This paper will explore the link between the microscopic world of neurons and neurotransmitters and the macroscopic physiological effects of LSD on the human subject. Both the actions of synapses and the outward behavioral and physical effects of LSD are well known, but the fundamental connection between these two phenomena is still a mystery to science.
In order to have any hope of understanding the complex biological action that LSD has on the human brain and our sense of perception, one must first appreciate the mechanics that lie beneath both neurotransmitters and neurons themselves. In the body, the brain and spinal cord make up what is known as the central nervous system, or the CNS. Each neuron in the human body connects to other neurons and communicates with them by means of electrical signals. These electrical signals must first pass between the small gap between neurons before it can be transmitted. The gaps between neurons are known as synapses. Messages constantly pass through the synapses between our neurons, and these messages allow us to sense, to think, and to act upon these feelings and thoughts. There are two main types of synapses: chemical and electrical. In chemical synapses, which are by far the more common, electrical signal pass from neuron to neuron through the use of mediating chemicals known as neurotransmitters. In electrical synapses, the neurons are in electrical contact with one another, and no intermediate chemicals are needed.
To truly understand the critical action of the neurons, we must investigate the chemical synapse at a microscopic level. The cell that is attempting to transmit the message, or impulse, is known as the pre-synaptic cell, and the cell receiving the impulse is known as the post-synaptic cell. When the pre-synaptic cell attempts to transmit an impulse, it first releases the neurotransmitter chemical through its outer membrane and into the synapse. The strength of the impulse determines to a certain extent the amount of neurotransmitter released. If this neurotransmitter is present in sufficient quantities, then it is absorbed by the post-synaptic cell, and this cell becomes more able to receive the impulse.
At this point, one may wonder exactly how this neurotransmitter makes the post-synaptic cell more receptive. This question is closely related to the method in which neurons accept and receive impulses. Each neuron involved in the transmission of impulses can be approximated as a container of negatively charged ions (like Cl-) sealed off from the environment, which is a sea of positively charged ions (like K+ and Na+). The cell "fires," or transmits an impulse to its related post-synaptic neurons when certain channels open up on the outer membrane of the neuron. This firing of the neuron is known as setting up of an action potential. When the channels on the neuron open, these channels allow a certain amount of positively charged ions into the cell. This movement of charge sets up a current which becomes the impulse. Certain factors influence when and how often these channels open. If the cell in question is a sensory one, like in the tips of our fingers, tactile, pressure, or temperature stimulation will cause the cells to "fire." If the cell is an interneuron, which transmits impulses from the CNS to the PNS, then action potentials will most likely arise from an impulse sent from a pre-synaptic cell. What neurotransmitters do is they change the permeability of the post-synaptic neuron's membrane, so that these channels on the membrane become either easier to open, or more difficult to open, and in turn, it is then simpler or more difficult for Na+ and K+ ions to enter, which then changes how easily it is for the cell to generate an action potential.
The two kinds of neurotransmitters that exist are excitory and inhibitory. Excitory neurotransmitters make it easier for the cell to allow positive ions in, and therefore decrease the threshold, or the smallest stimulation that will cause the cell to generate an impulse. Inhibitory neurotransmitter, on the other hand, make the neuron's membrane more permeable to negative ions, and increase the threshold.
The cell ceases to fire once there is no charge difference across the membrane, once the original pre-synaptic cell absorbs the neurotransmitter, once enzymes degrade the neurotransmitter, or once the amount of neurotransmitter diffuses down to almost nothing. Once the cell has fired, there is a certain period of time that exists before that cell can again generate an action potential. This time period is known as the refractory period. During this time, the charge inside the cell is nearly equal to the charge outside the cell, and it requires a great deal of stimulus to make this cell fire again. It is for this reason that many stimuli seem to fade if we are subjected to them several times within a reasonably short period. Certain neurotransmitters, like norepinephrine, instead of changing the threshold potentials, instead decrease the refractory period, resulting in neurons firing several action potentials for each stimulation.
Finally, yet another method of action of neurotransmitters is much more subtle. In this case, the neurotransmitters alter the neurotransmitter receptor sites on the post-synaptic neuron. Molecules that make it easier for the post-synaptic cell to be influenced by neurotransmitters are known as agonists, and those that make it more difficult are known as antagonists. For example, an antagonist that makes a cell less responsive to an inhibitory neurotransmitter would cause an excitory response.
