20 - Neurotox 2

Question 1

Toxins that target the AP

Answer 1

NT release (inappropriate)
* No or distorted signal to the next cell
* Interfere with Na+ channels and neurons

Question 2

What are some toxins that target APs?

Answer 2

1. Lidocaine
2. Tetrodotoxin
3. Saxitoxin (shellfish)
4. Ciguatera toxin (fish)

Question 3

Saxitoxin

Answer 3

Paralytic shellfish toxin
* Bioaccumulation from algal bloom
* Crosses BBB

Question 4

Ciguatera

Answer 4

Fish toxin
* bioaccumulation of plankton toxin
* ACTIVATES Na+ channels
* sensory and motor dysfunction
* Does NOT kill you

Question 5

Tetrodotoxin

Answer 5

Resident bacteria produce toxins
* Does NOT cross BBB
* Sensory, motor + autonomic
* BLOCKS Na+ channels
* Heat insensitive

Question 6

Tetrodotoxin actions

Answer 6

Blunts AP ➔ no NT release at NMJ
* Paralysed but conscious
* You can support respiration until toxin leaves channel
* No treatment: cardiac arrest ➔ heart attack

Question 7

Toxin that targets release of neurotransmitters (NT)

Answer 7

Botulinum toxin
* exposure via contaminated food, inhalation, infection

Question 8

Botulinum toxin

Answer 8

STOP release of NT
* Does NOT cross BBB
* Descending paralysis (flaccid)

Question 9

How does botulinum toxin interrupt synaptic transmission?

Answer 9

Snares (proteins) help vesicle membranes fuse ➔ NT release
* Botulinum CLEAVES snares
* Halt ACh release

Question 10

Treatment for botulinum poisoning

Answer 10

Equine antibodies to toxin, support respiration (days/months?).
* 95% survival with treatment, 50% without

Question 11

Toxins that target postsynaptic receptors

Answer 11

Domoic acid (amnesic shell-fish disease)

Question 12

Domoic acid

Answer 12

Bioaccumulates in plankton feeders (shellfish poor clearing)
* Kainic acid analogue ➔ activate GLUTAMATE and AMPA receptors
* Directly results in excessive Ca2+ entry

Question 13

Glutamate receptor excitotoxicity

Answer 13

Glutamate acts at a range of postsynaptic receptors
* Excessive activation ➔ excessive Ca2+ ➔ toxic effects
* Glutamate usually taken back up into neuron or surrounding glial cells to prevent overactivation

Question 14

Effect of high dose domoic acid

Answer 14

1. Initially: GIT symptoms
2. After several days: PERMANENT short-term memory loss, brain damage (areas like hippocampus + amygdala have ↑ glutamate Rs

Question 15

Toxins that target reuptake/release of NT

Answer 15

Many are drugs of abuse
* Psychostimulants (MDMA)

Question 16

Possible phases of toxicity of MDMA

Answer 16

1. Initial use
2. Rebound
3. Long term

Question 17

PTSD and MDMA

Answer 17

Highly efficacious in individuals with severe PTSD
* Safe and well-tolerated

Question 18

Target of MDMA

Answer 18

Serotonin system
* Serotonin/5HT is monoamine
* Exclusively released from Raphe nuclei
* Wide axon projection

Question 19

MDMA MOA

Answer 19

STOPS transporter from taking 5HT into terminal
* Can get in terminal ➔ push 5HT out
* REDUCE uptake and promote RELEASE

Question 20

Short term effects of MDMA

Answer 20

1. Warmth, empathy, sensory
2. Side effects: jaw clenching, hyperthermia, CV problems

Question 21

Hypothalamus and MDMA

Answer 21

Hypothalamus strongly regulated by serontonin
* Dysregulation of HR, BP, fluid retention, Kidney function, body temp

Question 22

What cause acute toxicity of MDMA

Answer 22

Blood lvls of toxicity similar to asymptomatic
1. Exercise or hot enviro
2. Underlying susceptibility

Question 23

MDMA toxicity main features

Answer 23

1. Sudden death (heart)
2. Extertional hyperpyrexia ➔ rhabdo + multi organ failure
3. Serotonin syndrome
4. Hyponatremia + cerebral oedema (excessive drinking and ADH release)
5. ++ more

Question 24

MDMA impurity

Answer 24

Aus low MDMA content (~16%)
* PMA - like MDMA, tox at lower dose, take longer to work
* People take more ➔ toxicity

Question 25

MDMA rebound ‘depression’

Answer 25

***Low*** mood and **irritability** * *Little* 5HT **effect** * *Little* 5HT available for **release** * Serotonin **production** and **reload**, will ***slowly*** go away

Question 26

Long-term MDMA Toxicity

Answer 26

Suggested ***damage*** to **serotonin** system * **Depression** + **anxiety** * *Paranoia* * **Sleep** and **memory** problems

Question 27

Difficulties in determining MDMA toxicity in humans

Answer 27

1. **Pop.** of *volunteers* 2. **MULTI**-drug use 3. ***Short***-term 4. ***Impurities*** 5. ***Social*** impacts 6. **Animals** *diff*

Question 28

Serotonin present in Cerebral Cx neurons (monkeys)

Answer 28

Monkeys given MDMA **2x day** for several days. * BUT *doesn't* follow the ***typical*** use * Maybe models the **SUB pop**. * **Oxidative** *stress* possibly results in **terminal** damage + **vascular** changes. * High **temp** *INCREASES* damage