Transcript Hallucinogens & Perception

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
7
3 Binds to receptors
4 +/- influence on post synaptic cell
6
5 Broken down by enzymes
2
6 reuptake of transmitter
7 formation & storage in
vesicles
3
5
4
(+ or -)
Drug Action
1
2
1
7
3
4
5
Drugs can effect
all stages
6
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
Agonist
Signal (+ or -)
Natural
Compound
(+ or -)
Antagonist
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
(“Magic” mushrooms)
Lophophora willimasii
(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
2h 45min
1h 25min
5h 45min
2h 30min
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
N
OH
Psilcybe mushrooms
(“Magic” mushrooms)
N
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.
CH3
H
Hallucinogens often have structure
similar to serotonin… here are a
selection of Indoleamine
hallucinogens
OH
H
N
H3C
N
HO
N
N
H
Serotonin (5-HT)
H
They all share a 5 member ring containing
Nitrogen joined to a benzene ring
H3C
N
CH3
H5C2
Psilocin
O
NC
H5C2
CH3
N
N
N
H
H
DMT
LSD
CH3
Serotonin (5-HT)
All 5-HT in the brain comes
from the raphe nucleus in
the brainstem, from there it
is sent all over the brain
H
N
THALAMUS
CORTEX
NUCLEUS ACCUMBENS
H
5-hydroxytryptamene
AMYGDALA
HO
HIPPOCAMPUS
N
H
Many receptor subtypes:
5-HT1 (A, B, D, E & F)
5-HT2 (A, B, & C)
5-HT3
5-HT4
5-HT5 (A & B)
5-HT6?
5-HT7?
RAPHE NUCLEUS
(rostral & dorsal)
CEREBELLAR
CORTEX
5-HT is associated with Mood, Sleep, Appetite,
Clinical Psychosis & Hallucinogens!!
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.
Cortex
Corticothalamic loops
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
• Presentation time 300msec
• 3 x 30 trials
rightward
motion
1 example of a Motion perception
experiment using psilocybin.
Trial 1
2nd Task: Coherent Motion
or
• 2 alternative forced choice: leftward
• Presentation time 300msec
• 3x 40 trials
Trial 40
or
rightward
motion
Why these motion tasks?
1) Subjective reports
People report increased sensitivity to
brightness, contrast and motion.
Contrast sensitivity
(local motion)
2) Anatomical/functional dissociation
Parietal Lobe
Frontal Lobe
MT/V5
Cells in V1 are
sensitive to Local
motion
Coherent motion
(global motion)
Temporal Lobe
V1
Cerebellum
MT seems to be
necessary for
coherent motion
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
Coherent motion
detection is impaired
Local motion detection
is unaffected
30
Coherence Sensitivity
Contrast Sensitivity
30
20
10
2
20
*
10
2
Pre-test
Pre-test
Peak ~ 120min
Placebo
Psilocybin
Peak ~ 120min
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