In order to translate this information to the macroscopic world, it is important to understand that many of the mind-altering drugs in use today, are psychologically active because they mimic or affect the production of the neurotransmitters that our body naturally produces. Our neurons are constantly receiving stimuli from the outside world. The vast majority of these stimuli are too weak to actually set up an action potential, and of those that set up a local action potential, fewer still are strong enough to be noticed by our conscious mind. If hallucinogens in a person's system lower the threshold at which our nerves fire, then these very weak stimuli, which the person without the drug would not even notice, will form a false image. Therefore, the over-active mind will create vivid hallucinations out of amplified stimuli from the ordinary world.
Serotonin and LSD
Though the precise biochemical action of hallucinogens is unknown, it is believed that it probably stems from a complex reaction with serotonin (5-HT) from the cortex to the spinal cord. In fact, LSD seems to closely resemble serotonin in structure. Thus, the study of serotonin reveals a great deal about LSD.
Though located in many cells throughout the body, it is the serotonin of the nervous system that concern the actions of LSD. It exists mainly in the Locus Coeruleus and Raphe Nuclei, or the midline of the upper brain stem. It is here that the chemical is believed to play a large role in moderating behaviors and moods. Anti-social personality disorders, violence, and impulsive behavior have been connected with its lowering. Severe depression and suicidal states are also connected to a low serotoin activity, while high serotonin corresponds to alertness.
These facts can be traced back to serotonin's importance in 'language'; that is in hearing, seeing words or objects, and motor (including voice) control. It plays this role by breaking sensory relay and exciting motor relay from the brain. The release of serotonin in doing this is self-regulating. As it is released by the synapses, it prevents further release.
Given this information, and knowing the effect of LSD and other hallucinogenic drugs, a connection should not seem surprising. In fact, LSD, along with psilocin, and DMT, contain indole rings very similar in makeup to those of serotonin. It is this similarity that allows LSD to mimic the serotin at the receptors and inhibit the firing of the serotonergic neurons.
The actions of serotonin(5-HT) and the effects of LSD on the human subject are inextricably linked. The neurological pathways that allow serotonin to regulate so many of the body's activities are the same ones that allow the LSD molecule to so profoundly affect the body. The true frontiers of chemistry lie here, in the serotonergic neurons and the bodies' response to the disruption of the normal pathways. As of now, there is still great confusion over how LSD affects the neurons, especially at the synaptic level.
It is important to first understand the workings of the neurotransmitters and the receptors involved with the 5-HT response in order to have a meaningful discussion of the different theories involving LSD action. Both the pre-synaptic and post-synaptic neurons contain receptors that allow neurotransmitters to modulate their activity. This modulation can take the form of a change in membrane permeability or a change in that neuron's production of a neurotransmitter.
On the serotonin neurons themselves, there seem to be two main types of receptors to which LSD and 5-HT both can attach. The two types are known the 5HT1 receptors, usually part of pre-synaptic neurons and the 5HT2 receptors, which are usually on the post-synaptic neuron. When a molecule becomes chemically attached to 5HT1 receptors of the serotonin producing neurons, the neuron slows or stops its production of serotonin, creating a negative feedback loop, where excess serotonin will halt further production. When a molecule binds to the 5HT2 receptors, the post-synaptic neuron is inhibited, and it is more difficult for it to generate an action potential. Apparently, serotonin will attach itself to either of these two receptors with equal frequency, but it has been proposed that LSD prefers the 5HT1 type to the 5HT2 type.
Among researchers, much importance is placed on the effects of LSD in the Raphe Nuclei, because it is a small area of the brain which contains most of the brain's serotonergic cells. Part of the function of the RN is postulated to be the protection of the brain from over-stimulation and sensory overload. It is also connected to many other areas of the brain, which if LSD action is truly based in the RN, would explain how such small doses can create such wide-ranging sensory and hallucinatory effects. As stated before, researchers are still working to discover exactly how LSD interacts with serotonin. While no one is sure as to the nature of this interaction, there are several theories that are still being tested today.
