings of irritation, restlessness, and tenseness, and later, intensely disagreeable sensations of unreality and depersonalization, inexplicable feelings of strangeness and mild confusion." (R. Schneckloth, 1957)

Among the LSD analogs, BOL-148 is important because it indicates that substitution at the 2-position can affect the whole molecule. Also, research into BOL-148 has indicated that LSD does not induce a psychosis by creating a relative deficiency of 5-HT within the brain. BOL-148 was shown to have more anti-5-HT activity than LSD in vitro and in vivo, thus if LSD worked by blocking 5-HT neurotransmission, BOL-148 would be expected to be a more potent hallucinogenic drug, but BOL-148 is inactive on many accounts.

“We therefore concluded that on the basis of these results with LSD and 2-brom-LSD it is difficult to admit a correlation of the psychic effects induced by LSD and its anti-5-HT property, since 2-brom-LSD possesses the same anti-5-HT activity in vitro and in vivo, but it lacks the psychotogenic action." (E. Rothlin, 1957)

References

BRADLEY P. B. and A. J. HANCE. (1956). The effects of intraventricular injection of d-lysergic acid diethylamide (LSD 25) and 5-hydroxytryptamine (serotonin) on the electrical activity of the brain of the conscious cat. J.Physiol.
132, 50-1P.

Dolphin, A., A. Enjalbert, J.P. Tassin, M. Lucas and J. Bockaert (1978). Direct interaction of LSD with central "beta"-adrenergic receptors. Life Sci. 22, 345-352.

Eidelberg E., M. Long and M. K. Miller. (1965). Spectrum analysis of EEG changes induced by psychotomimetic agents. Int.J.Neuropharmacol. 4, 255-264.

Fairchild M. D., D. J. Jenden, M. R. Mickey and C. Yale. (1980). EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline. Pharmacol.Biochem.Behav. 12, 99-105.

Harvey J. A. (2003). Role of the serotonin 5-HT(2A) receptor in learning. Learn.Mem. 10, 355-362.

HORITA A. and J. H. GOGERTY. (1958). The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of ISD. J.Pharmacol.Exp.Ther. 122, 195-200.

ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Relationships of psychotomimetic to anti-serotonin potencies of congeners of lysergic acid diethylamide (LSD-25). Psychopharmacologia. 1, 20-28.

ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25). Psychopharmacologia. 1, 109-116.

MONROE R. R. and R. G. HEATH. (1961). Effects of lysergic acid and various derivatives on depth and cortical electrograms. J.Neuropsychiatr. 3, 75-82.

SCHNECKLOTH R., I. H. PAGE, F. DEL GRECO and A. C. CORCORAN. (1957). Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation. 16, 523-532.

Schweigerdt A. K., A. H. Stewart and H. E. Himwich. (1966). An electrographic study of d-lysergic acid diethylamide and nine congeners. J.Pharmacol.Exp.Ther. 151, 353-359.

SHANTHAVEERAPPA, T. R., K. NANDY and G.H. BOURNE (1963). Histochemical studies on the mechanism of action of the hallucinogens D-lysergic acid diethylamide tartrate (lsd-25) and D-2-bromo-lysergic acid tartrate (bol-148) in rat brain. Acta Neuropathol. 3, 29-39.

TURNER W. J. and S. MERLIS. (1958). Chemotherapeutic trials in psychosis. III. 2-Brom-d-lysergic acid diethylamide (BOL 148). Am.J.Psychiatry. 114, 751-752.

Apical and basilar dendrites of pyramidal neurons

Scheibel and Scheibel used Golgi staining to study arrangements of dendrites in the spinal cord, and later, the neocortex. Dendrodendritic synapses are found in the bundles formed by basal and apical dendrites of pyramidal neurons.

APICAL DENDRITES

The cortex is filled with pyramidal cells, a type of neuron with a large cell body and very long dendrites extending in the basal and apical directions. The apical dendrites of pyramidal cells are oriented towards the pia of the brain. Figure 6 below is a drawing of 3-4 large pyramidal neurons with cell bodies in Layer 6, whose apical dendrites form a bundle extending to Layer 1.

From dendrites

A cross-section of a dendrite bundle is shown in the box (figure above), with an arrow pointing to the region where dendritic membranes are closely opposed. Microtubule and other proteins are stained at the site of communication between two dendrites. The current paths of individual neurons that summate in the extracellular space in and around the dendrites gives rise to summed extracellular potentials, the EEG, and rhythmic EEG potentials.

The next figure shows apical dendrite bundles in cat visual cortex. The bottom part of the figure represents a dendrite bundle cross-section. Each white spot represents one pyramidal cell dendrite, and where two white spots touch is the place of dendritic membrane contact. These constellations of dots are sometimes called puncta or puncta adherentia by histologists to refer to an ambiguous structure, but in many cases puncta resemble dendrites in cross-section.

From dendrites

BASILAR DENDRITES

The basilar dendrites of pyramidal neurons are very long. Scheibel and Scheibel were impressed with the peculiar length of the Betz cell basilar dendrites, and suggested that the great length of the dendrites was a unique feature for which these cells evolved. In mice, rats, and cats, giant pyramidal cells of Betz and large solitary cells of Meynert in visual cortex have long basilar dendrites organized into bundles. As shown in the figure below, the thickest patches of basilar dendrites are found in layer 5 and layer 2/3 of cat cortex. In human cortex, the basilar dendrite bundles can reach a length of 2000-3000 microns, with diameters of 12-40 um.

From dendrites

Part C of Figure 2 shows a close-up view of a dendrite bundle. The dendrite bundle contains 6-10 basilar dendrite shafts and varies in total diameter from 7-8 um to 1-3 um. It appears to change as individual dendrites are added or subtracted along its length.

From dendrites

The length of basilar dendrites permits Mountcastle's columns to link to each other, as shown in the figure below. Gap junction coupling at dendrite bundles could serve as an averaging mechanism, uniting the neurons involved into an assembly.

From dendrites

Studies on ventral horn motoneurons had led to a presumptive relationship between onset of reciprocal flexor-extensor activity in the muscle masses of the leg and the appearance of bundling in motoneuron dendrites. The onset of these dendritic bundles with the development of discrete items of output performance could have implications for non-motor memory as well. Scheibel and Scheibel surmised that age-related problems with cognitive association skills could be due, as shown in the figure below, to a loss of the large dendrite bundles generated by basilar shafts of giant pyramidal neurons.

From dendrites

Senility is associated with dendrite retraction and less thickness of basilar dendrite bundles. The figures above and below are from Golgi-impregnated sections of human cortex at different stages of aging. In particular, there is a loss of horizontal lengths (basilar dendrites) during aging rather than vertical (apical) dendrites. The decline of effective dendrite connectivity may be an important contribution for the fading of human consciousness.

From dendrites

Like the dendrite bundles in spinal cord, the thalamic reticular nucleus, and raphe, dendrite bundles formed by the apical and basilar dendrites of pyramidal neurons make direct dendrodendritic connections. It has been estimated that the dendritic bundles of the rabbit neocortex are characterized by such a close packing that about 20% of the surface of every dendrite is common to adjacent dendrite surfaces, separated by the extracellular space only. There are no intervening glia between the dendrites, and no post-synaptic specializations that resemble axon-synapses machinery. The means of communication between two dendrite membranes may involve gap junctions, extracellular field potentials, and nearby mitochondria and microtubules.

From dendrites

Reference

Roney K. J., A. B. Scheibel and G. L. Shaw. (1979). Dendritic bundles: survey of anatomical experiments and physiological theories. Brain Res. 180, 225-271.

LD50, lethal dose 50

Terrence McKenna explains the concept of LD50.

