Psychotomimetic drugs

Question 1

What are halluncinogens?

Answer 1

a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorized as either being psychedelics, dissociatives, or deliriants

Question 2

what is the active constituent in Ayahuasca?

Answer 2

Harmaline

Question 3

what is the active constituent in peyote?

Answer 3

Mescaline

Question 4

give two examples of hallucinogens that have been used historically in different cultures

Answer 4

Ayahuasca;
Peyote; used by Native Americans in religious ceremonies

Question 5

How does LSD compare to other hallucinogens?

Answer 5

LSD is very potent; it requires a low dose that lasts a long time

where Psilocybin 250ug/kg 3hrs
Mescaline 15ug/kg 12hrs

LSD 3ug/kg 10hrs

so potent it is most likely to act very specifically at receptor sites in the brain (with high affinity)

Question 6

LSD is a derivative of naturally occuring…

Answer 6

…ergot

Question 7

when was LSD first synthesised?

Answer 7

The psychedelic drug (or entheogen) lysergic acid diethylamide (LSD) was first synthesized on November 16, 1938, by the Swiss chemist Albert Hofmann in the Sandoz (now Novartis) laboratories in Basel, Switzerland
It was not until five years later on April 19, 1943, that the psychedelic properties were found.

Question 8

why was LSD first systhesised?

Answer 8

Ergot causes peripheral vasoconstriction, derivatives were sought after for treatment of haemorrhage (specifically control of post-partrum bleeding)

Question 9

what is synaethesia?

Answer 9

synaesthesia is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to involuntary experiences in a second sensory or cognitive pathway
‘when the senses are muddled’

Question 10

there is cross tolerance between LSD and…..

Answer 10

There is cross tolerance between LSD and mescaline

– if you take a drug over a period of time, your brain adapts to the presence of that drug, you wont experience the same effect (tolerance). Partly bcos metabolic effect but also changes in the brain, signalling pathways undergo homeostatic regulation.
If you have an individual tolerant to mescaline but niave to LSD, f they took LSD theyd need a higher dose to get the same effects as a first timer. Indicating they are acting on some of the same receptors
This suggests that both psychotomimetics act at the same class of receptor site

Question 11

what is cross tolerance?

Answer 11

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters.

Question 12

the structure of LSD and mescaline are similar to…

Answer 12

to 5-HT (serotonin)

Question 13

what initially indicated that LSD is a partial agonist of 5HT?

Answer 13

LSD DECREASES LEVELS OF 5-HT METABOLITES WHEN ADMINISTERED TO RATS

Question 14

how does 5HT modulate its own release?

Answer 14

release by binding pre synaptic autoreceptors
(inhibiting release of further 5-HT.)

Question 15

breifly what does LSd do in the brain?

Answer 15

In the brain it acts as a 5-HT receptor agonist/partial agonist - LSD decreases 5-HT turnover in the brain

Question 16

what are modality specific pathways?

Answer 16

specific sensory pathways arising through thalamus and to primary somatosensory cortex

Question 17

what did they first in investigate as the location of LSD altered perception? and why?

Answer 17

raphe nuclei
electrophrysiological recordings of neurons in raphe nuclei

Raphe neurones send extensive projection to the forebrain – well placed to alter interpretation of sensory signalling

Question 18

what does LSD do to neurons in raphe nuclei?

(include the receptor)

Answer 18

LSD decreases firing rate of raphe neurones (5-HT1A receptor)

Question 19

where are the receptors located that LSD binds to?

Answer 19

Autoreceptors
present on the pre synaptic membrane – LSD binds these receptors and it brings down the activity of the neurons

Question 20

what does LSD do to raphe nuclei neurons?

Answer 20

LSD reduces the activity of these neurons due to this activity at the 5HT1A autoreceptors

Question 21

why was it determined that raphe nuclei arent the location of the hallucinogenic effect

Answer 21

If this was the hallucinogenic mechanism then you would expect other hallucinogens to show the same effects
…but investigation of further classes of hallucinogens showed that they did not all exert this effect (e.g. mescaline)
Additional evidence to support this - Lesioning the raphe nucleus in rats: they can still discriminate between saline and LSD

Question 22

how do you know an animal is hallucinating?

Answer 22

The drug discrimination task – administer the animal a vehicle (the control), when given this It learns to press one of two levers to receive a food reward. When given the drug of interest, here LSD, the animal learns to press a particular lever depending on whether they are given saline or LSD

Question 23

electrophysiological studies on locus coeruleus neurons in the presence of LSD showed what results?

Answer 23

LSD increases activity in locus coeruleus neurones
also
LSD increases activity of subsets of neurones in the cortex
This excited interest around the locus coeruleus as the site of action for the hallucinogenic activity of LSD

Question 24

where are 5HT2A receptors located?