The description of the area of cutting edge work
The first postulated mechanism for the action of LSD involved its theorized affinity for pre-synaptic 5HT1 receptors. It was believed that the presence of LSD would flood the 5HT1 receptors, which would, in turn, force the serotonergic pre-synaptic neuron to cease serotonin production. This would lead to an increase in post-synaptic activity. All effects of LSD were believed to have their roots in this theorized suppression of serotonin.
The largest debate that still exists today involves the action of LSD on the 5HT2 receptors. The biggest question is whether LSD inhibits the 5HT2 receptors' uptake of serotonin, or whether it facilitates that uptake. In other words, they are trying to determine whether it is agonistic or antagonistic. For a great while, there was convincing evidence for both sides of the antagoinist/agonist argument and the researchers in the field lined up on both sides with seemingly contradictory evidence.
The newest theory attempts to resolve this debate without going against the accumulated evidence. In this case, it is theorized that LSD is only a partial agonist. According to this explanation of LSD action, the LSD molecule is more attracted to the post-synaptic 5HT2 receptors than the 5HT molecule. Once attached to the 5HT2 receptor, LSD can cause the same effect as normal serotonin (the damping of post-synaptic neural activity), but it does so much less effectively than serotonin. Thus, in experiment where the synapses being tested were devoid of the natural serotonin, LSD appeared to be agonistic and functioned as serotonin. However, when the experiments judged the activity of LSD against the normal activity of serotonin, the LSD, with the higher receptor affinity, blocked the serotonin, and the system behaved as if serotonin was reduced, because the less effective LSD was acting instead of the more effective LSD. This theory of LSD acting as an antagonist or as an agonist seems to be the most promising, but much more conclusive research needs to be conducted.
Neurobiologists study brain function at the level of neurons while psychologists look for the laws describing behavior and cognitive mechanisms. Many in these fields believe that it is possible that one day we will be able to understand complicated behaviors in terms of neuronal mechanisms. While research on the level of neurons and psychological mechanisms is fairly well developed, the area in between these is rather unclear. However, some progress has been made. Cognitive scientists have been able to associate mechanisms with areas of the brain and have also been able to describe the effects on these systems by various neurotransmitters. The lack of knowledge in the middle ground between neurobiology and psychology makes a description of the mechanisms of hallucinogens necessarily coarse. A brief exploration of the possible mechanisms of LSD will ensue, along with a deeper look at the more developed studies of the mechanisms on a neuronal level.
Researchers have attempted to identify the mechanism of LSD through three different approaches: comparing the effects of LSD with the behavioral interactions already identified with neuotransmitters, chemically determining which neurotransmitter and receptors LSD interacts with, and identifying regions of the brain that could be responsible for a wide variety of effects.
Initial research found that LSD structurally resembled serotonin (5-HT). 5-HT is implicated in the regulation of many systems known to be effected by LSD. This evidence indicates that many of the effects of LSD are through serotonin mediated pathways. Subsequent research revealed that LSD not only has affinities for 5-HT receptors but also for receptors of histamine, ACh, dopamine, and the catecholines: epinephrine and norepinephrine.
Two areas of the brainstem that are thought to be involved in LSD’s pathway are the Locus Coeruleus (LC) and the Raphe Nuclei. The LC is a small cluster of norepinephrin containing neurons in the pons beneath the 4th ventricle. It is responsible for the majority of norepinephrine neuronal input in most brain regions. While norepinephrine activity throughout the brain is mainly mediated by the LC, the majority of serotonergic neurons are located in the Raphe Nuclei (RN). The RN is located in the middle of the brainstem from the midbrain to the medulla. Along with the LC, the RN is part of the ascending reticular activating system. 5-HT inhibits ascending traffic in the reticular system; perhaps protecting the brain from sensory overload. It is also believed that post-synaptic 5-HT receptors in the visual areas are inhibited. It is apparent that an interruption of 5-HT activity would result in the excitation of various sensory modalities.
Current thought is that the mechanism of LSD is related to the regulation of 5-HT activity in the RN. However, the RN is also influenced by GABAergic, catecholamergic, and histamergic neurons. LSD has been shown to also have affinities for many of these receptors. Thus it is possible that some of its effects may be mediated through other pathways. Current research has focused on the effects of LSD on 5-HT activity.
