Psychotomimetic drugs Flashcards
What are halluncinogens?
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
what is the active constituent in Ayahuasca?
Harmaline
what is the active constituent in peyote?
Mescaline
give two examples of hallucinogens that have been used historically in different cultures
Ayahuasca;
Peyote; used by Native Americans in religious ceremonies
How does LSD compare to other hallucinogens?
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)
LSD is a derivative of naturally occuring…
…ergot
when was LSD first synthesised?
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.
why was LSD first systhesised?
Ergot causes peripheral vasoconstriction, derivatives were sought after for treatment of haemorrhage (specifically control of post-partrum bleeding)
what is synaethesia?
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’
there is cross tolerance between LSD and…..
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
what is cross tolerance?
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.
the structure of LSD and mescaline are similar to…
to 5-HT (serotonin)
what initially indicated that LSD is a partial agonist of 5HT?
LSD DECREASES LEVELS OF 5-HT METABOLITES WHEN ADMINISTERED TO RATS
how does 5HT modulate its own release?
release by binding pre synaptic autoreceptors
(inhibiting release of further 5-HT.)
breifly what does LSd do in the brain?
In the brain it acts as a 5-HT receptor agonist/partial agonist - LSD decreases 5-HT turnover in the brain
what are modality specific pathways?
specific sensory pathways arising through thalamus and to primary somatosensory cortex
what did they first in investigate as the location of LSD altered perception? and why?
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
what does LSD do to neurons in raphe nuclei?
(include the receptor)
LSD decreases firing rate of raphe neurones (5-HT1A receptor)
where are the receptors located that LSD binds to?
Autoreceptors
present on the pre synaptic membrane – LSD binds these receptors and it brings down the activity of the neurons
what does LSD do to raphe nuclei neurons?
LSD reduces the activity of these neurons due to this activity at the 5HT1A autoreceptors
why was it determined that raphe nuclei arent the location of the hallucinogenic effect
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
how do you know an animal is hallucinating?
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
electrophysiological studies on locus coeruleus neurons in the presence of LSD showed what results?
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
where are 5HT2A receptors located?
5HT2A receptors are present in temporal and prefrontal cortex, striatum, ventral tegmental area, and thalamus
locus coeruleus neurons release ____________ projections onto cortical neurons
locus coeruleus neurons release noradrenaline projecting onto cortical neurons,
how does the increased activity in locus coeruleus neurons by LSD indicate how hallucinations may come about?
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
what type of receptor are 5HT receptors?
All of the 5HT receptors are G protein coupled receptor with the exception of 5HT3 which is a ligand gated ion channel
which receptor class do LSD and phenethylamines (mescaline) both interact with?
5HT2A//2C
what is the rationale for plotting log1/ki against log1/ed50 of hallucinogenic activity towards 5HT2A/C
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
what is log1/ki?
the affinity of the drugs to the receptor
what is log1/ED50?
the dose of a medication that produces a desired pharmacologic effect in 50% of the studied patient population that takes the medication
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
evidence that the 5HT2A recptor isoform Is important in mediating the hallucinogenic potential of these drugs
which layer of pyrimidal neurons in the cortex does LSd increase activity in?
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
what is phencyclidine (PCP)?
PCP is a ‘dissociative’ anaesthetic
same class as Ketamine
causes a catatonic-like state without muscle relaxation
for what was Phencyclidine (PCP) initally used and why was it withdrawn from clinical use?
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
what were the effects of PCP in controlled studies?
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
what 2 main classes of receptor does PCP interact with?
which is responsible for its hallucinogenic effects
- 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
how did they discover which receptors PCP binds?
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
if you were going to investigate what causes synethesia what area of the brain would you look into?
If were interested in understanding how it does this, you would look at raphe nuclei, locus coerulus, thalamus, reticular formation
why was the locus ceoruleus investigated for involvmenet in hallucinogenic mechanisms?
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.
the thalamus processes … inputs and receives afferents from the …
the thalamus processes somatosensory inputs and receives afferents from the locus coeruleus
give an example of a phenethylamine
mescaline
brefily describe a potential mechanism for how LSD brings about its hallucinogenic effects