Answer 24

5HT2A receptors are present in temporal and prefrontal cortex, striatum, ventral tegmental area, and thalamus

Question 25

locus coeruleus neurons release ____________ projections onto cortical neurons

Answer 25

locus coeruleus neurons release noradrenaline projecting onto cortical neurons,

Question 26

how does the increased activity in locus coeruleus neurons by LSD indicate how hallucinations may come about?

Answer 26

Locus coeruleus neurons release noradrenaline onto cortical and thalamic neurons.
When LSD is present it acts as an agonist on 5-HT2A receptors, some of which are present on the temporal and prefrontal cortex and the thalamus
these receptors are autoreceptors responsible for negative feedback of serotonin release, when LSD is bound, the neurotransmitter release is sustained therefore leading to hyperactivity

Question 27

what type of receptor are 5HT receptors?

Answer 27

All of the 5HT receptors are G protein coupled receptor with the exception of 5HT3 which is a ligand gated ion channel

Question 28

which receptor class do LSD and phenethylamines (mescaline) both interact with?

Answer 28

5HT2A//2C

Question 29

what is the rationale for plotting log1/ki against log1/ed50 of hallucinogenic activity towards 5HT2A/C

Answer 29

if 5-HT2 receptor mediates hallucinogenic action of LSD then most potent hallucinogen should have the highest affinity for 5-HT2 – weakest hallucinogen should have the lowest affinity for 5-HT2

Question 30

what is log1/ki?

Answer 30

the affinity of the drugs to the receptor

Question 31

what is log1/ED50?

Answer 31

the dose of a medication that produces a desired pharmacologic effect in 50% of the studied patient population that takes the medication

Question 32

A good correlation when plotting Log1/Ki – the affinity of the drugs to the receptor 5HT2A by Log1/ED50 – the effective dose in producing a hallucinogenic effect indicated what

Answer 32

evidence that the 5HT2A recptor isoform Is important in mediating the hallucinogenic potential of these drugs

Question 33

which layer of pyrimidal neurons in the cortex does LSd increase activity in?

Answer 33

LSD increases activity of layer V pyramidal neurones in cortex

LSD acts on 5HT2A receptors (as an agonist or partial agonist)
These receptors are highly expressed in cortex: on pyramidal neurones

Question 34

what is phencyclidine (PCP)?

Answer 34

PCP is a ‘dissociative’ anaesthetic
same class as Ketamine
causes a catatonic-like state without muscle relaxation

Question 35

for what was Phencyclidine (PCP) initally used and why was it withdrawn from clinical use?

Answer 35

Introduced as a dissociative anastethic in the 60s but withdrawn from clinical use in 1965 due to ‘emergence phenomenon’
When people came round from the anaesthetic they reported hallucinations and psychosis

Question 36

what were the effects of PCP in controlled studies?

Answer 36

 Alterered body image “my arms and legs feel distant’
 Feeling of isolation
 Cognitive disorganization
 Drowsiness and apathy
 Negativism and/or hostility
 Euphoria and inebriation
 Hypnagogic (dreamlike) states

Question 37

what 2 main classes of receptor does PCP interact with?

which is responsible for its hallucinogenic effects

Answer 37

• sigma opiate receptor- modulates NAdr release, expressed presynaptically on the locus coeruleus neurons. This doesn’t seem to explain its hallucinogenic actions
• PCP is a non-competitive antagonist of the NMDA (glutamate receptor) – this is thought to be the reason for hallucinogenic effects. NMDA is a ligand gated ion channels whose endogenous ligand is glutamate, excitatory channels (cation). PCP blocks the ion channel

Question 38

how did they discover which receptors PCP binds?

Answer 38

Take rat homogenate and incubate it with PCP and you find the class of receptor it binds to
Radioligand binding studies have shown that PCP interacts with 2 main classes of receptor

The evidence for This came from rat studies where they looked at the levels of dopamine and it was found following administration of PCP, dopamine increased. Electrophysiological studies showed that this was a result of an increase of activity of the ventral tegmental area neurons.

VTA =Major part of the brain synthesising dopamine

Question 40

if you were going to investigate what causes synethesia what area of the brain would you look into?

Answer 40

If were interested in understanding how it does this, you would look at raphe nuclei, locus coerulus, thalamus, reticular formation

Question 41

why was the locus ceoruleus investigated for involvmenet in hallucinogenic mechanisms?

Answer 41

these neurons are present in the reticular formation, involved in processing sensory information in the brain.
Located in the midbrain with projections to different limbic regions of the brain and the cortex.

Question 42

the thalamus processes … inputs and receives afferents from the …

Answer 42

the thalamus processes somatosensory inputs and receives afferents from the locus coeruleus

Question 43

give an example of a phenethylamine

Answer 43

mescaline

Question 43

brefily describe a potential mechanism for how LSD brings about its hallucinogenic effects