Current related work
The current focus of much of today’s research on LSD is whether it is an agonist or an antagonist. Molecules that excite receptors are labeled agonists, while molecules that inhibit the action and interfere with the binding of the receptor are known as antagonists. Pierce and Peroutka have argued that LSD has a number of antagonistic properties. They observed that spiperone, a 5-HT antagonist doesn’t block the behavior of LSD. Another piece of evidense is that radio ligand binding studies have shown that the affinity of a 5-HT2 receptor agonist is pH dependent while the affinity of 5-HT2 receptor antagonist is pH independent. The action and effects of LSD is pH independent. (Peroutka & Pierce 1990)
This study also looked at 5-HT2 receptors that are connected to a phosphatidylinositol (PI) second messenger system. PI turnover rate has been found to be stimulated by 5-HT and the reverse is true for 5-HT2 antagonists. LSD doesn’t stimulate PI turnover. This was a further example of antagonistic behavior by LSD.
Also observed in this study was the excitement of central nervous system neurons by 5-HT receptors. This was caused by a decrease in K+ conductance which can be attributed to the activation of 5-HT2 receptors. LSD was shown to inhibit CNS neurons, again displaying antagonistic tendencies.
While these scientists seem to have created a credible argument on the antagonistic properties of LSD, subsequent studies have leaned in the opposite direction. Glennon has developed a number of counterpoints to Pierce and Peroutka’s evidense. He studied the effects of LSD on the PI turnover rate at differing doses. This yielded vastly different results due to the fact that LSD has biphasic responses. That is it illicits the opposite effects at low doses as those at high doses. (Glennon 1990) This study indicated that LSD acts as a partial agonist. The LSD produced approximately twenty five percent of the PI turnover as was observed to be produced by 5-HT. From this, it can be concluded that LSD has a higher affinity for 5-HT receptors than 5-HT, but a lower efficacy. If LSD acts as a partial agonist with low efficacy, it could compete with 5-HT for 5-HT2 receptors. However, since 5-HT is a more potent agonist than LSD, the agonistic tendencies of LSD are masked and it appears to behave antagonistically.
Glennon also observed the effects of LSD on platelet aggregation. This action is affected by 5-HT2 mechanisms. Hallucinogens, such as LSD, were shown to be antagonized by 5-HT2 antagonists, such as keratin, in the presence of platelet aggregation. This also supports the argument that LSD is agonistic.
The Heffter Organization is currently working to sponsor a new study in Zurich, Switzerland and La Jolla California. They will study the interaction of LSD and keratin. The project will combine state-of-the-art psychological, brain imaging, and psychophysiological methods to explore the mechanisms of action and sites of keratin in humans. Human subjects will be used for the first time. The volunteers will be treated with psychedelic agents, such as LSD, and another drug whose corresponding receptors are known. Drug effects will be monitored using psychological scales of altered states of consciousness, flourodeoxyglucose Position Emission Tomography (PET) imaging of the metabolic activities of various parts of the brain, and psychophysiological measures of information processing and attention filtering. The PET studies will enable the determination of which areas of the human brain are activated or inactivated. This in turn will tell whether the drug in an agonist or antagonist. Glennon also observed that the relationship between LSD and 5-HT2a and 5-HT2c receptors is like that between 5-HT1 and 5-HT2 receptors. 5-HT1 receptors antagonize the 5-HT2 receptors. His study showed that LSD had an affinity for 5-HT2a and 5-HT2c sites and is antagonized by 5-HT1. This is evidense that LSD is agonistic.
The Fishberg Research Center in Neurobiology at Mount Sinai School of Medicine did a study this year mapping the binding sites of the 5-HT2a receptor. They tested the interaction between LSD and the receptor binding sites. They used site directed mutagenesis of serine Ser3.36(159)-->Ala and Ser3.36(159)-->Cys The results showed that the affinity of LSD to the 5-HT2a site was unaffected by the mutation.
The Heffter Organization is sponsoring another upcoming study of the effects of LSD. David L. Nichols, Ph.D. will try to develop receptor binding profiles for lysergamides that have been tested in humans. This will attempt to derive correlations between pharmacological effects and affinity for particular receptors. Statistical tests will be used to determine which receptors are most likely to attract LSD. As related in the above paragraph, current research indicates that it will have an affinity for 5-HT2a, but an interaction at one or more of the other receptors may be contributing to the exceptional potency of LSD.
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