Psychedelics 102 student notes psychedelic102lessonStudent
All the information presented in this lesson is all “news” – or was in 2007. The
science behind psychedelic drugs is absolutely infantile.
Lysergamides (LSD, psilocybin, and ibogaine) all share very related chemical structure. That
structure is shared with the neurotransmitter serotonin. None-the-less, how and where it binds,
and what binding is responsible for hallucinations has been a challenging set of questions. This
lesson reconstructs the step-by-step discoveries that helped scientists understand the science
behind hallucinations. And, surprisingly, that story is not as much about the thalamus as we
had predicted (recall the job of the thalamus and think why it was a likely player in
After successfully completing this lesson you will be able to:
Understand how radioactive ligands help us understand the molecules to which a drug can bind
Understand how animal studies can be used to examine hallucination-causing drugs
Understand that neurotransmitters have multiple receptor types with overlapping spatial localizations
Understand how transgenic animals can be used to address questions about the role of receptors and
Before you begin!
Where does serotonin bind?
When is radioactivity usefulWhy might animal studies be useful in testing the impact of mindaltering drugs?
Previously learned material
What is the difference between an agonist and an antagonist?
What goes on in the thalamus?
What goes on in the cerebral cortex?
Lesson 27: Psychedelic 102 – Lysergamides on
the Cell and Behavior
How and where do lysergamides bind? How do we know?
Where are the binding sites located in the brain?
Which binding sites must be occupied in order for hallucination to result?
What is the role of animal studies in addressing these questions?
How does knowing about regulation of gene expression help us understand these questions?
Serotonin receptor subtypes, 1A, 1C, and 2A
Dimethyl tryptamine (DMT), bufotenin, ayahuasca
Locus coeruleus (LC)
Gene splicing, gene regulatory elements, transgenic animals
Activity One: Literature Review
1) Please review the abstract from a 2007 paper in the journal “Neuron” (PMID 17270739 ). As you read
– it is OK (encouraged) for you to take the phrases “regulate phospholipase C” and “pertussis toxinsensitive heterotrimeric G(i/o) proteins and Src” and call them “cellular outcome A” and “cellular
outcome B”. Each are very specific measurements of a cell’s response to a stimulus.
Neuron. 2007 Feb 1;53(3):439-52.
Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated
signaling pathways to affect behavior.
González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon
SC, Gingrich JA.
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect
perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet
closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain
2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By
genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are
sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and
nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons.
However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and
LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also
involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the longelusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
2) The findings of this paper were summarized in Scientific American
http://www.scientificamerican.com/article.cfm?id=how-hallucinogens-play-th. Please read this two page
paper. In this paper, read “signaling cascade” to be “cellular outcome A and or B”.
3) Follow-up questions:
Previously, scientists understood that LSD (and related lysergamides) bind where?
What does the group use as a control – a molecule that binds without causing hallucinations?
Why do they look at a head-twitch response in mice?
What does a hallucination-causing drug do (to behavior and “cellular outcomes”) that a nonhallucination-causing drug which binds to the same molecule?
What did these scientists learn about the thalamus that made some people suspicious of the work?
Activity Two: One More Partying Mouse
Visit the last mouse shown on the Mouse Party site. She is the one sitting in a stunned way, waving her
hand in front of her face. As you watch, jot down your notes about:
Which receptors does LSD bind to?
Where are these receptors located?
Does the binding to different serotonin receptor types result in similar outcomes?
Why does a person (or mouse) using LSD become alert and sensitive to new stimuli?
Activity Three: Serotonin-resembling Psychedelic Drugs
Twice before, you have “met” drugs that influence serotonin synapses. MDMA interferes with, and
reverses serotonin recycling. Anti-depressants elevate serotonin levels in the synapse as well. The
psychedelics discussed in 101 and 102 also impact serotonin synapses. To understand this took as little
as examining the molecules. See the molecules shown, left to right, LSD, psilocybin, ibogaine (not in
yet), and serotonin. While their branches differ, each has an “indole amine”. An indole is a two-ring
compound. Amine means that within one ring, one finds a nitrogen in one position instead of a carbon.
Besides LSD and psilocybin, there are other lesser-known psychedelic
drugs that share this structure and are thought therefore to bind to
similar targets. Some of these are ibogaine, dimethyl tryptamine, and
ingredients in the ayahuasca vine (used by South American Shamen).
“Lisuride” is also an indole amine based molecule that binds to the same cellular targets. As you
previously learned in Unit 2, not everything that binds to a receptor exerts the same effect on a cell!
Agonists and antagonists exert opposite effects when compared to each other. But it is possible for there
to be an in-between – for a molecule to exert SOME of the same effects as another, not only opposite
effects. So called partial agonists are going to be a focus of this lesson.
Image citations – LSD: gnu free documentation license
http://commons.wikimedia.org/wiki/File:Lysergic_acid_chemical_structure.png , psilocybin: “public
domain” http://commons.wikimedia.org/wiki/File:Psilocybin_%281%29.png ,
ibogaine: (can’t find a way to remove black background http://commons.wikimedia.org/wiki/File:Ibogaine.png
serotonin:”ineligible for copyright - http://commons.wikimedia.org/wiki/File:Serotonin-skeletal.png ,)
TEST OF CONTENT
Which of the following are indole amines (check all that apply)?
Activity Four: Pinpointing the Hallucination-Responsible Receptors Down, in
The experimental evidence that helped us understand where serotonin-resembling psychedelic binding
must occur to result in hallucinations tell a nice, progressive story of the process of science. Please view
the attached presentation to go through these experimental steps. This is a very complex story. To help
you keep track of it as you go, consider filling out this chart.
Activity Five: Reading
ABSTRACT FROM PMID 17270739
Abstracts full article reference : Neuron. 2007 Feb 1;53(3):439-52. Hallucinogens recruit
specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. González-Maeso J, Weisstaub
NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA.