Hallucinogens & PerceptionHallucinogens & PerceptionThis tutorial provides an introduction to This tutorial provides an introduction to

basic concepts of neuropharmacology and basic concepts of neuropharmacology and a more detailed discussion of the influence a more detailed discussion of the influence

of hallucinogens on perception.of hallucinogens on perception.

For more tutorials on visual perception visitFor more tutorials on visual perception visitviper2go on the Viper website viper2go on the Viper website www.viperlib.comwww.viperlib.com

Olivia Carter (2007)

H3CO NH2

H3CO

H3CO

Pharmacology ofPharmacology of PerceptionPerception

Structure in the BrainStructure in the Brain

~ 100 billion neurons in the brain~ 100 billion neurons in the brain

~ 0.15 quadrillion synapses in ~ 0.15 quadrillion synapses in the cortexthe cortex

Brain & spinal cord Neuron Dendritic spines

Signalling in the Brain: NeuronSignalling in the Brain: Neuron

Signal goes from the Signal goes from the cell body down the axoncell body down the axon

Neuron fires (action potential) Neuron fires (action potential) –– All or noneAll or none……..-- single units of activity single units of activity

Signals receivedSignals received

++

++

-

-

-

-

+

+ +

+

Axon terminal

At rest the neuron has a negative charge, At rest the neuron has a negative charge, an action potential is triggered when the an action potential is triggered when the charge becomes sufficiently positivecharge becomes sufficiently positive

Signalling in the Brain: SynapseSignalling in the Brain: Synapse

Neurons influence each other through Neurons influence each other through chemical signals (neurotransmitters)chemical signals (neurotransmitters)

11 SynthesisSynthesis

22 Release from synaptic vesiclesRelease from synaptic vesicles

33 Binds to receptorsBinds to receptors

44 +/+/-- influence on post synaptic cellinfluence on post synaptic cell

55 Broken down by enzymesBroken down by enzymes

66 reuptake of transmitterreuptake of transmitter

77 formation & storage in formation & storage in vesicles vesicles

Cycle of NeurotransmittersCycle of Neurotransmitters

22

33

44 (+ or -)

55

66

7711

11

22

33

44

55

66

77

Drug ActionDrug Action

Drugs can effect Drugs can effect all stagesall stages

22

33

44 (+ or -)

55

66

7711

Action at the receptorAction at the receptor

1) drugs generally act by mimicking (agonists) or 1) drugs generally act by mimicking (agonists) or blocking (antagonists) natural neurotransmittersblocking (antagonists) natural neurotransmitters

2) Specific to receptor subtypes2) Specific to receptor subtypes

AgonistAgonistNaturalNatural

CompoundCompound AntagonistAntagonist

(+ or -) (+ or -)Signal

Receptor specificityReceptor specificityEach neurotransmitter can only act on specific receptors (lock aEach neurotransmitter can only act on specific receptors (lock and key)nd key)

In reality receptors are not simple In reality receptors are not simple ““openopen--shutshut”” gatesgates…… They have complex They have complex structures and it is often a small change in their shape that wistructures and it is often a small change in their shape that will ll ““openopen”” a a channel, or cause it to channel, or cause it to ““do its thingdo its thing””. .

SummarySummary

-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”

-- Recent history:Recent history: Albert Hofmann discovered LSD in 1943 Albert Hofmann discovered LSD in 1943 & isolated/synthesised psilocybin (& isolated/synthesised psilocybin (““magic mushroomsmagic mushrooms””) in ) in 1958.1958.

-- Mechanism:Mechanism: The exact action of these drugs is not The exact action of these drugs is not knowknown. However that the majority of hallucinogens (LSD, n. However that the majority of hallucinogens (LSD, Psilocybin, Mescaline etc) Psilocybin, Mescaline etc) activate theactivate the Serotonin 5Serotonin 5--HTHT2A2Areceptor. receptor.

PsilcybePsilcybe mushroomsmushrooms(“Magic” mushrooms)

Lophophora Lophophora willimasiiwillimasii(peyote cactus)

Basic facts about hallucinogensBasic facts about hallucinogens-- Effects:Effects: rarely cause full hallucinations but commonly rarely cause full hallucinations but commonly induce striking perceptual distortions, mystical experiences & induce striking perceptual distortions, mystical experiences & altered sense of selfaltered sense of self

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 pattHallucinogens also cause illusions of motions. Objects and patterns are often seen erns are often seen to move, without actually changing location to move, without actually changing location –– similar to the sense of motion that similar to the sense of motion that occurs when your eyes move over this pattern (occurs when your eyes move over this pattern (Note Note that different mechanisms are that different mechanisms are likely to be responsible for this illusion and the action of hallikely to be responsible for this illusion and the action of hallucinogens). lucinogens).

OH

N

H

NCH3

H3C

PsilocinPsilocin

PsilcybePsilcybe mushroomsmushrooms(“Magic” mushrooms)

Psilocybin in magic mushrooms is broken down into psilocin when it is digested. Psilocin is believed to be the structure that makes you hallucinate.

Psilocybin (psilocin)Psilocybin (psilocin)

OH

N

H

NCH3

H3C

PsilocinPsilocin

HO

NH

NH

H

Serotonin (5Serotonin (5--HT)HT)

N

H

NCH3NC

OH5C2

H5C2

LSDLSD

N

H

NCH3

H3C

DMTDMT

They all share a 5 member ring containing They all share a 5 member ring containing Nitrogen joined to a benzene ringNitrogen joined to a benzene ring

Hallucinogens often have structure Hallucinogens often have structure similar to similar to serotoninserotonin…… here are a here are a

selection of selection of IndoleamineIndoleaminehallucinogenshallucinogens

Many receptor subtypes:Many receptor subtypes:55--HT1 (A, B, D, E & F)HT1 (A, B, D, E & F)55--HT2 HT2 (A, B, & C)(A, B, & C)55--HT3HT355--HT4HT455--HT5 (A & B) HT5 (A & B) 55--HT6? HT6? 55--HT7?HT7?

THALAMUSTHALAMUS

RAPHE NUCLEUSRAPHE NUCLEUS(rostral & dorsal)(rostral & dorsal)

AMYGDALAAMYGDALA

HIPPOCAMPUSHIPPOCAMPUS

CORTEXCORTEX

NUCLEUS ACCUMBENSNUCLEUS ACCUMBENS

CEREBELLAR CEREBELLAR CORTEXCORTEX

55--HT is associated with Mood, Sleep, Appetite, HT is associated with Mood, Sleep, Appetite, Clinical Psychosis & Clinical Psychosis & Hallucinogens!!Hallucinogens!!

AllAll 55--HT in the brain comes HT in the brain comes from the raphe nucleus in from the raphe nucleus in the brainstem, from there it the brainstem, from there it is sent all over the brainis sent all over the brain

HO

N

H

NH

H

Serotonin (5Serotonin (5--HT)HT)

55--hydroxytryptamenehydroxytryptamene

55--HTHT2A2A receptors are found in a number of specific brain regions receptors are found in a number of specific brain regions (particularly along cortical(particularly along cortical--thalamic pathways). However, new research thalamic pathways). However, new research suggests 5suggests 5--HTHT2A2A receptors in the prefrontal cortex are particularly receptors in the prefrontal cortex are particularly relevant in hallucinogen effects.relevant in hallucinogen effects.

Location of 5Location of 5--HTHT2A2A receptorsreceptors

Location of 5Location of 5--HTHT2A2A ReceptorsReceptors

55--HTHT2A2A receptors are found predominantly on the dendrites of layer V receptors are found predominantly on the dendrites of layer V pyramidal cells. pyramidal cells.

Corticothalamic loopsCorticothalamic loops

ThalamusThalamus

Cor

tex

Cor

tex

55--HTHT2A2A activation disrupts corticothalamic loops, exactly how this hapactivation disrupts corticothalamic loops, exactly how this happens pens is a matter of debate. It was thought that the effect was at theis a matter of debate. It was thought that the effect was at the ““inputinput”” to the to the cortex from the thalamus. Now it appears hallucinogens primarilycortex from the thalamus. Now it appears hallucinogens primarily effects effects ““outputoutput”” from layer V to thalamus. from layer V to thalamus.

Corticothalamic loops & consciousnessCorticothalamic loops & consciousness

Corticothalamic loops are an integral part of many theories Corticothalamic loops are an integral part of many theories of consciousnessof consciousness…… for example, for example,

--TononiTononi:: BMC Neuroscience (2004) 5:42BMC Neuroscience (2004) 5:42

““The fact that consciousness as we know it is generated by the The fact that consciousness as we know it is generated by the thalamocortical system fits well with the information integratiothalamocortical system fits well with the information integration n theory.theory.””

-- DehaeneDehaene:: PlosBiologyPlosBiology (2005) 3: 0911(2005) 3: 0911--2727

““we provided a framework of a formal architecture of we provided a framework of a formal architecture of thalamocortical areasthalamocortical areas…… which plays a key role in .. which plays a key role in .. ““access to access to consciousness.consciousness.””

Note:Note: most of the recent research was done using most of the recent research was done using slices of mouse prefrontal cortex.slices of mouse prefrontal cortex.

55--HTHT2A2A receptors are also found in other places including:receptors are also found in other places including:

-- Claustrum Claustrum (the function of this area is unknown but Crick & Koch believe (the function of this area is unknown but Crick & Koch believe it is likely to be relevant to consciousness it is likely to be relevant to consciousness –– Crick & Koch (2005) Crick & Koch (2005) Phil. Trans. R. Phil. Trans. R. Soc. BSoc. B 360360 12711271--12791279))

-- Ventral StriatumVentral Striatum

-- HippocampusHippocampus

-- AmygdalaAmygdala

Not so simple!Not so simple!

Serotonin and PerceptionSerotonin and Perception---- Hallucinogen experiments Hallucinogen experiments ----

Hallucinogens as a research toolHallucinogens as a research tool

-- Model psychosis:Model psychosis: The majority of current research uses The majority of current research uses hallucinogens to induce transient psychosishallucinogens to induce transient psychosis--like episodes like episodes in normal people, to better understand pharmacology of in normal people, to better understand pharmacology of clinical psychosis and to improve drug development. clinical psychosis and to improve drug development.

-- Perceptual pharmacology:Perceptual pharmacology: Hallucinogens effect sensory Hallucinogens effect sensory perception, emotions and can induce spiritual perception, emotions and can induce spiritual experiences.experiences.

-- Consciousness:Consciousness: To date, no research has been done in To date, no research has been done in this area. Hallucinogens and anaesthetics seem to this area. Hallucinogens and anaesthetics seem to influence opposite ends of the consciousness spectrum influence opposite ends of the consciousness spectrum and seem to act on systems in the brain often discussed and seem to act on systems in the brain often discussed in models of consciousness. in models of consciousness.

1 example of a Motion perception experiment using psilocybin.

•• 2 alternative forced choice: leftward rightward 2 alternative forced choice: leftward rightward motion motion •• Presentation time 300msecPresentation time 300msec•• 3 x 30 trials 3 x 30 trials

Trial 1Trial 1 Trial 30Trial 30

oror

1st task: Contrast Sensitivity for moving gratings1st task: Contrast Sensitivity for moving gratings

22ndnd Task: Coherent MotionTask: Coherent MotionTrial 1Trial 1 Trial 40Trial 40

or or

•• 2 alternative forced choice: leftward rightward 2 alternative forced choice: leftward rightward motion motion •• Presentation time 300msecPresentation time 300msec•• 3x 40 trials3x 40 trials

1 example of a Motion perception experiment using psilocybin.

Contrast sensitivityContrast sensitivity(local motion)(local motion)

Coherent motion(global motion)

V1

Frontal Lobe

Temporal LobeCerebellum

MT/V5

Parietal Lobe

Processing of global, but not local, motion direction is deficieProcessing of global, but not local, motion direction is deficient in schizophreniant in schizophrenia-- Chen Y, Nakayama K, Levy D, Chen Y, Nakayama K, Levy D, MatthysseMatthysse S and S and HolzmanHolzman P. (2003) P. (2003) SchizophrSchizophr ResRes 6161:215:215--227.227.