"We want to take an excursion here and learn a little pharmacology. If you're going to talk about pharmacology, there is one concept that you should get straight, and that's called LD50. It means "lethal dose 50". What does this mean? Well, you have 20 rats and you give them a certain amount of, let's say, mescaline. When half the rats die, that dose, expressed as milligrams per kilogram of body weight, is called the LD50. And when pharmacologists assess the danger in a drug, they ask the following question, "what is the relation of the LD50 to the effective dose?", and if the LD50 of a drug is only 20 times the effective dose, that's considered an incredibly toxic, dangerous, and dubious drug. A good drug is a drug where the LD50 is 200 times more than the effective dose. In the case of LSD, the LD50 for man has never been determined. That's how safe LSD is. We're talking about lethality here, not you know. So people say, "Well are there unsafe psychedelics?" Well, yes, you just look up the LD50s, line them up, and see which ones have the better ratios. By that measurement, by that standard, LSD is the most desirable. But the LD50 of psilocybin is very impressive. You can take 100 times the effective dose of psilocybin and expect to live. Mescaline, not. Mescaline has a bad profile. As an amphetamine, if you took 20 times the effective dose of mescaline, you would probably die. Of course, an effective dose of mescaline is nearly a gram of pure material, 700 milligrams. If you took 20 times 700 milligrams you would be taking nearly 2/3 of an ounce of mescaline..." (Terrence McKenna)

The LD50 of LSD varies from species to species. Rabbit is the most sensitive species known, with LD50 of 0.3 mg/kg i.v. The LD50 for rats is ten times higher at 16.5 mg/kg i.v. Mice tolerate 46-60 mg/kg i.v. LSD (Passie et al, 2008). An intraperitoneal dose of LSD 5.0 mg/kg reportedly caused death in a rat within 30-45 minutes and was associated with cardiac irregularities and general rigidity of musculature (Sylar et al, 1971). A too high dose of LSD typically causes animals to expire by paralysis, bradycardia, or respiratory failure; these effects probably involve centers in the caudal brain stem.

In an experiment with Macacus rhesus, one animal received 240 ug/kg and the other 140 ug/kg, which are enormous doses of LSD. In terms of a 70 kg person, the animals received 168 and 98 hits of LSD. These doses did not produce an excited behavior in monkeys as small doses do, but instead produced sedation. The monkeys became quiet and more sluggish around the cage, and did not jump about the cage as they did before. The monkeys lived.


Reference

Passie, T., J.H. Halpern, D.O. Stichtenoth, H.M. Emrich and A. Hintzen 2008. The pharmacology of lysergic acid diethylamide: A review. CNS Neurosci. Ther. 14, 295-314.

Sklar, S., K.A. Nieforth and M. Malone 1971. Synthesis and preliminary screening of N-ethyltryptamine derivatives related to reserpine and lysergic acid. J. Pharm. Sci. 60, 304-306.

Microtubule inhibitors block sense of touch in cockroaches

Microtubules are involved in the sense of touch, vision, and other senses. The cockroach's sense of touch is probably related to the organization of microtubules.

Mechanical stimulation is sensed by a cockroach through the spines (Campaniform sensilla) on its leg. There is a burst of spikes in the bipolar nerve cell (sensory neuron) associated with the spine, by pressing gently on the mechanoreceptor apparatus in the cockroach leg.

From Microtubules

The cockroach's sense of touch was disrupted from 1 to 2 hr after exposure to colchicine or vinblastine, drugs known to disassemble microtubules. Whereas before tactile stimulation the microtubules are demonstrably intact, electron microscopy showed no microtubules in the bipolar cell connected to the sensilla treated with colchicine or vinblastine. Also, the typical burst of spikes produced by tactile probe was replaced by neuronal silence after colchicine drug treatment.

Besides the physical evidence showing microtubule detachment from the basal body in the cockroach spine, there was a change in the electrophysiological response of the bipolar nerve cell after microtubule disruption. These experiments support the hypothesis that sense perception is related to the organization of microtubules in the dendrites of neurons. It is suggested that the proliferation of microtubules in sensory processes may serve to increase the gain of the cell membrane.


Reference

Moran D. T. and F. G. Varela. (1971). Microtubules and sensory transduction. Proc.Natl.Acad.Sci.U.S.A. 68, 757-760. 10.1073/pnas.68.4.757

Serotonin-binding protein and LSD

Serotonin-binding protein

A ~50 kDa protein that binds serotonin was first identified in 1974. It was discovered by passing all of the soluble extracts of a cell over a 5-HT affinity column, and then eluting the column with 5-HT. The protein was stored with 5-HT to prevent degradation.

Serotonin-binding protein is expressed in enteric and central serotonergic neurons, including enterochromaffin cells, the nuclei raphe dorsalis, centralis superior, raphe medianus, raphe magnus, raphe obscurus, and raphe pallidus. Also, dense staining with antibodies to serotonin-binding protein was found in the supraependymal plexus lining the ventricular surfaces.


Serotonin-binding protein and LSD

In 1977, Shih and colleagues performed spectroscopic analysis of free LSD and LSD bound to serotonin-binding protein. Free LSD exhibited max fluorescence at 435 nm with excitation at 330 nm, while serotonin-binding-protein-bound-LSD shifted its fluorescence and excitation maximum to 465 nm and 375 nm. These results suggest that the interaction between LSD and serotonin-binding-protein caused a delocalization of the molecular orbital electrons and thereby lengthened the electronic conjugation of the drug molecule.

Figure 2 below shows the excitation (330 nm) and emission (435 nm) wavelengths of free LSD.

From lsd spectroscopy

Figure 3 shows the excitation (375 nm) and emission (465 nm) wavelengths for protein-bound-LSD.

From lsd spectroscopy

An increase in the absorption and emission wavelengths was also observed when bovine serum albumin (BSA) was mixed with LSD, as shown in Figure 4 below. Peak 1 is the fluorescence of BSA. Peak 2 is shifted towards longer wavelengths, and represents the BSA-LSD charge complex.

From lsd spectroscopy

Generally, a shift of the absorbance towards longer wavelengths can be accomplished by adding Sulfur, Nitrogen, or Oxygen to a molecule, which increases the number of loosely bound electrons. Serotonin-binding-protein and other proteins contains lone pairs of electrons from S, N, and O that can add to the pi-electron system of the LSD molecule, thus modifying its spectra absorbance.


References

Shih J. C. and J. Rho. (1977). The specific interaction between LSD and serotonin-binding protein. Res.Commun.Chem.Pathol.Pharmacol. 16, 637-647.

Qualia of blue

What makes up the qualia of blue? Where does the meaning of blue actually lie? In the rays of blue light itself, or in your interpretation of blue? The fact that we perceive such "things" as blue light or macroscopic objects lying at distinct places is due, partly at least, to the structure of our sensory and intellectual equipment. Even if blue light were abundant in the universe, it would still require a human brain to decode the message of blue light. Whatever we see as "blue" is a construct of the brain, and blue may be merely an interpretation of otherwise white light. In Moby Dick, Melville wrote,

"Consider that the mystical cosmetic which produces every one of her hues, the great principle of light, for ever remains white or colorless in itself, and if operating without medium upon matter, would touch all objects, even tulips and roses, with its own blank tinge-" (H. Melville, 1851)

I love Melville's description of mind as "medium upon matter". Our access to the mystical cosmetic is largely mediated through our senses and other factors.

when kids accidentally ingested LSD

There are reports of autistic or schizophrenic children who have taken LSD in a therapeutic setting, with variable effects. What happens when psychologically normal kids accidentally ingest LSD? Here are 3 anecdotal cases.

CASE 1

In 1966 on a Wednesday morning in April, a 5-year-old girl accidentally ingested 100 ug LSD on a sugar tablet in the refrigerator belonging to her 18-year-old uncle. Her name was Donna, but after the trip she substitutes Deborah for herself Donna, and thought that her body had been torn in half. The story told by the interviewing psychiatrist is very descriptive:

"Within an estimated 15 or 20 minutes the patient began to scream and cry, creating a commotion that awakened the household and alerted the uncle to the mishap. She was alternately screaming and silent. During her quiet periods she was motionless and unresponsive and apparently unaware of her surroundings. Physical examination about three hours after ingestion showed a screaming child with a temperature of 99 F (37 C), a pulse rate of 130 beats per minutes, 30 respirations per minutes, dilated pupils, and hyperreflexia. Treatment consisted of bed-rest and intravenous infusion of saline. Blood cell count and findings from examination of the urine were normal. The serum glutamic oxoloacetic transaminase value was elevated to 82 units and the alkaline phosphatase was elevated to 20.1 units."

