The Psychedelic Effects Of Dlysergic Acid Diethylamide Lsd Were Discovered By Dr Albert Hoffman By Accident In 1938 In The

.. epletion of 5-HT through negative feedback in pre-synaptic autoreceptors.7 The depletion of 5-HT was thought to be responsible for the effects on the previously described systems innervated by the serotonergic neurons. A number of subsequent observations have called this theory into doubt however. Low doses of LSD effect behavior but do not depress firing in the RN.8 The behavioral effects of LSD outlast the modification of RNN firing.8 While repeated dosage of LSD results in a decrease of behavioral modifications (tolerance), its effects on the RN are unchanged.8 Other hallucinogens such as mescaline and DOM do not effect R neurons.8 Depletion of 5-HT does not eliminate the effectiveness of LSD. If LSD worked by inhibiting the 5-HT output of pre-synaptic 5-HT neurons, it should be ineffaceable if 5-HT is depleted.

The opposite result was actually observed; depletion enhances LSD activity.9 Mianserin, a 5-HT2 receptor antagonist, blocks LSD behavior but does not block LSD’s depression of RN neurons.9 While LSD does cause a decrease in the autoreactive firing of RN neurons, this appears to be an effect and not the cause. These observations are considered however to be compatible with a post-synaptic model. Subsequent research found that LSD and other hallucinogens have a high affinity for post-synaptic 5-HT1 and 5-HT2 receptors. In fact there is significant correlation between the affinity of a hallucinogen for these receptors and its human potency. While it seems logical that 5-HT activity is modulated at 5-HT receptor sites, it is possible that LSD could be affecting 5-HT receptor activity indirectly through adrenic or dopaminic pathways. However, blocking these receptors caused no change in LSD’s activity on the 5-HT receptors, thus it appears that 5-HT activity is indeed modified by 5-HT receptors.10 While evidence indicates that LSD is a 5-HT1 agonist, it is debated whether the effects on 5-HT2 receptors is agonistic or antagonistic.11 Theory: LSD Post-synaptically Antagonizes 5-HT2 Receptors Initial post-synaptic theories postulated that LSD was a 5-HT2 agonist. Pierce and Peroutka (P&P), however, argued that LSD has a number of antagonistic properties and called into doubt some of the evidence presented as being compatible with agonist activity.

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The primary evidence for agonistic behavior comes from observations that the effects of LSD are inhibited by 5-HT2 antagonists. P&P pointed out that this is not always the case. For example, some 5-HT2 antagonists such as spiperone do not block LSD behavior. In addition, radioligand binding studies have shown that the affinity of 5-HT2 receptor agonists is pH dependent while the affinity of 5-HT2 receptor antagonists and LSD are pH independent.9 5-HT2 receptors are connected to a phosphatidylinositol (PI) second messenger system. PI turnover has been found to be stimulated by 5-HT and antagonized by 5-HT2 antagonists. P&P found that nM concentrations of LSD do not stimulate PI turnover.

Therefore, LSD does not act as a classic agonist. They also found that nM concentrations of LSD inhibited the stimulatory effect of 10M 5-HT. The ability of LSD to inhibit a concentration 1000x greater is consistent with it being a 5-HT2 antagonist P&P also point out that the excitatory effects of 5-HT on CNS neurons appears to be caused by a decrease in K+ conductance attributable to activation of 5-HT2 receptors. P&P found that LSD inhibits this effect in rat somatosensory pyramidal neurons. This also is evidence that LSD acts in an antagonistic role.9 The final line of evidence presented by P&P was from smooth muscle studies.

The guinea pig trachea contracts when M concentrations of 5-HT are present. The ability of 5-HT antagonists to inhibit this effect correlates with the antagonists affinity for the 5-HT2 binding site. Thus it appears that this muscle contraction is 5-HT2 mediated. It was found that nM concentrations of LSD did not cause muscle contraction and inhibited the agonistic effects of M concentrations of 5-HT. This also is compatible with the actions of an antagonist. Theory: LSD Post-synaptically Partially Agonizes 5-HT Receptors Many of the apparent contradictions in evidence in the debate over whether LSD acts as a 5-HT2 agonist or antagonist can be reconciled by the theory that LSD acts as a partial 5-HT2 agonist.

