Serotonergic System

Question 1

What are psychedelic drugs?

Answer 1

Primary effect is altering perceptions

They rarely cause pure hallucinations.

Question 2

What are examples of classic hallucinogens?

Answer 2

LSD
Psilocybin
Bufotenine 
Mescaline 
MDMA

Question 3

What properties does MDMA have?

Answer 3

Hallucinogenic and amphetamine (stimulant) properties.

Increases the activity of both serotonergic and dopaminergic.

Question 4

What is another name for serotonin?

Answer 4

5HT

Question 5

How are serotonin precursors ingested?

Answer 5

Through diet, such as turkey, tuna, hallibut, salmon, sardines and cod, dairy products, nuts and seeds.

Question 6

How does serotonin synthesis work?

Answer 6

Ingest precursors through diet

Tryptophan goes to 5-Hydroxytryptophan goes to 5HT/Serotonin

Question 7

Where are serotonin containing neurons found?

Answer 7

In the raphe nuclei of the brain stem

Question 8

What are the behavioural functions of serotonergic projection from raphe?

Answer 8

• To frontal cortex may be important for regulating mood.
• To the basal ganglia may help control movements as well as obsession compulsion.
• To limbic areas may be involved in anxiety and panic.
• To the hypothalamus may regulate appetite and eating behaviour

Question 9

What are the behavioural functions of serotonergic projection descending to the brain?

Answer 9

• Serotonergic neurons in the brainstem regulate sleep.
• Serotonergic neurons descending down the spinal cord may be responsible for controlling certain spinal reflexes that are part of the sexual response, such as orgasm and ejacualtion.
• The chemoreceptor trigger zone in the brainstem can mediate vomiting.

Question 10

How many serotonin receptors are there?

Answer 10

At least 4 major categories of receptors

• 2 Key presynaptic receptors
• Several post synaptic receptors

Question 11

What are they two key presynaptic receptors?

Answer 11

5HT1A - Located at dendrites of cell body, slows neuronal impulse flow through serotonin neuron.

5HT1D - Located on the presynaptic axon terminal , inhibits 5HT release

Question 12

How can serotonin be manipulated?

Answer 12

Diet - Eating trytophan (essential amino acid) rich diet.

Drugs- SSRIs such a fluoxetine (Prozac) or ecstasy

Question 13

Who are two big researchers in MDMA?

Answer 13

Curran and Parrott.

Question 14

What dosage is MDMA taken in?

Answer 14

Usually in tablets, capsules or pills

75 to 150mg, although experienced users often take more (Parrott, 2005)

Question 15

How is MDMA metabolised?

Answer 15

Absorbed from the gastrointestinal tract and its onset of action is typically within 30 minutes of ingestion even though the time to peak plasma concentrations is approx 2-3 hours. (Kolbrich et al, 2008)

Question 16

What are the mechanisms of MDMA in action?

Answer 16

Release of serotonin, noradrenaline and dopamine.

Release of oxytocin, a neuropeptide involved in affiliative behaviours (Dumot et al,. 2009)

Question 17

What are the mechanisms of MDMA at receptors?

Answer 17

MDMA increases release of serotonin
MDMA is a 5HT receptor agonist
Blocks the serotonin transporter (SERT)

Pretends to be serotonin so increases neurotransmission

Question 18

What happens at the synapse when MDMA is taken?

Answer 18

Serotonin floods the synaptic gap, releases serotonin from vesicles. Then binds with postsynaptic receptors and there is a massive increase in serotonergic activity.

Question 19

How is dopamine involved at the synapse when MDMA is taken?

Answer 19

MDMA also releases dopamine

Dopamine is released into the synapse with serotonin

Question 20

What is dopamine implicated in?

Answer 20

Control and regulation of movement and its two major pathways are often referred to as the pleasure pathways.

Explains the fluidity of movement and increased feelings of happiness that people experience when take MDMA

Question 21

What is Monoamine Oxidase?

Answer 21

An enzyme that breaks down serotonin. After reuptake pumps remove the serotonin, MAO breaks most of it down.

Question 22

What happens at the synapse when experiencing come down?

Answer 22

• There is still serotonin in the synaptic gap but it is reduced.
• Uptake pumps are still removing serotonin from the synapse and MAO is still breaking it down.
• Dopamine haven’t lowered as much as serotonin because it replenishes itself more quickly than serotonin.
• Loss of serotonin in the vesicles –> no more serotonin left to be released.

Question 23

What could happen with MDMA taking at receptors?

Answer 23

Depending on the amount of MDMA, serotonin might be depleted to the extent that fewer receptors are activated than before ecstasy was taken.

Question 24

How might people feel on the come down?

Answer 24

• ‘Ate up’ feeling
• Users can become depressed
• Feeling non-social, tired and irritable

Question 25

Why does taking more MDMA after come down not work?

Answer 25

Does depend on how much taken - Brain needs time to rebuild serotonin levels (can take up to 2 weeks) - Larger the dose, the greater serotonin depletion and longer it takes for the brain to replenish it.

Question 26

What are possible acute effects of taking ecstasy?

Answer 26

Increased feelings of empathy, feelings of closeness to others, sociability. Decreases aggressiveness and defensiveness Increased feelings of acceptance Derealization-causes the surrounding to feel different or ‘unreal’. Time-perception alterations Difficulty concentrating

Question 27

How might oxytocin be involved in ecstasy?