"After four or five hours of hospitalization and intermittent napping, the patient became relatively calm, unfrightened, and responsive. At the same time she expressed many bizarre and apparently delusional ideas, such as that her body was cut off at the waist, that she was not herself but was a girl named Dorothy (a name similar to her own, Donna), that it was not she but Dorothy who had eaten supper, that she had gone home and her bed was occupied by a girl named Dorothy. The following morning, after an uneventful night's sleep, she seemed superficially responsive and rational. However, she still maintained that Donna had gone home during the night and that she was Dorothy and she wrote her name as Dorothy. In the course of the morning she became better oriented and began to recognize that she was Donna again."

"Psychiatric examination on the afternoon of April 7, about 30 hours after ingestion, showed a quiet, unreactive, apathetic girl. She responded promptly when questioned, and displayed an alertness that was in marked contrast to her prevailing apathetic mood. Her emotional range was very narrow and lacked normal modulation. Her verbalizations, although brief, were responsive and appropriate and she had a fairly good recollection of the events preceding hospitalization. In contrast to her condition of a few hours earlier, she was oriented and lucid. Her thinking was somewhat concrete. She was not able to express subjective feelings or experiences. It was inferred from her refusal to stand her complaint that her legs "hurt" that she was experiencing either paresthesias or a residuum of the preceding day's profound distortion of body image. She described a dream in which "they stole my mommy and tried to cut her in half" which seemed to be expressing the same distortion of body image or body perception." (D.H. Milman, 1967)

A psychiatric evaluation 5 days later showed that Donna was still abnormal and her IQ had dropped. At evaluation five months later, IQ levels had returned to normal, and the girl had returned completely to her typical behavior with flexible thinking processes. At the final examination nine months after the incident, the patient was in first grade and progressing well. She had a normal IQ, good concentration and cheerful mood with logical and appropriate thinking.

The substitution of her name for Dorothy provides an example of "depersonalization" after LSD, which generally refers to one not being oneself. The description of her body being torn in half suggests that she experienced a major alteration in body image.


CASE #2

A 25-month male infant ingested an estimated 200 ug LSD in the form of 2 purple microdots.

"At 10:30 AM on the day of admission the mother noted the onset of unusual behavior in her child: He appeared unsteady and stumbled, he was frightened and screamed while looking at a colored rug, at the ceiling, or upon seeing a housefly, and he frequently opened his eyes widely and covered his ears with his hands as if to block out unpleasant sounds. The mother recalled she had had two tablets of LSD, purple microdots, in her purse; she found the purse opened and both tablets missing. The child was taken to a local hospital where the family's physician noted that the child was in a state of "stark terror." He clung tightly to his mother, screaming at apparent visual hallucinations perceived on the walls of the examining room; he did not fix his gaze on persons or other objects." (B.M. Ianzito, 1972)

The child received an intramuscular injection of 10 mg chlorpromazine at 12:20 PM, one hour after which he had normal vital signs, was quiet, and fixed his gaze on objects for brief periods. Chlorpromazine seemed to be effective in the case of this 2-year old, although in other subjects chlorpromazine has reportedly intensify the LSD experience.


CASE #3

In 1973, a 23-month male infant admitted to hospital had ingested one LSD tablet 2 hr before admission. The child was very hysterical and hyperreactive. He was given 15 mL ipecac syrup to induce vomiting and he was given water, and a urine sample was collected for spectroscopy analysis. At 3 hours, the patient had calmed down and at 4 hours could recognize his mother. He was sent home from the hospital 2 days later in general good condition.

The dosages of LSD given to these 3 children were well above the adult threshold levels, and there was no indication of brain damage. Screaming and crying seemed to be a common reaction to LSD within the first 2 hours. There was a temperature increase to 99 F in the 5-year-old girl, consistent with an emotionally hyperactive state.


Reference

Ianzito B. M., B. Liskow and M. A. Stewart. (1972). Reaction to LSD in a two-year-old child. J.Pediatr. 80, 643-647. 10.1016/S0022-3476(72)80064-7

Milman D. H. (1967). An untoward reaction to accidental ingestion of LSD in a 5-year-old girl. JAMA. 201, 821-825. 10.1001/jama.201.11.821

Mueller R. G. and G. E. Lang. (1973). Fluorescent spectra of lysergic acid diethylamide: observations on a gastric extract. Am.J.Clin.Pathol. 60, 487-492.

LSD dose

The effective dose of LSD varies enormously among species. In salamander, the effective LSD dosage is 700,000 ug/kg. Intracranial injections of 300 ug/kg in goldfish produce the characteristic LSD fish surfacing reaction. In mouse the effective dose is 180 ug/kg of body weight. With LSD behavioral changes are discernible in rat at 80-160 ug/kg but in the cat at 25 ug/kg. A 20 ug/kg LSD affects pigeons' performance in learned discrimination tasks. In rabbit the effective dose is 15 ug/kg. In man, where we have the advantage of verbal reporting, the effective dose is less than 1 ug/kg. According to Albert Hofmann, the effective human dose of LSD is 0.5 ug/kg.

A flat dosage of 100 ug per person is used commonly in human LSD research. This dosage quantity is convenient to remember because it doesn't take body weight in kilograms into consideration. A dosage of 100 ug per person typically results in dramatic symptoms, but the threshold for activity generally is placed at 20 ug LSD per person.

Very low doses of LSD (4-40 ug per person) were tested in human volunteers by Greiner and colleagues in 1958. Psychic changes were established by way of interviews and measurement of pupil size, heart rate, and galvanic skin response. The data below showed that mood and psychomotor effects were detectable in human volunteers at dosages as low as 4 ug LSD per person, which is approximately 0.05 ug/kg of body weight, or 10 times less than the effective dose according to Albert Hofmann. The objective measures showed that the galvanic skin response was activated after only 7 ug LSD per person. There was a dose-dependent increase in pupil size, heart rate, and other parameters.

From lsd dose

The researchers observed sudden shifts in affect in the volunteers after 4 ug, 7 ug, or 12 ug of LSD per person, but no significant changes in thought process or content. This data puts the threshold dose for LSD intoxication at about 20 ug per person.

LSD is one of the most potent drugs known to man. Whereas most drugs are administered at doses of tens or hundreds of milligrams, LSD is active at tens or hundreds of micrograms. The potency of LSD is best compared to other drugs on a log scale, as shown in Figure 1 below. It can be seen that the concentration of an active dose of alcohol is about a million times as great, expressed in terms of weight, as the concentration of LSD.

From lsd dose

Of course, the effective dose of LSD depends highly on the person, set, and setting. The dose threshold may be lower for people who are generally inexperienced with drugs, and higher for alcoholics and drug addicts.

“Familiarity with other drugs which produce psychological changes is also relevant. Alcoholics and drug addicts seem better able to cope with the LSD experience than normal subjects. I have had more difficulty with anxiety and panic in normal subjects than in patients who have had long experience with drugs.” (A. Hoffer, 1965)

Fasting or not can change the effective LSD dose too. Plasma concentrations of orally ingested LSD were twice as much on an empty stomach. The amount of the meal as well as the pH of the stomach will influence LSD absorption.


References

GREINER T., N. R. BURCH and R. EDELBERG. (1958). Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum. AMA Arch.Neurol.Psychiatry. 79, 208-210.

Passie T., J. H. Halpern, D. O. Stichtenoth, H. M. Emrich and A. Hintzen. (2008). The pharmacology of lysergic Acid diethylamide: a review. CNS Neurosci.Ther. 14, 295-314.

