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Hallucinogens & Perception

This tutorial provides an introduction to


basic concepts of neuropharmacology and
a more detailed discussion of the influence
of hallucinogens on perception.

Olivia Carter (2007)

For more tutorials on visual perception visit


viper2go on the Viper website www.viperlib.com
H3CO NH2

H3CO
H3CO

Pharmacology of Perception
Structure in the Brain
Brain & spinal cord Neuron Dendritic spines

~ 100 billion neurons in the brain

~ 0.15 quadrillion synapses in


the cortex
Signalling in the Brain: Neuron
At rest the neuron has a negative charge,
an action potential is triggered when the
- charge becomes sufficiently positive
+ +
- +
+
-
Axon terminal
Signals received

-
+
+
+
+
Signal goes from the
cell body down the axon

Neuron fires (action potential) – All or none….


- single units of activity
Signalling in the Brain: Synapse

Neurons influence each other through


chemical signals (neurotransmitters)
Cycle of Neurotransmitters
1 Synthesis

2 Release from synaptic vesicles


1
3 Binds to receptors 7

4 +/- influence on post synaptic cell 6


5 Broken down by enzymes
2
6 reuptake of transmitter

7 formation & storage in 3


vesicles 5

4 (+ or -)
Drug Action
1

2
1
3 7

4 Drugs can effect 6


all stages
5
2
6

7 3
5

4 (+ or -)
Action at the receptor
1) drugs generally act by mimicking (agonists) or
blocking (antagonists) natural neurotransmitters
2) Specific to receptor subtypes

Natural
Agonist Compound Antagonist

Signal (+ or -) (+ or -)
Receptor specificity
Each neurotransmitter can only act on specific receptors (lock and key)

In reality receptors are not simple “open-shut” gates… They have complex
structures and it is often a small change in their shape that will “open” a
channel, or cause it to “do its thing”.
Summary

-Neurons communicate through neurotransmitter


release at synapses

-The action of neurotransmitters can be altered at


many stages in many different ways.

- Receptors either act as ion channels (gates) or the


cause down stream effects within the neuron
through a “second messenger”
Basic facts about hallucinogens
- Effects: rarely cause full hallucinations but commonly
induce striking perceptual distortions, mystical experiences &
altered sense of self
- Recent history: Albert Hofmann discovered LSD in 1943
& isolated/synthesised psilocybin (“magic mushrooms”) in
1958.
- Mechanism: The exact action of these drugs is not
known. However that the majority of hallucinogens (LSD,
Psilocybin, Mescaline etc) activate the Serotonin 5-HT2A
receptor.

Psilcybe mushrooms Lophophora willimasii


(“Magic” mushrooms) (peyote cactus)
Hallucinogens have striking effects on perception! These drawings, by an
artist under the influence of LSD, illustrate the perceptual changes
experienced over the time course of the drug effects.

Prior to LSD 1h 25min 2h 30min

2h 45min 5h 45min 8h
Hallucinogens also cause illusions of motions. Objects and patterns are often seen
to move, without actually changing location – similar to the sense of motion that
occurs when your eyes move over this pattern (Note that different mechanisms are
likely to be responsible for this illusion and the action of hallucinogens).
Psilocybin (psilocin)
H3C
CH3
N
OH

Psilcybe mushrooms N
(“Magic” mushrooms)
H

Psilocin

Psilocybin in magic mushrooms is


broken down into psilocin when it is
digested. Psilocin is believed to be
the structure that makes you
hallucinate.
Hallucinogens often have structure H3C
similar to serotonin… here are a CH3
H N
H selection of Indoleamine
N
hallucinogens OH
HO

N
H N

They all share a 5 member ring containing H


Serotonin (5-HT) Nitrogen joined to a benzene ring
H3C Psilocin
O
CH3 H5C2
N NC CH3
N
H5C2

N N
H
H

DMT LSD
Serotonin (5-HT)
All 5-HT in the brain comes THALAMUS CORTEX
from the raphe nucleus in
the brainstem, from there it NUCLEUS ACCUMBENS

is sent all over the brain


H
H
N
5-hydroxytryptamene AMYGDALA

HO

HIPPOCAMPUS
N
H CEREBELLAR
CORTEX
RAPHE NUCLEUS
(rostral & dorsal)
Many receptor subtypes:
5-HT1 (A, B, D, E & F)
5-HT2 (A, B, & C)
5-HT3
5-HT4
5-HT5 (A & B) 5-HT is associated with Mood, Sleep, Appetite,
5-HT6? Clinical Psychosis & Hallucinogens!!
5-HT7?
Location of 5-HT2A receptors

5-HT2A receptors are found in a number of specific brain regions


(particularly along cortical-thalamic pathways). However, new research
suggests 5-HT2A receptors in the prefrontal cortex are particularly
relevant in hallucinogen effects.
Location of 5-HT2A Receptors

5-HT2A receptors are found predominantly on the dendrites of layer V


pyramidal cells.
Corticothalamic loops

Cortex

Thalamus

5-HT2A activation disrupts corticothalamic loops, exactly how this happens


is a matter of debate. It was thought that the effect was at the “input” to the
cortex from the thalamus. Now it appears hallucinogens primarily effects
“output” from layer V to thalamus.
Corticothalamic loops & consciousness

Corticothalamic loops are an integral part of many theories


of consciousness… for example,

-Tononi: BMC Neuroscience (2004) 5:42

“The fact that consciousness as we know it is generated by the


thalamocortical system fits well with the information integration
theory.”