Dr. Glennon presented a number of arguments for this theory including data from his own research and from the studies discussed by P&P in the previous section. One of the primary tools used by Glennon to determine the effects of various chemicals on the interactions between LSD and 5-HT was drug discrimination training in rats. Rats were trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline. Training with DOM stimuli generalized to many indolealkylamine and phenalkylamine hallucinogens. DOM was chosen instead of LSD as a training drug because of concern that LSD had a number of pharmacological effects.

It was thought that if the rat was trained with LSD, it might makes discriminations based on one of the pharmacological effects of LSD other than its effects on 5-HT. With this tool, Glennon demonstrated that a number of 5-HT2 antagonists inhibited the ability of rats to discriminate LSD from saline. This indicates that LSD acts as a 5-HT2 agonist. Glennon offered no explanation for P&P’s observation that some antagonists such as spiperone do not have this effect. However, spiperone and a few other similar antagonists appear to only be about 40% effective in inhibiting 5-HT2 sites due to its relative nonselectivity.13 As discussed in the previous section, PI turnover has been found to be stimulated by 5-HT and is antagonized by 5-HT2 antagonists.

In another study of the effects of LSD on PI turnover, it was found that LSD acted as a partial agonist (it produces approximately 25% of the effect caused by 5-HT). The apparent difference between this second study and P’s is that the second study tested the effects at a variety of doses. From this it was concluded that while LSD has a higher affinity for 5-HT receptors than 5-HT does, it has a lower efficacy. This is compatible with P&P’s observation that nM concentrations of LSD inhibited the stimulatory effects of uM 5-HT. If LSD acted as a partial agonist with low efficacy, it could compete with 5-HT in binding to 5-HT2 receptors.

Since 5-HT is a more potent agonist than the LSD, the effects of LSD would appear antagonistic. Glennon argued that the guinea pig trachea may not be a good example since 5-HT does not work through a PI mechanism in this case. In the rat aorta, however, 5-HT does hydrolize PI and the contractile effects of 5-HT are antagonized by ketanserin (a 5-HT2 antagonist). While LSD was not tested, another hallucinogen, DOB, was found to have an agonistic effect that could be antagonized by ketanserin. This suggests that LSD acts agonistically in the rat aorta. Glennon points out that it may well be the case that in other cases, the effects may be antagonistic.

However, these effects could be explained if LSD had a low efficacy for the receptor. Hyperthermia and platelet aggregation are both affected by 5-HT2 mechanisms. Hallucinogens such as LSD have been shown to behave agonistically and in the case of platelets, to be antagonized by 5-HT2 antagonists such as ketanserin.11 LSD often has a biphasic response in which low doses have the opposite effects of higher doses. The head twitch response in rodents is believed to be 5-HT2 mediated. At low doses, it has been found that LSD elicits a head-twitch response while at higher doses it antagonizes the response. The rat startle reflex is amplified at low dosages of LSD while decreased at higher doses.

This biphasic behavior can also be explained if LSD behaves as a partial agonist.11 In summary, this theory claims that: “LSD is a high-affinity, low efficacy, nonselective 5-HT agonist; in the absence of another agonist it may function as an agonist, whereas in the presence of a high efficacy agonist, it will function as an antagonist.” 11 Theory: LSD Post-synaptically Agonizes 5-HT1 Receptors Glennon also gave another possible explanation for the antagonistic activity of LSD. There is some evidence that 5-HT1 receptors have an antagonistic relationship with 5-HT2 receptors. As discussed in the previous section, head twitch behavior is believed to be 5-HT2 mediated. DOI acts as a 5-HT2 agonist and elicits head twitch. 5-OMe DMT also is a 5-HT agonist but has less efficacy than DOI.

If the subject is pretreated with 5-OMe DMT, the effects of DOI are attenuated (because many of the receptors are filled with the lower efficacy 5-OMe DMT molecules.) It has been found that A 5-HT1 agonist (8-OH DPAT) can also cause DOI attenuation. Other studies have also demonstrated that 5-HT1 agonists can behave functionally as 5-HT2 antagonists.11 Glennon argued that this theory is lent extra credence from the observation that 5-HT2 and 5-HT1c have similar relationships with various hallucinogens. A number of these hallucinogens have been shown to be 5-HT1c agonists. Like 5-HT2 sites, the affinity of hallucinogens for 5-HT1c sites correlates with their hallucinogenic potency in humans. Thus another explanation of the biphasic behavior of LSD is that increasingly higher doses of LSD cause increased antagonism of the 5HT2 receptor through agonism of 5HT1 receptors.