LSD charge-transfer complexes 3. LSD-riboflavin

Hallucinogenic agents are probably electron donors in some key step involving a charge-transfer complex with a biological acceptor molecule entity. Continuing the discussion of LSD-small molecule complexes, we will see that the same electrostatic and charge-transfer forces in LSD-TCNE, and LSD-NAD+ complexes are present in a LSD-riboflavin complex.

In 1958, Isenberg and Szent-Gyorgyi mixed LSD-25 with riboflavin-5'-phosphate and observed a red color at –78 C. They discovered a LSD-riboflavin complex in which the riboflavin molecule has taken up one electron from LSD. The formation of a LSD-riboflavin complex confirms the hypothesis that the transferred electron (e.g. to reduce riboflavin) comes from the pi-electron pool of the LSD indole system. These results showed that LSD functions as an electron donor in the formation of riboflavin charge-transfer complexes. In the same publication, the authors reported on tryptopan-riboflavin, 5-HT-riboflavin, and 1-methyl-medmain-riboflavin complexes, all of which led to the appearance of a red color at -78 C. The results are shown in Table 1 below.

From hallucinogens HOMO, charge-transfer

Histidine-riboflavin or tyrosine-riboflavin did not give a red color, suggesting that no charge-transfer complex was formed, and that histidine and tyrosine are inferior in electron-donating ability compared to drugs such as tryptophan and LSD. There were variations among the drugs which formed a charge-transfer complex with riboflavin. For example, the 5-HT-riboflavin complex was 7X stronger than the tryptophan-riboflavin complex indicating that serotonin was a better electron donor than tryptophan.

The charge-transfer complex formed by flavins with proteins via their tryptophans is of major biological significance. Some tissues such as liver have a great quantity of strongly bound flavin. The brown color of the liver can be attributed to the flavin radical formed in a charge-transfer interaction with liver protein.


References

Isenberg I. and A. Szent-Gyorgyi. (1958). FREE RADICAL FORMATION IN RIBOFLAVIN COMPLEXES. Proc.Natl.Acad.Sci.U.S.A. 44, 857-862. doi:10.1073/pnas.44.9.857

LSD charge-transfer complexes 2. LSD-NAD+

The electron acceptor NAD+ forms a charge-transfer complex with LSD and other drugs, in which an electron is transferred from the highest occupied molecular orbital (HOMO) of the LSD pi system to the lowest empty molecular orbital of NAD+. In 1967, Fulton and colleagues studied the wavelength of the absorption maximum of NAD+ charge-transfer complexes and the ionization potential energies of various electron donors, including LSD (7.8 electron Volts), indole (7.9), uric acid (7.5), promazine (7.2), promethazine (7.2), and chlorpromazine (7.3).

“We have shown that NAD+ of concentration 1.03E-2M, when mixed with fairly strong electron donors, such as substituted pteridines, uric acid, serotonin creatine sulphate, lysergic acid, and phenothiazines, gave solutions which were coloured yellow to orange because of the formation of charge-transfer complexes" (A. Fulton, 1967)

From hallucinogens HOMO, charge-transfer

Table 1 lists the HOMO energies and ionization potential energies of several electron donors, including LSD, and the absorption maximum of its donor-NAD+ complex.

The authors found that the absorption maximum of the charge-transfer complex correlated reasonably with the ionization potential of the electron donor drug, but not so well with the energies of the HOMO, perhaps because there are many approximations involved in the theoretical studies of the HOMO energy, although a year later, Millie's research reported a correlation between the absorption maximum and kHOMO energies.

As listed in Table 1, the LSD-NAD+ charge-transfer complex had an absorption maximum at 340 nm, which is the absorption maximum of the native LSD molecule. This compares to the 520 nm absorption maximum that is characteristics of LSD-TCNE or LSD-Ehrlich complexes.



References

Fulton A. and L. E. Lyons. (1967). Electron-accepting strength of NAD+. Aust.J.Chem. 20, 2267-2268.

LSD absorption and fluorescence

The LSD molecule contains a number of pi-electrons. These pi-electrons absorb electromagnetic radiation very strongly, like many aromatic or conjugated systems. LSD absorption is maximal at 320 nm, and LSD fluorescence is maximal at 435 nm. These values are somewhat flexible depending on the spectrophotometer, with some authors reporting LSD absorption at 325 nm, and LSD fluorescence at 445 nm. The spectroscopic properties of radioactive [3H]-LSD are the same as LSD, with a maximum fluorescence at 445 nm, and an excitation wavelength of 325 nm. For LSD spotted onto chromatography plates, maximum excitation occurs at 330 nm, and emission at 410 nm. Spots of LSD on thin-layer chromatography plates give a violet-blue fluorescence under a UV lamp.

From lsd spectroscopy

Muller and Lang carefully studied the absorption and fluorescence of LSD as a function of pH. As shown in Figure 1 above, there is a minor excitation peak at 240-250 nm in addition to the major excitation peak of LSD at 330 nm. The major excitation peak of LSD could be shifted by placing the LSD sample in either acid or alkali conditions. The major LSD excitation peak was 327 nm in 0.01 N HCl and 319 nm in 0.05 M Na2HPO4. In basic solution, the 319 nm peak was approximately 25% greater in amplitude than the height of 327 nm in HCl. Major emission peaks of LSD were at 420-430 nm, with a shoulder at 536 nm.

In 1971, in situ fluorometry was performed on LSD using quinine as an internal reference. As seen in the figure below, quinine (A2, B2) and LSD (A1, B1) have the same excitation and fluorescence wavelengths.

From lsd spectroscopy

LSD fluorescence can be used to check its potency. Niwaguchi and colleagues found a linear relationship between fluorescence emission intensity and the amount of LSD on thin-layer chromatograms. If the 9,10 double bond of the D-ring is intact, blue fluorescence is observed under UV lamp.

Since the fluorescence emission intensity is proportional to the amount of LSD, the concentration of an unknown LSD solution can be measured in a Farrand or Bowman spectrophotometer. After blanking with water at 300 nm, solutions of LSD are scanned with 350 to 250 nm light, and the maximum absorbance, which occurs at approximately 330 nm, is compared to a standard solution of LSD. As little as 0.001 microgram of LSD, or 1/100,000 of a dose, can be analyzed this way, thus LSD detected by spectroscopic methods has better sensitivity than LSD detection by coloration with Van Urk reagent.

LSD is among the most fluorescent substances known. LSD is more strongly fluorescent than NN-DMT, diethyltryptamine, psilocybin, or mescaline. For comparison, DMT absorbs at 280 nm, and fluoresces at 350 nm. Psilocybin absorbs at 270 nm and fluoresces at 340 nm.


LSD decomposition

It has been reported that LSD loses its fluorescence very rapidly upon strong ultraviolet irradiation, as shown in the decomposition curves below. After just 5 seconds of irradiation at 320 nm, the LSD fluorescence reading was significantly diminished.

From lsd spectroscopy

If UV irradiation was continued for 15 to 60 minutes, a significant amount of decomposition of LSD was shown by paper chromatography. Only 10% of LSD remained after 60 min UV irradiation while in the control experiment 90% of LSD remained after 17 h standing in the dark.

From lsd spectroscopy

A decrease in LSD fluorescence with irradiation occurs when UV light catalyzes the hydration of LSD to a non-fluorescent derivative. A molecule of water is added across the C9-C10 double bond of LSD to produce the non-fluorescent lumi-derivative. In 1972, Upshall and colleagues described an easy-to-follow procedure for analyzing LSD in human plasma, by measuring the difference in fluorescence (318 nm excitation, 413 nm fluorescence) of plasma extracts before and after intense UV irradiation (at 254 nm). This analytical method (detection of change) is greatly preferable to a direct reading of UV fluorescence in plasma, since the plasma blank reading has sufficient enough magnitude to seriously interfere with the determination of LSD. Upshall determined an average of 1-10 ng LSD per 1 mL human plasma.