3) Clinical3) Clinical

2) Anatomical/functional dissociation2) Anatomical/functional dissociation

1) Subjective reports 1) Subjective reports People report increased sensitivity to People report increased sensitivity to brightness, contrast and motion.brightness, contrast and motion.

Why these motion tasks?Why these motion tasks?

Cells in V1 are Cells in V1 are sensitive to Local sensitive to Local

motionmotion

MT seems to be MT seems to be necessary for necessary for

coherent motion coherent motion detectiondetection

PsilocybinPlacebo

Con

tras

t Sen

sitiv

ityC

ontr

ast S

ensi

tivity

PrePre--test test Peak ~ 120min Peak ~ 120min 2 2

10 10

20 20

30 30

2 2 Peak ~ 120min Peak ~ 120min

Coh

eren

ce S

ensi

tivity

Coh

eren

ce S

ensi

tivity

PrePre--test test

10 10

20 20

30 30

*

ResultsResults

Local motion detection Local motion detection is is unaffectedunaffected

Coherent motion Coherent motion detection is detection is impairedimpaired

-- High level but not low level motion processing was High level but not low level motion processing was impaired.impaired.

-- In line with Schizophrenia findings.In line with Schizophrenia findings.-- Successful transfer of information from retina, LGN to V1Successful transfer of information from retina, LGN to V1

-- These results suggest that hallucinogens do not effect These results suggest that hallucinogens do not effect sensitivity to individual motion signals, but instead disrupt sensitivity to individual motion signals, but instead disrupt the brains ability to integrate the individual motion signals the brains ability to integrate the individual motion signals in order to generate a percept of a single motion direction. in order to generate a percept of a single motion direction.

Future QuestionsFuture Questions-- If hallucinogens do not change sensitivity to the incoming If hallucinogens do not change sensitivity to the incoming sensory information, where does the feeling of increased sensory information, where does the feeling of increased sensitivity to contrast, motion & colour come from? sensitivity to contrast, motion & colour come from?

SummarySummary

Take Home MessageTake Home Message

1)1) Pharmacology is relevant!Pharmacology is relevant!Activity of neurons is crucial, but it is the pattern of activitActivity of neurons is crucial, but it is the pattern of activity that y that determines our moment to moment state depends on determines our moment to moment state depends on neurotransmitters. neurotransmitters.

2) There is remarkable specificity in the action of 2) There is remarkable specificity in the action of hallucinogens.hallucinogens.Many drugs exist that activate many receptors but there is Many drugs exist that activate many receptors but there is something special about those that activate the 5something special about those that activate the 5--HTHT2A2A receptor. receptor.

3) Pharmacology is great research tool.3) Pharmacology is great research tool.Drugs that alter perception provide a fantastic opportunity to Drugs that alter perception provide a fantastic opportunity to manipulate network properties of the brain in a systematic way. manipulate network properties of the brain in a systematic way.

Huxley, A. (1954) The doors of perception (available to downloadHuxley, A. (1954) The doors of perception (available to download from the web at from the web at http://www.druglibrary.org/schaffer/lsd/doors.htmhttp://www.druglibrary.org/schaffer/lsd/doors.htm) ) -- * a fantastic description of the phenomenology* a fantastic description of the phenomenology

Carter OL, Pettigrew JD, Burr DC, Carter OL, Pettigrew JD, Burr DC, AlaisAlais D, D, HaslerHasler F, F, VollenweiderVollenweider FX (2004) Psilocybin impairs highFX (2004) Psilocybin impairs high--level but level but not lownot low--level motion perception. level motion perception. NeuroreportNeuroreport 15: 194715: 1947--19511951 -- *A detailed report of the motion *A detailed report of the motion experiment experiment described in the previous slidesdescribed in the previous slides

Nichols DE (2004) Hallucinogens. Nichols DE (2004) Hallucinogens. PharmacolPharmacol TherTher 101: 131101: 131--81 81 --*A very detailed review*A very detailed review