Answer 27

Proposed that oxytocin mediates the effects of MDMA on prosocial behaviour (Thompson et al 2007) However, debate about whether oxytocin in result of taking MDMA or whether behaviour after taking increases oxytocin.

Question 28

What are some undesirable effects of MDMA?

Answer 28

Nausea, headache, hallucination, agitation, palpitations, abdominal cramps, hypothermia, seizure, dizziness, allergic reactions.

Question 29

What are some desirable effects of MDMA?

Answer 29

``` Liking effects Euphoria Relaxed Arousal Sociable ```

Question 30

What are effects that happen 24-48 hours after taking drug?

Answer 30

Reports of a crash à Muscles ache, fatigue, depression, irritability, difficulty concentrating, headache (Peroutka et al 1988, Solowji et al, 1992).

Question 31

What did Curran and Travil (1997) study?

Answer 31

Studied people in days after they had taken ecstasy Increased rating of disconnected, sad and bored Had lower mood than alcohol users the day after taking the drug, but were even more depressed 4 days later at which point scores of some users were in the range of clinical depression.

Question 32

What are the physiological effects of MDMA?

Answer 32

Altered eye alignment due to increased extraocular (muscles that control eye movement) muscle tension, Jaw clenching Decreased appetite Dry mouth Increase in blood pressure and heart rate Mild neurological side effects include pupillary dilation and tremors, but more serious consequences include seizures, strokes and coma.

Question 33

What are potentially dangerous side effects of MDMA?

Answer 33

Hepatotoxicity - effects on the liver (liver damage) Hyperthermis Effects on the heart and blood vessels Ecstasy raises body temperature through vasoconstriction (blood vessel narrowing) which slows heat loss. MDMA increases the desire to exercise beyond the user’s limitations. The ambient temperatures in clubs and excessive exercise both increase body temperature Sometime the tablets are not 100% pure and contain other dangerous substances that also raise body temperature. Hypothermia is probably the result of an interaction of drug effects, setting of use and user’s behavoiur. When overheating occurs, the body loses fluids MDMA may mask the feeling of thirst Dehydration impairs sweating and therefore cooling - essential to take fluids to prevent dehydration But too much fluid is also dangerous - electrolytes in blood can be diluted to dangerous levels à hypernatremia can be fatal.

Question 34

How can you reduce risk when taking MDMA?

Answer 34

Stay cool Drink electrolytes (Don't exceed 500ml/hr.) ``` Don't take if have: Heart condition Prone to seizures Have had meningitis Predisposition to heat sensitivity Are taking MAOIs, SSRIs, SNRIs, TCAs. ```

Question 35

What are some potential psychiatric problems? Psychotic

Answer 35

Although rare, can produce state of intoxication which mimics psychosis, such as paranoia, but does not last more than a few days normally. It most frequently occurred in regular or experienced users. In the cases reported the recovery percentage is poor (34.5% full recovery) (Baggot et al, 2001)

Question 36

What are some potential psychiatric problems? | Affective

Answer 36

Typically anxiety shown through acute panic response or chronic panic disorder In some cases the panic attacks quickly resolve although in others anxiety or panic attacks could persist for weeks. The recovery percentage from the cases reported was good.

Question 37

What are some potential psychiatric problems? | Depression

Answer 37

Chronic ecstasy use is often followed by longer lasting depression

Question 38

What are some potential psychiatric problems? | Depersonalization and derealization

Answer 38

Depersonalization refers to the feeling that one is not ‘real’ and that one is detached and unable to feel emotion. Derealization is the feeling that the surroundings feel different or unreal.

Question 39

What are potential short term psychological problems (up to a week after use)

Answer 39

Depressed Moods Irritability Anxiety Decreased alertness Fatigue Drowsiness Impaired cognitive function

Question 40

What are long term effects of MDMA?

Answer 40

Lowered serotonin levels can cause depression Users operating on lower-than-normal serotonin levels most of the time which can lead to depression, if taken often enough that serotonin levels are depleted before it can replenish itself.

Question 41

What is the most probable cause of ecstasy-related depression

Answer 41

Down-regulation of receptors The brain is built to adapt to changing circumstances One of the ways the brain adapts is through the up-and-down regulations of receptors. Serotonin receptors will down-regulate over time if bombarded with large amounts of serotonin. This may lead to depression, even after brain serotonin levels have been restored because number of receptors have been reduced.

Question 42

What are the potential long-term psychological problems (Weeks or months after)

Answer 42

Increased anxiety Dysphoric Moods Increased sensitivity to Emotions Increased Impulsivity Impaired cognitive performance

Question 43

What are some methodological problems of studying MDMA?

Answer 43

Animal studies have tended to use doses which are much higer than the doses used by humans. Human studied have tended not to account for the fact that most ecstasy users are poly-drug users or have failed to test the purity of the MDMA used.

Question 44

What evidence is there for MDMA neurotoxicity?

Answer 44

- Basic arguement = whether it will damages terminal buttons of an axon which produced serotonin - Ricaurte, Yuan, Hatzidimitriou, Cord & McCann (2002) reported severe neurotoxicity but later retracted in 2003. Overall = no evidence that it is neurotoxic and causes neuronal atrophy or neuronal death in the brain.

Question 45

What is meant by MDMA neurotoxicity?

Answer 45

The way in which MDMA could cause damage to the brain.