From lsd spectroscopy

Upshall's analytical method is superior to spectroscopic techniques that are based on one measurement of LSD fluorescence, because contents of plasma can obscure the native fluorescence of the LSD molecule. When Aghajanian and colleagues measured LSD concentrations in human plasma in 1964, they found a concentration which corresponded to a level of LSD in the plasma that was higher than expected based on a known injection amount. In this case, the contents of plasma may have added to the native fluorescence of the LSD molecule because the researchers obtained a value of 6-7 ng/mL plasma, about 10X higher than expected. The difference in fluorescence of plasma extracts before and after intense UV irradiation is the best way to a measure LSD concentrations in human plasma.


References

AGHAJANIAN G. K. and O. H. BING. (1964). Persistence of Lysergic Acid Diethylamide in the Plasma of Human Subjects. Clin.Pharmacol.Ther. 5, 611-614.

AXELROD J., R. O. BRADY, B. WITKOP and E. V. EVARTS. (1956). Metabolism of lysergic acid diethylamide. Nature. 178, 143-144. 10.1038/178143a0

BOYD E. S. (1958). The fluorometric determination of lysergic acid diethylamide and ergonovine. Arch.Int.Pharmacodyn.Ther. 115, 43-51.

Niwaguchi T. and T. Inoue. (1971). Studies on quantitative in situ fluorometry of lysergic acid diethylamide (LSD) on thin-layer chromatograms. J.Chromatogr. 59, 127-133. 10.1016/S0021-9673(01)80012-1

Sperling A. (1972). Analysis of hallucinogenic drugs. J.Chromatogr.Sci. 10, 268-275.

Upshall D. G. and D. G. Wailling. (1972). The determination of LSD in human plasma following oral administration. Clin.Chim.Acta. 36, 67-73.

Theoretical studies of the LSD HOMO energy

The highest occupied molecular orbital (HOMO) energies of hallucinogens have been thoroughly investigated, experimentally as well as theoretically. There is a direct relationship between molecular orbital parameters and hallucinogenicity. It is well-known that hallucinogen dose is correlated with the affinity to 5-HT receptors, but within this index are other relationships more directly related, in this case, the HOMO energy of the hallucinogen molecule. Receptor affinities reflect the likelihood of formation of a charge-transfer complex between drug and receptor, and these charge-transfer energies are directly related to the HOMO energy of electron donor molecules, or in this case, hallucinogen molecules. Other factors such as hydrophobicity and steric factors are incorporated within the index of receptor binding as well, but some minimum level of HOMO energy is necessary for hallucinogenic activity. Here is a chronological review of the research on HOMO energies of hallucinogen molecules.

In 1965, Snyder and colleagues calculated the HOMO energies of several hallucinogens using the Huckel method. Table 4 below lists the HOMO energy for LSD, psilocin, and TMA-2. The authors used the value (HOMO=0.218) obtained by Karreman and Szent-Gyorgyi for the LSD HOMO energy.

From hallucinogens HOMO LEMO

Psilocin, LSD, TMA-2, and TMA had a more energetic HOMO compared to the non-hallucinogenic drugs tyramine, dopamine, and phenyethylamine. Snyder and colleagues concluded that there is a relationship between hallucinogenic activity and the ability to donate electrons, as indicated by the energy of the HOMOs.

In 1968, Millie and colleagues investigated the HOMO energy of 1-methyl-LSD. They report Ehomo=0.487 for 1-methyl-LSD, thus placing 1-methyl-LSD somewhere in between 4-methoxy-indole and 5-methoxy-indole in terms of its electron donor ability. To my knowledge, Millie, Kang and Green, and Karreman and Szent-Gyorgyi are the only authors that have calculated the Ehomo for LSD-type molecules.

In 1970, Kang and Green calculated the HOMO energy of 13 psychotomimetic amphetamines, using the INDO (intermediate neglect of differential overlap) method, which is superior to the Huckel method. Table I lists the HOMO energy, Eh, of the hallucinogenic amphetamines. The most potent drugs had a smaller Eh value. There was a linear correlation between Eh and hallucinogenic activity in man.

From hallucinogens HOMO LEMO

Kang and Green also reported the Ehomo value for N,N-DMT and LSD, in Table 1 (below).

From hallucinogens HOMO, charge-transfer

In Kang and Green's research, the compound 4-hydroxy-N,N-DMT (psilocin, Eh=-0.4493) was predicted to be more potent than LSD (Eh=-0.4745) going by Eh value alone, but overall, these authors were successful at correlating the actions of hallucinogens agents with Huckel molecular orbital calculations.

In 1971, Nieforth wrote a review about HOMO energy and hallucinogens, which copied Snyder's 1965 data.

From hallucinogens HOMO LEMO

Nieforth concluded that electronic energy parameters were not the only factor involved in the biological activity of hallucinogens, since other compounds such as chlorpromazine are powerful electron donors and do not possess hallucinogenic activity. (5)

By 1979, another review on hallucinogen HOMO energies appeared, which reproduced Snyder's 1965 data yet again.

From hallucinogens HOMO LEMO

Gupta verified the conclusion that there is a highly significant correlation between Ehomo and hallucinogenic activity, but he suggested that a charge-transfer phenomenon may not be the only factor responsible for the biological activity of the drugs. According to Gupta, the theory of charge-transfer formation does not fully explain drug potency in the case of anesthetic drugs.

By 1987, another review summarized the charge-transfer complexes of receptors with hallucinogens.

“In hallucinogens the electron transfer is considered to be an outer-sphere, charge-transfer process. An overall electrostatic interaction with the receptor is envisioned as a result of the charge transfer from the aromatic portion of hallucinogens to their putative receptors. .. The hallucinogenic activity of phenyl alkyl amines, indole alkl amines, and LSD was first linked to the electron transfer ability of these drugs almost three decades ago. Huckel molecular orbital calculations of a series of hallucinogenic drugs and their nonhallucinogenic structural analogues indicated the close relationship between the HOMO energy, an index of electron-donating ability, and the hallucinogenic potency. Based on these results, an electron donation model of interaction between hallucinogenic drugs and their putative receptors was proposed. Later, a series of more sophisticated molecular orbital calculations confirmed the trends initially observed with the simple Huckel method. The HOMO energies of hallucinogens were also assessed experimentally, via measurements of ionization potentials and charge-transfer capabilities of these drugs. A good agreement was obtained between the calculated and the experimentally-deduced HOMO energies.” (Kolb,V.M., 1987)

The HOMO energy, which is an index of electron-donating ability of a molecule, has been studied because of its relation to the threshold dose of hallucinogen drugs. The HOMO energy reflects the compounds’ ability to donate electrons in a charge-transfer type of interaction, thus molecular orbital calculations of hallucinogen molecules support a charge-transfer mechanism of action of hallucinogenic drugs.

References

1. Snyder S. H. and C. R. Merril. (1965). A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proc.Natl.Acad.Sci.U.S.A. 54, 258-266. doi:10.1073/pnas.54.1.258

2. Millie P., J. P. Malrieu, J. Benaim, J. Y. Lallemand and M. Julia. (1968). Researches in the indole series. XX. Quantum mechanical calculations and charge-transfer complexes of substituted indoles. J.Med.Chem. 11, 207-211. doi:10.1021/jm00308a003

3. Kang S. and J. P. Green. (1970). Steric and electronic relationships among some hallucinogenic compounds. Proc.Natl.Acad.Sci.U.S.A. 67, 62-67. doi:10.1073/pnas.67.1.62

4. Kang S. and J. P. Green. (1970). Correlation between activity and electronic state of hallucinogenic amphetamines. Nature. 226, 645.

5. Nieforth K. A. (1971). Psychotomimetic phenethylamines. J.Pharm.Sci. 60, 655-665. doi:10.1002/jps.2600600502

6. Kolb V. M. (1987). Electron-transfer and charge-transfer clastic binding hypotheses for drug-receptor interactions. Pharm.Res. 4, 450-456. doi:10.1023/A:1016415202819

Charge-transfer mechanism of drugs 1. LSD and wool protein

The biological activity of hallucinogens is related to molecular orbital parameters which involve the concept of charge-transfer. A charge-transfer complex forms between the electron-rich aromatic ring of the hallucinogen molecule and the electron-deficient component of the receptor active site.

It was shown as early as 1954 that hallucinogen dose is correlated with the ability of the drug to participate in a charge-transfer mechanism. In 1954, researchers found that LSD had an abnormally high affinity to wool protein surfaces. It was shown that LSD forms a charge-transfer complex with wool protein, and that the energy of formation of the drug-wool complex was somehow related to psychosis. The wool affinity versus drug dose was studied for mescaline, methamphetamine, LAE, and LSD. The results are shown in the figure below. The higher the affinity of a drug for wool, the lower the amount of that drug required to cause a model psychosis. This plot includes mescaline and LSD and is surprising for that reason, since most workers in this area believe that these compounds influence different receptors.

From hallucinogens HOMO, charge-transfer

Hallucinogens have lone-pair electrons and biological receptors such as wool protein have vacant orbitals. A drug-receptor charge-transfer complex forms as a result of charge transfer from the electron-donating hallucinogen molecule to the putative receptors. The charge-transfer complexing abilities of the aromatic rings of psychoactive amphetamines are important in the production of hallucinogenic activity. This basic observation was made in 1954 with wool protein and LSD, and it has been verified since by experimental and theoretical methods. Domelsmith clearly showed that hallucinogenicity was correlated with ionization potential energy in 1977, and Snyder and others showed that hallucinogenicity was correlated with HOMO energy. It is well-known that Glennon and colleagues, in 1984, found an excellent correlation between the affinity of indoleamine and phenethylamine hallucinogens for 5-HT2 receptors and hallucinogenic potency in humans. In this sort of model, the effective dose of a hallucinogen is only determined by the drug-receptor complex formation.

The principle of drug-receptor binding by a charge-transfer mechanism applies to non-hallucinogen molecules as well. In a series of binding agonists to the adrenergic receptor, measures of receptor binding (pDa or Ki) were directly related to the ionization potential energy (IE1) of the agonists.

From Domelsmith ionization potential

It is mostly assumed that LSD forms a charge-transfer reaction with a G-protein coupled receptor, but LSD could bind an electron acceptor yet unidentified.


Reference

FISCHER R. (1954). Factors involved in drug-produced model psychoses. J.Ment.Sci. 100, 623-631.

Indole charge-transfer complexes

What is a charge-transfer complex? A charge-transfer is simply the shift of electrons from one molecule to another. There is a electron donor and electron acceptor molecule. The electron donor possesses a weakly bound electron or pair of electrons, and the electron acceptor has vacant orbitals. When a single electron participates in the transfer, the transferred electron goes from the highest filled orbital of the donor to the lowest empty orbital of the acceptor. The resulting charge-transfer complex can be a strikingly different color than the reagents.

5-HT is an exceptional electron donor that has the propensity to form donor-acceptor complexes with many electron acceptors, such as picric acid. In the formation of serotonin-picrate crystals, serotonin is the donor molecule and picrate is the electron acceptor. A red-colored charge-transfer complex is formed when serotonin is added to picric acid.

The geometry of charge-transfer electronic transitions has been studied with crystal structures of serotonin-picrate. In serotonin-picrate crystals, the nitro groups of picric acid interact with C2 and C3 of the indole ring, suggesting that the nitro group of the electron acceptor associates with the pi electron cloud of 5-HT.

"It is significant that the observed geometry is such that charge-transfer electronic transitions apparently can occur and impart color to the [red serotonin picrate] crystals." (C.E. Bugg, 1970)

Indoles in general form charge-transfer complexes. The exceptional electron-donating ability of the indole nucleus is related to a high-lying pi electron on the carbon atom at position-3 of the indole donor. Serotonin, tryptophan, aminotryptophan, and methoxytryptophan all function as electron donor molecules in the formation of charge-transfer complexes. These indole donors can pair with electron acceptor molecules of biological importance, such as riboflavin, nicotinamide, or DPN.

Tryptophan is an indole derivative, and it is a better electron donor than most aromatic amino acids, thus proteins are known to participate in charge-transfer reactions via their tryptophan residues. When tryptophan is mixed with riboflavin, and cooled to -78 C, a strong red color is observed. Tryptophan also forms a charge-transfer complex with electron acceptors DPN+ or TPN+. At the temperature of dry ice, tryptophan-DPN+ and tryptophan-TPN+ complexes had a yellow color, with strong absorption in the region of 400 nm.

Overall, serotonin is a better electron donor than tryptophan. This has been shown theoretically by calculating the kHOMO energy of 5-HT and tryptophan, and experimentally by mixing 5-HT or tryptophan with the same electron acceptor, riboflavin. 5-HT and tryptophan both form charge-transfer complexes with riboflavin but serotonin complexes much more strongly, thus it has been verified that serotonin is a better electron donor than tryptophan. The physiological properties of 5-HT might be related to the exceptional electron donor capabilities of the hydroxyindole moiety.

Coming to y favorite indole, LSD, with kHOMO=0.218-0.487, is an extremely good electron donor, and LSD has been shown to form charge-transfer complexes with the small molecules such as riboflavin, TCNE, and dimethylaminobenzaldehyde. Also, LSD forms charge-transfer complexes with electron acceptor macromolecules, such as wool protein, dopamine receptors, and 5-HT2A receptors. It has long been suspected that psychoactive drugs, including chlorpromazine and phenothiazine derivatives, function as electron donors in a key step involving charge-transfer interactions. Drugs may donate or accept electrons, disrupting the normal pathway for electron transport and thus interfering with oxidation-reduction processes such as the respiration chain.



References

Bugg C. E. and U. Thewalt. (1970). Crystal structure of serotonin picrate, a donor-acceptor complex. Science. 170, 852-854. 10.1126/science.170.3960.852

Isenberg I. and A. Szent-Gyorgyi. (1959). On Charge Transfer Complexes between Substances of Biochemical Interest. Proc.Natl.Acad.Sci.U.S.A. 45, 1229-1231. 10.1073/pnas.45.8.1229

SZENT-GYORGYI A., I. ISENBERG and J. McLAUGHLIN. (1961). Local and pi-pi interactions in charge transfer. Proc.Natl.Acad.Sci.U.S.A. 47, 1089-1094. 10.1073/pnas.47.8.1089

Ergotamine mysteries

LSD is related to ergotamine. There are many unsolved mysteries related to ergotamine chemistry.

Two and a half millennia ago, Grecians celebrated Demeter by drinking kykeon, a drink made from fermented barley water. This special drink contained ergotamine and caused in participants intensive psychic changes, which cleared their souls, and made them accept death not so much as harm as a blessing, as one of the ancient diarists reported. Kykeon was consumed on a 14 mile walk from Athens to Eleusis, which culminated in a mysterious all-night ceremony. The site of Eleusis was burned by a Christian barbarian, according to Terrence McKenna.

Ergot is the name given to the dark-colored fungus growing on pods of rye (below). It is a horn-shaped growth that is typically in the neighborhood of 10 to 15 mm long, and can reach diameters of about 5 mm. The ergot consists of tightly interwoven hyphae of fungus. The ergotamine-containing fungus is named Claviceps purpurea.

From LSD research

Breads made from contaminated grains may have led to bizarre events in history such as the Salem Witch Trials in 1692. Around 1830, in rural areas of Germany, the scientist Karl von Reichenbach built a special conservatory for studying "sensitive" individuals, and he refracted moonbeams into the room for their amusement. Presumably, von Reichenbach's "sensitives" were patients who had consumed ergotamine from contaminated bread crops.

LSD exhibits a low transport number in glass pipettes

The ionotophoretic method for the application of drugs from micropipettes is important for the good spatial and temporal resolution which it offers. With ionotophoretic methods, drugs can be applied to single neurons. Ionotophoretic experiments significantly change the natural chemical environment of a neuron, yet the effects of drugs on neuron spiking are frequently measured with ionotophoresis.