-------------------------------------- (more references) (more references) --------------------------------------------BeiqueBeique JC, JC, ImadImad M, M, MladenovicMladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5L, Gingrich JA, Andrade R (2007) Mechanism of the 5--hydroxytryptamine 2A hydroxytryptamine 2A

receptorreceptor--mediated facilitation of synaptic activity in prefrontal cortex.mediated facilitation of synaptic activity in prefrontal cortex. Proc Proc NatlNatl AcadAcad SciSci U S A U S A 104: 9870104: 9870--55

Carter OL, Burr DC, Pettigrew JD, Wallis GM, Carter OL, Burr DC, Pettigrew JD, Wallis GM, HaslerHasler F, F, VollenweiderVollenweider FX (2005a) Using psilocybin to investigate the FX (2005a) Using psilocybin to investigate the relationship between attention, working memory and the Serotoninrelationship between attention, working memory and the Serotonin1A&2A receptors. 1A&2A receptors. J Cog NeuroscienceJ Cog Neuroscience17: 149717: 1497--15081508

Carter OL, Pettigrew JD, Carter OL, Pettigrew JD, HaslerHasler F, et al (2005b) Modulating the rate and F, et al (2005b) Modulating the rate and rhythmicityrhythmicity of perceptual rivalry alternations of perceptual rivalry alternations with the mixed 5with the mixed 5--HT2A and 5HT2A and 5--HT1A agonist psilocybin. HT1A agonist psilocybin. NeuropsychopharmacologyNeuropsychopharmacology 30: 115430: 1154--6262

GonzalezGonzalez--MaesoMaeso J, J, WeisstaubWeisstaub NV, et al (2007) Hallucinogens Recruit Specific Cortical 5NV, et al (2007) Hallucinogens Recruit Specific Cortical 5--HT(2A) ReceptorHT(2A) Receptor-- Mediated Mediated Signaling Pathways to Affect Behavior.Signaling Pathways to Affect Behavior. NeuronNeuron 53: 43953: 439--5252

GouzoulisGouzoulis--MayfrankMayfrank E, E, HermleHermle L, L, ThelenThelen B, Sass H (1998) History, rationale and potential of human expeB, Sass H (1998) History, rationale and potential of human experimental rimental hallucinogenic drug research in psychiatry. hallucinogenic drug research in psychiatry. PharmacopsychiatryPharmacopsychiatry 31 31 SupplSuppl 2: 632: 63--88

LambeLambe EK, EK, AghajanianAghajanian GK (2007) Prefrontal cortical network activity: Opposite effectGK (2007) Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and s of psychedelic hallucinogens and D1/D5 dopamine receptor activation. D1/D5 dopamine receptor activation. Neuroscience Neuroscience 145: 900145: 900--1010

DE DE PrestiPresti & DE Nichols. Biochemistry and & DE Nichols. Biochemistry and neuropharmacologyneuropharmacology of psilocybin mushrooms. In of psilocybin mushrooms. In Teonanacatl:SacredTeonanacatl:SacredMushrooms of VisionsMushrooms of Visions (edited by R (edited by R MetznerMetzner). Green Earth Foundation (2004). ). Green Earth Foundation (2004).

VollenweiderVollenweider FX, Geyer MA (2001) A systems model of altered consciousness: iFX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drugntegrating natural and drug--induced induced psychoses. psychoses. Brain Brain ResRes BullBull 56: 49556: 495--507507

VollenweiderVollenweider FX, FX, VollenweiderVollenweider--ScherpenhuyzenScherpenhuyzen MF, MF, BablerBabler A, Vogel H, Hell D (1998) Psilocybin induces A, Vogel H, Hell D (1998) Psilocybin induces schizophreniaschizophrenia--like psychosis in humans via a serotoninlike psychosis in humans via a serotonin--2 agonist action. 2 agonist action. NeuroreportNeuroreport 9: 38979: 3897--902902

WeisstaubWeisstaub NV, Zhou M, Lira A, et al (2006) Cortical 5NV, Zhou M, Lira A, et al (2006) Cortical 5--HT2A receptor signaling modulates anxietyHT2A receptor signaling modulates anxiety--like behaviors like behaviors in mice. in mice. Science Science 313: 536313: 536--4040

ReferencesReferences