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Molecular Neuroscience III > 4 - Hallucinogens > Flashcards

4 - Hallucinogens Flashcards

1
Q

Why is alcohol considered to some to be the most harmful hallucinogen?

A

Because it has a very high risk for doing risk to others

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2
Q

What did Albert Hofmann synthesize LSD from?

A

ergotamine, which is an alkaloid produced by fungus that grows on grain

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3
Q

Many hallucinogens share a similar structure to what neurotransmitter?

A

5-HT

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4
Q

5-HT2A can induce psychadelic effects by acting on ____ cells in the _____ (part of the brain)

A

Pyramidal neurons in the prefrontal cortex

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5
Q

LSD is involved in the activation of what two G protein-coupled receptors?

A
  • All dopamine receptor subtypes
  • All Adrenoreceptor subtypes
  • Serotonin 52a receptor activates phospholipase A2 (instead of PLC)
  • And other serotonergic receptors
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6
Q

How can hallucinogens be used to treat alcoholism?

A

The delirium effects of these drugs may be enough to develop an aversion to alcohol. However, clinical trials yield unclear results.

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7
Q

How harmful are hallucinogens?

A

According to criteria set by a team of UK experts, the hallucinogenic drugs (Mushrooms, LSD, Ketamine) belong to a group of low harm risk whereas alcohol, heroin and crack are on the other, high risk, end of the scale.

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8
Q

List some common hallucinogens and the systems they work on

A
  • 5-HT agonism
  • cannabinoid agonism (i.e., D9- tetrahydro-cannabinol),
  • NMDA antagonism (i.e., phencyclidine, ketamine),
  • muscarinic receptor antagonism (i.e., scopolamine),
  • k opioid agonism (i.e., salvinorin A),
  • mixed action monoamine release (i.e., 3,4-methylenedioxmethamphe- tamine [MDMA]), and more.
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9
Q

Describe the effects of LSD, which are similar to other hallucinogens.

A

LSD’s effects typically begin within 30 to 90 minutes of ingestion and may last as long as 12 hours. Users refer to LSD and other hallucinogenic experiences as “trips” and to the acute adverse experiences as “bad trips.” Although most LSD trips include both pleasant and unpleasant aspects, the drug’s effects are unpredictable and may vary with the amount ingested and the user’s personality, mood, expectations, and surroundings. LSD also has dramatic effects on the senses. Colors, smells, sounds, and other sensations seem highly intensified. In some cases, sensory perceptions may blend in a phenomenon known as synesthesia, in which a person seems to hear or feel colors and see sounds etc.

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10
Q

Describe (broadly) the chemical structure of hallucinogens

A
  • Many hallucinogens share structural similarity with neurotransmitter 5-HT.
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11
Q

What are two main categories of hallucinogens that act via serotonergic receptors?

A

Hallucinogens that act via serotonergic receptors activation can be classified into two main categories: tryptamines (eg. psylocibin, LSD) and phenethylamines (eg. mescaline). All are agonists of the 5-HT2A receptors.

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12
Q

What has to happen to psilocybin for it to be active?

A

Psilocybin is inactive; it has to be metabolized in the user body by alkaline phosphatases that cleave phosporyl esther, to hydroxy compound – psilocin.

Psilocybin is orally active, with effective doses in the range of 6–20 mg. The onset of action is typically 20–30 min, with the effects completely gone within about 4–6 hr.

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13
Q

Describe the biosynthesis of mescaline in peyote cactus.

How potent is mescaline?

A

Mescaline is synthesized from L-tyrosine in peyote cactus (Lophophora williamsii) and also in some other cacti species.

Peyote cactus is harvested by “peyoteros” for sale to the Native American Church.

Mescaline is about 1,000–3,000 times less potent than LSD and about 30 times less potent than psilocybin.

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14
Q

How is the effect of hallucinogens unpredictable? How does this create issues in conducting research?

A
  • The effects are usually unpredictable and depend on the expectations of the user (‘‘set’’) and the environment (‘‘setting’’) in which the use takes place. Volunteers given LSD in a clinical settings and warned that they might experience schizophrenia-like symptoms indeed often did suffer panic, anxiety, negative effects, and feelings of insanity. The effect is highly dependent on the personality of the drug taker.
  • The unpredictability of an effect makes clinical research with LSD and other hallucinogens a real challenge. The bad “trips” make also difficult to find volunteers for clinical studies.
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15
Q

True or false? The use of hallucinogens is declining

A

The use of hallucinogens was popular among high-school students however in the last years this behavior has been constantly declining.

The motivation for taking hallucinogens is usually not connected with reward but rather with curiosity and “self-discovery”

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16
Q

What is psilocybin a precursor of? How does its effects compare to ketamine?

A

Psylocybin (precursor of psilocin an 5-HT2A agonist and ketamine (an NMDA receptor antagonist) dose-dependently induce an overlapping altered states of consciousness. Psilocybin effects are stronger within the perceptual alterations whereas ketamine more affects the control and cognition.

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17
Q

How must DMT and MDMT administered for their hallucinogenic properties?

A

The simple tryptamines DMT and 5-MeO-DMT are not active orally but are typically smoked or nasally insufflated. The duration of action for these simple tryptamines is very short, with the effects typically dissipated in less than 1 hr for DMT and 20–30 min for 5-MeO-DMT. The dose of DMT is typically 60– 100 mg of the free base and 6–20 mg for 5-MeO-DMT.

18
Q

What is the most active and least active hallucinogens?

A
  • LSD (tartrate) is “per os” active and is the most potent of all the hallucinogens, with doses ranging from 0.05 to 0.20 mg. LSD is also very long acting, with effects that can last as long as 10–12 hr.
  • Mescaline is orally active but is the least potent of all the classical hallucinogens. Mescaline is also a long-acting compound, with effects that can last up to 10–12 hr. Effective doses of the sulfate salt are in the 200–400 mg range.
19
Q

Describe hallucinogen toxicity and addiction

A
  • Hallucinogens produce altered states of consciousness, but at doses that are not toxic to mammalian organ systems.
  • In contrast to many other abused drugs, hallucinogens do not induce drug dependence or addiction and are not considered to be reinforcing substances.
  • There is no literature report of successful training animals to self-administer classical hallucinogens, indicating that these substances do not possess the necessary pharmacology to either initiate or maintain dependence.
20
Q

Why are hallucinogens not usually addicting?

A

Nearly all hallucinogens lack affinity either for DA receptors or for the DA uptake transporter and therefore do not directly affect DA neurotransmission.

21
Q

What are three pathologies associated with hallucinogens?

A
  • Flashbacks (can persist for months after use)
  • Accidents (eg. staring at the sun, retina damage)
  • Psychosis (can lead to depression, suicide)
22
Q

What receptors do hallucinogens activate ‘to cause their effects?’

A

5-HT2a receptors

They also activate 5-HT2c receptors, but effects were blocked with 5-HT2a antagonists

23
Q

How do people accumulate tolerance to hallucinogens?

A

It was observed development of rapid tolerance to hallucinogens, which correlated with down-regulation of the 5-HT2A receptor.

24
Q

Where is the highest density of 5-HT2a receptors found in the brain?

A

Cortical pyramidal neurons

25
Q

Which G protein are 5-HT2a receptors coupled to? What does activation of 5-HT2a receptor lead to?

A

Gαq

Stimulation by hallucinogens (and other things) leads to stimulation of phospholipase A2.

26
Q

Why do hallucinogens induce effects very similar to that observed in psychosis?

A

There is a lot of evidences for a decrease in the density of cortical 5-HT2A receptors in schizophrenia, an effect that is particularly visible in the dorsolateral PFC.

27
Q

What is a specific indicator of 5-HT2a mediated response from hallucinogens?

How is this an especially good marker for hallucinogens?

A

A ‘head twitch’ behaviour

  • A rapid rotational jerk of the head, which can be easily distinguished from species grooming or scratching behaviours.
  • Several previous studies have established that direct and indirect 5-HT agonists induce this effect, and that 5-HT2 receptor antagonists selectively block the head twitch. The potency with which antagonists attenuate the head twitch response is highly correlated with the antagonist’s affinity for 5-HT2A receptors.

The non-hallucinogenic agonists of 5-HT2A do not induce head twitch.

28
Q

What is a selective behavioural model for 5-HT2a agonist activity in the rodent.

A

The drug-elicited head twitch response

29
Q

Which layer of the anterior cortex are most involved in the actions of hallucinogens?

A

Densest 5-HT2A receptor band is localized to either layer IV and to layer V of pyramidal cells of anterior cortex.

30
Q

How do 5-HT2a agonists differ in their action on the somatosensory cortex?

What does this indicate for designing medicines?

A

5- HT2A agonists induce different patterns of cellular signaling.

  • DOI and lysergic acid diethylamide LSD induce expression of genes egr-1, egr-2 (transcriptional regulators) and period-1 (circadian rhythm
  • Whereas non hallucinogenic lisuride hydrogen maleate (LHM) does not affect expression of these genes
  • Three genes, c-fos, N-10 (nuclear receptor), and I- kBa (inhibitor of NF-κB, which is a transcription factor involved in immune response), showed a similar modulation by all three agonists.
  • The results indicate possibility to design medicines, which will specifically interact with molecular target (eg. 5-HT2A or other GPCRs) to precisely control the specific signal transduction cascade and in consequence the cell response.
31
Q

Describe 5-HT2a signalling and modulation of gene transcription factors in cortical neurons. (3)

A
  • Both hallucinogenic LSD and non-hallucinogenic R-Lisuride increase expression of early gene transcription factor c-fos.
  • LSD increase also expression of early growth response protein 2 (egr-2)
  • R-Lisuride does not affect egr-2 expression.
32
Q

What are the differential effects of hallucinogenic and non-hallucinogenic 5-HT2a agonists caused by (molecular cause). This accounts for the effects of one being inhibited by pertussin toxin (PTX) and not the other.

A

LSD but not R-Lisuride stimulate egr-1-2 in many cortical areas. egr-1 is an early growth response protein 1 (former Zif268). The effect of LSD but not R-Lisuride is inhibited by pertussin toxin (PTX) which indicate involvement of Gi/o protein in the
mechanism of action of this hallucinogen.

33
Q

Describe agonist induced internalization of 5-HT2a receptors

A

In controls both 5-HT and DOI induce 5-HT2A receptors internalization. The process of internalization of 5-HT2A persists in arrestins knockout after DOI but not 5-HT which indicates that hallucinogenic DOI mediates receptor internalization in independent
from b-arrestins manner. Similar effects of hallucinogens were observed in mice
(controls and arrestins-KO) primary cortical neuronal cultures.

May explain tolerance.

34
Q

Describe G protein and β-arrestin-mediated hallucinogenic signaling (3 models)

How is this relevant for drug design?

A

Our understanding of GPCRs signalling undergoes constant evolution.

  • In a classical model (a) the G proteins mediate signal transduction and b-arrestins mediate desensitization and internalization of receptor.
  • Later the (b) model was proposed where b-arrestins act also as multifunctional adaptor proteins interacting with variety of kinases.
  • More recently some research data suggest also the (c) model with biased agonism, in which some compounds acting on GPCRs can stimulate b-arrestin without inducing G protein signalling.
  • It has been also found that some substances can act on GPCRs and activate signalling cascade without involvement of b-arrestins

The presence of a range of differently regulated mechanisms connected to GPCRs opens the possibility to design a new generation of drugs that each will trigger very precisely a singular receptor signalling pathway to obtain variety of effects upon acting on the same receptor.

35
Q

5-HT2A and a1b-adrenergic receptors interact with opiates and psychostimulants. Describe how D-amphetamine or morphine can increase locomotion, and how this can be blocked.