A iontophoretic pipette is a thin metal wire in a glass cylinder, that is filled with a solution of drug. A "retaining" current is passed through the micropipette via the wire to suppress the spontaneous release of drug. A large retaining current will greatly depress the release of drug from the pipette tip, although no value of retaining current will prevent completely the diffusional efflux of drug from the ionotophoretic pipette. When the experimenter is ready to release the drug, an "ejection" current is applied. This stimulus is applied as a brief current pulse, not a steady current. There is a theoretical relationship between the ejection current and release of drug ions. The drug solution will be expelled from the tip of the pipette, depending on the amount of current passed, and the drug's "transport number," which is the ratio of drug released to charge passed.

LSD has an exceptionally low transport number (t=0.02) for a chemical substance, thus very long periods of iontophoresis must be used for LSD. Most of the LSD molecules tend to stay in the pipette, even with large ejection currents. In comparison, acetylcholine and 5-HT have high transport numbers (t=0.2-0.4), and require short bursts of current to be released from the pipette.

When dealing with iontophoretic release of drugs from pipettes, we usually want to know the amount of drug released, but the value known with confidence is the ejection current. To calculate the transport number of each drug, the electrophysiologist must use pipettes that are filled with a radioactive isotope of the drug, and different ejection currents. The figure below plots the electrical charge (ucoulomb) in the pipette versus iontophoretic release (pmol) of [3H]-LSD. LSD-25 release from pipettes was directly proportional to the charge passed through the pipette. The transport number of LSD was obtained from this data by multiplying the slope (expressed in mol/coulomb) by Faraday's number.

From lsd transport number

In 1974, Haigler and colleagues reported that the transport number of LSD (0.0023) was much smaller than 5-HT (0.219). According to these researchers, 100 nA of ejection current of LSD would be equivalent to 1 nA ejection current of 5-HT in terms of the number of drug molecules ejected.

“since equal currents of both agents inhibit the raphe, LSD emerges as being more potent than 5-HT, molecule for molecule, on the raphe neurons." (H.J. Haigler, 1974)

Some researchers found it difficult to pass current through LSD-containing glass electrodes.

“It was often impossible to pass current through barrels containing 2% LSD 25 solution for long periods. Longer applications of LSD 25 from a 0.5% solution had a depressant action on 22 out of 35 neurons tested.” (Boakes,R.J., 1970)

Chlorpromazine and Levallorphan, a drug similar to naloxone, have low transport numbers too. The transport numbers of chlorpromazine and Levallorphan are 0.0858 and 0.0737.

A molecule's transport number is easy to measure and it reveals the similarity between drugs like chlorpromazine and LSD. The unique physical properties of chlorpromazine and LSD are due to the phenothiazine ring, which is absent from 5-HT molecules. The similarity of electronic properties between chlorpromazine and LSD is clearly more significant than those shared by LSD and 5-HT.

Reference

Boakes R. J., P. B. Bradley, I. Briggs and A. Dray. (1970). Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25. Br.J.Pharmacol. 40, 202-218.

Bradley P. B. and J. M. Candy. (1970). Iontophoretic release of acetylcholine, noradrenaline, 5-hydroxytryptamine and D-lysergic acid diethylamide from micropipettes. Br.J.Pharmacol. 40, 194-201.

Haigler H. J. and G. K. Aghajanian. (1974). Lysergic acid diethylamide and serotonin: a comparison of effects on serotonergic neurons and neurons receiving a serotonergic input. J.Pharmacol.Exp.Ther. 188, 688-699.

Zieglgansberger W., G. Sothmann and A. Herz. (1974). Iontophoretic release of substances from micropipettes in vitro. Neuropharmacology. 13, 417-422. 10.1016/0028-3908(74)90129-4

LSD chromatography

The formation of a charge-transfer complex is accompanied by the appearance of a new color band. Histologists have long been interested in charge-transfer reactions for developing staining procedures based on the appearance of a visible color. For example, Romanowsky-Giemsa staining is due to azure B and eosin Y molecules, which act as electron acceptor and donor in the formation of a purple-colored charge-transfer complex.

Electron acceptor reagents have been used as color test reagents for the detection of hallucinogenic drugs. This was shown in 1973, when twenty different hallucinogens were applied to chromatography plates and then sprayed with one of various chromogenic reagents. The formation of a color band was dependent on the electron-donating properties of the drug molecule.

“As would have been expected, the polycyclic and consequently more “electron-rich” hallucinogens, such as the harmine derivatives gave stronger colors than the simple monocyclic beta-phenylethylamines derivatives such as mescaline, TMA, DOM, or 2,3-dimethoxy-amphetamine,” (R.A. Heacock, 1973)

The tryptamine derivatives DMT, methyltryptamine, and alpha-methyltryptamine reacted strongly with tetracyanoethylene (TCNE), an electron acceptor. Beta-carboline derivatives 6-methoxyharmalan and harmaline gave intense colors with TCNE and all electron acceptors studied. Ibogaine and LSD were easily detected with TCNE. The chromatographic evidence suggests that the broadly defined class of hallucinogens function as electron donors, because one of the most characteristic evidence for a charge-transfer process is the appearance of a new absorption band.

Erspamer was the first scientist to study enteramine (serotonin) in depth. His technique involved staining with the Ehrlich reaction to test for the presence of serotonin. Also referred to as Van Urk's reagent, Ehrlich's reagent is 2% dimethylaminobenzaldehyde in hydrochloric acid, and forms a purple charge-transfer complex with serotonin as well as most indoles, LSD and chlorpromazine. A purple charge-transfer complex is formed when Ehrlich's reagent is mixed with LSD. According to Hofmann, psilocybin gave a violet color characteristic of indoles in Van Urk reactions.

From lsd spectroscopy

The LSD-Van Urk complex produces an absorption band at 520 nm. Chlorpromazine can be detected by Van Urk reagent, giving an absorption peak at 520 nm. As predicted by its HOMO energy, chlorpromazine is an excellent electron donor, so it is not surprising that chlorpromazine would form a charge-transfer reactions with the electron acceptor Van Urk reagent.

"The procedure allows for a simple, rapid, and accurate determination of small quantities of chlorpromazine." (B.S. Murty, 1970)

Chlorpromazine is considered to be an antipsychotic drug and LSD is considered to be one of the most powerful hallucinogen drugs known to man, and there are many electronic similarities between LSD and chlorpromazine. LSD and chlorpromazine both have a low transport number, and they both react with Van Urk reagent to produce a macromolecular complex with an absorption peak at 520 nm. The similarites between LSD and chlorpromazine could be related to their common anthracene-like structure, known to have exceptional electron-donating and electron-receiving properties.


Reference

Heacock R. A. and J. E. Forrest. (1973). The use of electron-acceptor reagents for the detection of some hallucinogens. J.Chromatogr. 78, 240-250. 10.1016/S0021-9673(01)99063-6

HOFMANN A. (1961). Chemical pharmacological and medical aspects of psychotomimetics. J.Exp.Med.Sci. 5, 31-51.

Murty B. S. and R. M. Baxter. (1970). Spectrophotometric determination of chlorpromazine in pharmaceutical dosage forms. J.Pharm.Sci. 59, 1010-1011. 10.1002/jps.2600590721

LSD antagonizes serotonin pain

5-HT and histamine are involved in allergic shock and pain responses. A painful swelling of the rat paw was triggered by an injection of 1 ug 5-HT.

The 5-HT edema reaction in rat paw was completely blocked by LSD and some LSD derivatives, lending support to the hypothesis that LSD functions as an anti-serotonin agent. Certain LSD derivatives actually antagonized the 5-HT swelling reaction more effectively than LSD. Preparations of UML-491, 1-methyl-lysergic acid butanolamide, had a similar effect as LSD in 4-6X smaller doses. Figure 2 below shows that pre-treatment with 1-methyl-lysergic acid butanolamide caused a dose-dependent decrease of 5-HT pain in the rat paw. Pain was assessed by taking measurements of the thickness of the paw every 15 minutes during two hours after the 5-HT injection. As shown below, the maximal swelling occurred within the first half hour and then diminished. At a dose of 70 ug/kg, UML-491 almost completely prevented the swelling reaction.