- Dehaene: PlosBiology (2005) 3: 0911-27

“we provided a framework of a formal architecture of


thalamocortical areas… which plays a key role in .. “access to
consciousness.”
Not so simple!

Note: most of the recent research was done using


slices of mouse prefrontal cortex.

5-HT2A receptors are also found in other places including:


- Claustrum (the function of this area is unknown but Crick & Koch believe
it is likely to be relevant to consciousness – Crick & Koch (2005) Phil. Trans. R.
Soc. B 360 1271-1279)

- Ventral Striatum

- Hippocampus

- Amygdala
Serotonin and Perception
-- Hallucinogen experiments --
Hallucinogens as a research tool

- Model psychosis: The majority of current research uses


hallucinogens to induce transient psychosis-like episodes
in normal people, to better understand pharmacology of
clinical psychosis and to improve drug development.

- Perceptual pharmacology: Hallucinogens effect sensory


perception, emotions and can induce spiritual
experiences.

- Consciousness: To date, no research has been done in


this area. Hallucinogens and anaesthetics seem to
influence opposite ends of the consciousness spectrum
and seem to act on systems in the brain often discussed
in models of consciousness.
1 example of a Motion perception
experiment using psilocybin.
1st task: Contrast Sensitivity for moving gratings
Trial 1 Trial 30

or or

• 2 alternative forced choice: leftward rightward motion


• Presentation time 300msec
• 3 x 30 trials
1 example of a Motion perception
experiment using psilocybin.

2nd Task: Coherent Motion


Trial 1 Trial 40

or or

• 2 alternative forced choice: leftward rightward motion


• Presentation time 300msec
• 3x 40 trials
Why these motion tasks?
1) Subjective reports
People report increased sensitivity to Contrast sensitivity
brightness, contrast and motion. (local motion)
2) Anatomical/functional dissociation
Cells in V1 are
Parietal Lobe sensitive to Local
Frontal Lobe
motion
MT/V5

Coherent motion
(global motion)
MT seems to be
necessary for
Temporal Lobe V1 coherent motion
Cerebellum detection
3) Clinical
Processing of global, but not local, motion direction is deficient in schizophrenia
- Chen Y, Nakayama K, Levy D, Matthysse S and Holzman P. (2003) Schizophr Res 61:215-227.
Results
Local motion detection Coherent motion
is unaffected detection is impaired

30 30

Coherence Sensitivity
Contrast Sensitivity

20 20
*

10 10

2 2
Pre-test Peak ~ 120min Pre-test Peak ~ 120min

Placebo
Psilocybin
Summary
- High level but not low level motion processing was
impaired.
- In line with Schizophrenia findings.
- Successful transfer of information from retina, LGN to V1

- These results suggest that hallucinogens do not effect


sensitivity to individual motion signals, but instead disrupt
the brains ability to integrate the individual motion signals
in order to generate a percept of a single motion direction.

Future Questions
- If hallucinogens do not change sensitivity to the incoming
sensory information, where does the feeling of increased
sensitivity to contrast, motion & colour come from?
Take Home Message
1) Pharmacology is relevant!
Activity of neurons is crucial, but it is the pattern of activity that
determines our moment to moment state depends on
neurotransmitters.

2) There is remarkable specificity in the action of


hallucinogens.
Many drugs exist that activate many receptors but there is
something special about those that activate the 5-HT2A receptor.

3) Pharmacology is great research tool.


Drugs that alter perception provide a fantastic opportunity to
manipulate network properties of the brain in a systematic way.
References
Huxley, A. (1954) The doors of perception (available to download from the web at
http://www.druglibrary.org/schaffer/lsd/doors.htm) - * a fantastic description of the phenomenology
Carter OL, Pettigrew JD, Burr DC, Alais D, Hasler F, Vollenweider FX (2004) Psilocybin impairs high-level but
not low-level motion perception. Neuroreport 15: 1947-1951 - *A detailed report of the motion experiment
described in the previous slides
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101: 131-81 -*A very detailed review
------------------- (more references) ----------------------
Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5-hydroxytryptamine 2A
receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci U S A
104: 9870-5
Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005a) Using psilocybin to investigate the
relationship between attention, working memory and the Serotonin1A&2A receptors. J Cog Neuroscience
17: 1497-1508
Carter OL, Pettigrew JD, Hasler F, et al (2005b) Modulating the rate and rhythmicity of perceptual rivalry alternations
with the mixed 5-HT2A and 5-HT1A agonist psilocybin. Neuropsychopharmacology 30: 1154-62
Gonzalez-Maeso J, Weisstaub NV, et al (2007) Hallucinogens Recruit Specific Cortical 5-HT(2A) Receptor- Mediated
Signaling Pathways to Affect Behavior. Neuron 53: 439-52
Gouzoulis-Mayfrank E, Hermle L, Thelen B, Sass H (1998) History, rationale and potential of human experimental
hallucinogenic drug research in psychiatry. Pharmacopsychiatry 31 Suppl 2: 63-8
Lambe EK, Aghajanian GK (2007) Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and
D1/D5 dopamine receptor activation. Neuroscience 145: 900-10
DE Presti & DE Nichols. Biochemistry and neuropharmacology of psilocybin mushrooms. In Teonanacatl:Sacred
Mushrooms of Visions (edited by R Metzner). Green Earth Foundation (2004).
Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced
psychoses. Brain Res Bull 56: 495-507
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces
schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9: 3897-902
Weisstaub NV, Zhou M, Lira A, et al (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors
in mice. Science 313: 536-40