How is a1b receptor deficiency compensated in mice

A
  • D-amphetamine or morphine-induced dopamine release in the striatum can increase locomotion
  • This can be completely blocked by either prazosin, an a1b-adrenergic blocker, or SR46349B, a 5-HT2A receptor antagonist.
  • In a1b receptor-deficient mice the lack of adrenergic component in this pathway is most probably compensated by increased 5-HT2AR signalling.
36
Q

What is psilocybin’s effects on the human brain, observed ‘in vivo?’

What does this effect suggest for psilocybin as a treatment?

A
  • Psilocybin (2 mg i.v.) in healthy volunteers surprisingly decreases brain activity and connectivity in the hub regions, such as the thalamus and anterior/posterior cingulate cortex and also in the medial prefrontal cortex.
  • The activation of medial prefrontal cortex is observed in depression therefore authors suggest possibility of use of psilocybin to treat depression.
37
Q

How are psilocybin effects inconsistent? (3)

A
  • Brain imaging studies using 18fluorodeoxyglucose [18FDG] positron emission tomography (shows changes in the cerebral metabolism of glucose) revealed that moderate doses of s-ketamine and psilocybin in healthy volunteers increased neuronal activity in the prefrontal cortex and associated limbic regions and in subcortical structures, including the thalamus
  • [18FDG] PeT brain imaging studies have demonstrated that the intensity of altered states of consciousness is correlated with drug-induced activation of a prefrontal– parietal network and the deactivation of a striato–limbic amygdalocentric network
  • The discrepancies between observed de-activation and increase of brain activity may be a result of different methods used for measuring brain activity but also may be a consequence of different drug doses, “set and setting” and
    the choosing of participant in these studies.
38
Q

How does stress alter the response to hallucinogens?

A
  • Stress stimulates response to 5-HT and specific 5-HT2a agonists in the PFC
  • Stimulation of CRFR1 (Corticotropin releasing factor receptor 1) increased 5-HT2R surface expression by inducing rapid recycling of 5-HT2R-containing endosomes
39
Q

What is salvinorin A from Salvia divinorum? (4)

A
  • Salvinorin A is a non-alkaloidal hallucinogen,
  • It does not act via 5-HT2A receptors stimulation, but the k opioid receptor selective agonist.
  • It has antinociceptive effects in mice, and this action is not present in k opioid knockout.
  • In animal models, KO induces depressive-like behaviors.
40
Q

What is the legal status of Salvinorin A in Canada?

A

As of February 2011, Health Canada has not authorized for sale any natural health products which contain S. divinorum as an ingredient.
• Results from the Canadian Alcohol and Drug Use Monitoring Survey (CADUMS) reveal that, in 2009, 1.6% of Canadians aged 15 years and older have reported using S. divinorum at least once in their lifetime, with a much higher rate of use (7.3%) in youth aged 15-24.
• The results from the Canadian 2008-2009 Youth Smoking Survey also show that 5% of 15 year olds have used S. divinorum in the past year.
• The 2009 Ontario Student Drug Use and Health Survey (OSDUHS) indicated that 5.4% of Ontario students in grades 7-12 reported ever using S. divinorum and 4.4% of these students reported using this substance in the past year.

41
Q

What are two new classes of designer drugs?

A
  • Several phencyclidine (PCP)-derived designer drugs constantly appear on the black market.
  • b-phenethylamines show affinity to 5-HT2 receptors and act as agonists or antagonists at different receptor subtypes.
  • Radioactive 2C-I was synthesized as a label for the 5-HT2 receptor and as a potential brain scanning agent for nuclear medicine.
42
Q

List three therapeutic uses of hallucinogens

A
  • LSD can change personal attitudes towards death in terminally ill patients
  • Inducing aversive, delirium like effects to treat alcoholism
  • Serotonin plays an important role in OCD so hallucinogens may be able to help

Molecular Neuroscience III (8 decks)

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