Methylation of LSD occurs in the drugs MLD-41 and UML-491. These two drugs together with LSD were the most effective compounds at blocking 5-HT pain in the rat paw. Other LSD derivatives had no effect on the pain reaction, for example, hydrogenation of LSD led to a loss of blocking activity of nearly 90%.

Figure 4 below shows that UML-491 was more effective at inhibiting rat paw edema than LSD. The 2-position methyl group seems to be important for the physiological activity in this case, since UML-491 was more potent at inhibiting rat paw edema than lysergic acid butanolamide (unmethylated UML-491).




Phenothiazine derivatives are nearly as effective as LSD at preventing 5-HT pain. Benditt found that 5-HT- or histamine-edema of rat's paw could be prevented by the prior administration of chlorpromazine. Antihistamine drugs including phenothiazine, chlorpromazine, promethazine, and diethazine partly prevented 5-HT-edema, although these drugs were not as effective as LSD or UML-491. Relative to LSD (if LSD inhibits 5-HT edema by 100%), chlorpromazine inhibited 5-HT edema by 64%. UML-491 was the most potent derivative tested, inhibiting 5-HT edema by 440%, and MLD-41 inhibited 5-HT edema by 91%.

Drugs that block 5-HT or histamine are used to control allergic reactions. In guinea pig who inhaled an aerosol spray of 5-HT or histamine, LSD prevented death by anaphylactic shock. The research showing that LSD and UML-491 can prevent 5-HT-induced swelling is where Abramson found support for his ideas about LSD and UML-491 as therapeutic drugs for allergies.



Reference

BENDITT E. P. and D. A. ROWLEY. (1956). Antagonism of 5-hydroxytryptamine by chlorpromazine. Science. 123, 24.

CERLETTI A. and W. DOEPFNER. (1958). Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids. J.Pharmacol.Exp.Ther. 122, 124-136.

DOEPFNER W. and A. CERLETTI. (1958). Comparison of lysergic acid derivatives and antihistamines as inhibitors of the edema provoked in the rat's paw by serotonin. Int.Arch.Allergy Appl.Immunol. 12, 89-97.

Dorsal root neurons in spinal cord

The neuronal pathways for sensations of touch are well-known. The primary sensory neurons for touch and proprioception are located nearby the spinal cord, in clusters (e.g. ganglia) of neurons referred to as dorsal root ganglia. Sensory endings of dorsal root ganglion cells are superficially located in the skin. For example, the Pacinian corpuscle is a large subcutaneous mechanoreceptor that senses vibration. A single Pacinian corpuscle is innervated by one dorsal root neuron, which has its cell body in the dorsal root ganglion. Stimuli that indent or otherwise deform the receptive surface of the Pacinian corpuscle are conveyed to the dorsal root neuron, but first this information (sense of vibration) must cover a distance of meters between the mechanoreceptor and the cell body. Since axons are known to cross such distances, the appendage of the dorsal root ganglion neuron that carries the sensory current from the Pacinian corpuscle has been mistakenly referred to as an axon, when it is actually a myelinated dendrite. The thick extension of the dorsal root ganglion neuron must be a dendrite since dendrites are always oriented towards the external world, and carry sensory current toward the cell body. This will be discussed later. Dorsal roots carry sensory information into the spinal cord from muscles and skin, and from internal organs.

Each dorsal root ganglion cell has a thick and a thin process. The thick, outer branch grows towards the periphery and ends in the skin. The thin conducting process has ascending and descending fibers, which carries the current as far as the medulla. Ramon-Cajal's diagram below places the dorsal root ganglion neuron (D) in context with its skin receptors (D') and axon projections to the medulla. From the medulla, another neuron carries the sensory current to the thalamus and cortex. The classical afferent pathway involves peripheral nerve, synapse in spinal cord, synapse in thalamus and projection to the cortex.

From Ramon y Cajal

All dorsal root ganglion cells belong to a primordial group of neurons called bipolar neurons. There are many similarities between dorsal spinal ganglion cells, bipolar cells of the olfactory bulb, bipolar cells in the retina, and spiral ganglion in the organ of hearing. All of these sensory neurons were bipolar in the embryo. Cajal wrote:

"the bipolar cell is a very common phase in the evolution of nerve cells of the spinal cord, cerebrum, and retina." (Cajal, 1933)

The neurons in the dorsal root ganglia are bipolar at first. By adulthood in nearly all mammals, the bipolar cells have converted into unipolar spinal ganglion cells. The figure below shows the transition of bipolar to unipolar spinal ganglion neuron.



In the process of transitioning to a unipolar spinal ganglion cell, the nucleus and cell body migrate away from the conducting process, so that the signal traveling from the periphery bypasses the cell body. Certain fish are an exception, and maintain the more primordial bipolar spinal ganglion cells in adulthood.

Each bipolar cell exhibits two primordial extensions, a thin and thick branch. The thick process gathers external stimuli and is typically associated with dendrite function, while the thin process conducts information away from the cell body. As a general rule, the thick processes of bipolar cells contact ciliated cells or mechanoreceptors at the periphery (e.g. Pacinian corpuscle), which are directly involved in gathering sound or pressure waves. Dendrites usually grow towards the external stimuli, for example, dendrites are involved with vision pathways. The dendrites of bipolar neurons contact rods and cones, which are special ciliated cells. In the ear, ciliated hair cells convey the auditory stimulus gathered to the "thick process" of auditory bipolar nerve cells. In other words, the dendrites of auditory bipolar nerve cells end among ciliated hair cells. Then the axon ("thin process") of the auditory bipolar cell travels in a nerve fiber called the vestibulocochlear nerve towards the auditory cortex.

Bipolar sensory neurons are derived from epithelial layers. In worms, the bipolar or fusiform sensory neurons originate from the ectodermal layer, and then occupy a submuscular position. Nemertinea provides an example of the gradual displacement of the nervous apparatus into the ganglia of the body. Individual bipolar sensory neurons begin to function as sensory transducers before they aggregate into ganglia, thus it is likely that there are many patches of primary sensory neurons, such as the ventral 5-HT neurons, which represent some of the sensory neurons which originated recently by the epidermis, and recently began to migrate toward the center of the brain. Whereas centers for touch and proprioception (dorsal root ganglion neurons) form recognizable ganglia near the center of the body cavity, there are bipolar sensory neurons that are still clustering. It is unclear what sensory inputs these neurons can detect.

Cajal noticed that in both retina and olfactory bulb, dendrites are always oriented toward the external world. Dendrites usually follow a path towards the locations from which they receive their external influences. Axons are always oriented toward central neural centers. Based on this observation, Ramon-Cajal proposed that dendrites conduct centripetally while axons conduct away from the cell body. To his dismay he realized that centripetal current conduction in dendrites could not constitute a general rule of operation in the case of the dorsal root sensory ganglia, where axonal-looking processes were oriented toward the periphery, however Cajal reexamined this issue 2 years later, and he then realized (1923) that the processes in sensory ganglion neurons that appeared to be axons were, in fact, dendrites. The appendage of the dorsal root ganglion neuron that towards the periphery is formed by protoplasmic stretching of the cell body. The whole cell body migrates, leaving a dendrite trail in its path like a snail. As seen in Ramon-Cajal's figure of the transition stage of bipolar to unipolar ganglion cells (Figure 235 above), the neurite that is mistakenly called the dorsal root ganglion axon is generated by a form of protoplasm stretching. The dendrite structure left behind the migrating cell body is very different from an axon appendage, which is generated by a growth cone. The trunk that contains the two processes of a bipolar neuron before they bifurcate is the result of cell body migration, therefore according to Ramon-Cajal it constitutes part of the cell body rather than an axonal fiber. The part of the neuron that is most proximal to external stimuli was once part of the cell body.



Reference

Ramon-Cajal, S. (1990). New ideas on the structure of the nervous system in man and vertebrates; Swanson, N., Swanson, L. W., Eds.; MIT Press: Cambridge.