Although, the pre-synaptic theory seems to be fairly well discredited, it is interesting to note that there is debate as to whether pre-synaptic serotonin autoreceptors are of the 5-HT1 type. Whether serotonergic autoreceptors are 5-HT1 or not, it has been demonstrated that there are also post-synaptic 5HT-1 receptors.12 While the role of these receptors is not completely known, some researchers have hypothesized that 5-HT1 receptors may be involved in the regulation of norepinephrine.13 As discussed previously, the majority of norepinephrine neurons are located in the LC which also has system wide innervation. Recent research on 5-HT receptors calls the theory that 5-HT1 agonism results in 5-HT2 antagonism into question. Since Glennon’s paper, the 5-HT1c receptor has been reclassified as 5-HT2c. Since the 5-HT2 receptors discussed in this paper belong to the same family as what was called the 5-HT1c receptor, these have been reclassified as 5-HT2a.14 Since “5-HT1c” is a member of the 5-HT2 family, it is not surprising the LSD affinities are similar for the two receptors. While these reclassifications do not necessarily discount the theory that one receptor has an antagonistic effect on the other, it seems likely that the evidence for this may need to be re-evaluated in terms of recent findings.

Conclusion The lack of understanding about the mechanisms of LSD is indicative of the problems involved in the bridging of the worlds of psychology and neurobiology. As more is learned about the roles and interactions of various neurotransmitters, receptors, and on a larger scale: portions of the brain, the mystery will be further unraveled. With this caveat emptor firmly in mind, it seems that the best explanation of LSD’s effects is that it behaves as a high affinity partial 5-HT agonist. Depending on the presence of other molecules and its own concentration, LSD can have either agonistic or antagonistic effects on post-synaptic 5-HT2 family receptors. This modulation of 5-HT behavior is probably responsible for many of the effects attributable to LSD. LSD also has an affinity for other neurotransmitter receptors that play important roles in the brain stem such as norepinephrine, dopamine, and histamine.

It is also hypothesized that LSD may modulate neural responses to these transmitters through its activity on 5-HT1 receptors. Both the Locus Coeruleus and the Raphe Nuclei are part of the ascending reticular activating system which is implicated in the sensory modalities. The inhibition of 5-HT in the RN and release of norepinephrine from LC neurons results in a flood of information from the sensory system reaching the brain. Some of the cognitive effects of LSD could be attributed to the effects of brain stem innervation to areas of the brain such as the cerebral cortex and the hippocampus. References 1.(1995): “FAQ-LSD” From internet newsgroup: alt.drugs.psychedelics 2.Sankar (1975): “LSD: A Total Study” 3.Ashton H (1987): “Brain Systems Disorders and Psychotropic Drugs” 4.Snyder (1986): “Drugs and the Brain” Sci Am Books Inc.

From FAQ-LSD 5.Nicholls J, Martin R, Wallace B (1992): “From Neuron to Brain: Acellular andMolecular Approach to the Function of the Nervous System” 6.Aghajanian GK(1980): “Mescaline and LSD Facilitate the Activation of Locus Coeruleus Neurons by Peripheral Stimulation” Brain Res 186:492-496 7.Jacobs, B (1985): “An Overview of Brain Serotonergic Unit Activity and its Relevance to the Neuropharmacology of Serotonin.” From: Green, A: Neuropharmacology of Serotonin 8.Jacobs, B, Trulson M, Heym J, (1981): “Dissociations Between the Effects of Hallucinogenic Drugs on Behavior and Raphe Unit Activity in Freely Moving Cats” Brain Res 215:275-293 9.Pierce P, Peroutka S (1990): “Antagonist Properties of d-LSD at 5-Hydroxytryptamine2 Receptors”. Neuropsychopharmacolgy 3(5-6):509-517 10.Moret C (1985): “Pharmacology of the Serotonin Autoreceptor” From: Green, A: Neuropharmacology of Serotonin 11.Glennon R (1990): “Do Classical Hallucinogens Act as 5-HT2 Agonists or Antagonists?” Neuropsychopharmacolgy 3(5-6):509-517 12.Green R, Heal D (1985): “The Effects of Drugs on Serotonin Mediated Behavioral Models” From Green, A: Neuropharmacology of Serotonin 13.Leysen J (1985): “Characterization of serotonin receptor binding sites” From Green, A: Neuropharmacology of Serotonin 14.Borne R. (1994) “Serotonin: The Neurotransmitter for the 90s” URL: From: Drug Topics Oct, 10 1994:108.