Lecture 6- CNS stimulants part 2

Question 1

What is the main excitatory transmitter in insects?

Answer 1

Acetylcholine (whereas ours is glutamate)

And insects use glutamate at their neuromuscular junction, swapped over what we have.

Question 2

Why can tobacco be used as an insecticide?

Answer 2

Nicotine in tobacco gives massive stimulation because similar to acetylcholine and the insect falls off the plant and the plant survives. Protects tobacco from insects. There’s one insect that’s immune but that’s the exception.

Question 3

What does nicotine act on?

Answer 3

Nicotine acts on central nicotinic AChR’s, but the net effect is complicated. (the ligand-gated ionotropic channels, have their own ion pore, allow sodium in and potassium out so usually associated with stimulation/excitation)

Question 4

Where are nAChRs located?

Answer 4

nAChR’s are heavily expressed in cerebral cortex, hippocampus and ventral tegmentum (and widely found elsewhere)
nAChR’s are located pre- and post-synaptically and are ligand-gated cation channels

Question 5

What do nicotinic acetylcholine receptors do?

Answer 5

nAChR’s enhance transmitter release and increase neuronal excitability

Question 6

What does nicotine do to nicotinic acetylcholine receptors do?

Answer 6

Nicotine both activates the receptors AND induces desensitisation.
Chronic administration (daily smokers) leads to increased numbers of nAChR’s by changing expression from DNA.
Overall effect may be a result of balance in the 2 processes – excitation and synaptic block.

Question 7

How long does nicotine stay in the synapses for?

Answer 7

Nicotine is not removed from the synapse as fast as acetylcholine. Acetylcholinesterase breaks down acetylcholine really quickly. Doesn’t chew up nicotine very quickly so nicotine persists. Unusual.

Question 8

How does nicotine cause synaptic block?

Answer 8

Transmitter (nicotine) binds to receptor and persists so receptor goes into inactive desensitized state. This is different from closed state before binding, as it can’t be activated. By hanging around, nicotine puts a lot of nicotinic receptors into desensitization. We call this synaptic block.

Question 9

Why do you get withdrawal from smoking?

Answer 9

Because you’ve got more nicotinic acetylcholine recepotrs in the synapses which aren’t being stimulated anymore.

Question 10

What are the behavioural effects of nicotine??

Answer 10

Nicotine inhibits spinal reflexes, causing measurable muscular relaxation (possibly by stimulating glycinergic Renshaw cells! these are the glyconergic neurones which have nicotinic acetylcholine receptors on) SO relaaaaxing

Low nicotine doses cause central arousal; large doses sedation – reaction times improve after small doses and nicotine enhances learning (in rats!).

Causes excitation in the meso-limbic dopaminergic reward system - rats will choose to drink nicotine solutions over plain water (not just humans which will seek it out)

Question 11

What is the active ingredient in cannabis?

Answer 11

Mainly 9-tetrahydrocannabinol (THC)
also cannabidiol (CBD, precursor to THC)
and cannabinol (breakdown product of THC)
(these two lack psycho-activity, but can be used as anticonvulsants)

Question 12

Pharmacological effects of cannabis in CNS?

Answer 12

Sense of “relaxation” and well-being (like ethanol, but without potential aggression and recklessness (loss of inhibitions)

Feeling of “sharpened awareness”

Subjective “slowing down” of time

Analgesia

Anti-emetic activity (uses for chemotherapy?)

Question 13

Pharmacological effects of cannabis in periphery?

Answer 13

Tachycardia (can be blocked by blocking sympathetic drive)

Vasodilatation (produces the typical “blood-shot” eye look

Reduction in intraocular pressure

Bronchodilatation

Anti-emetic activity

Question 14

Adverse effects of cannabis?

Answer 14

• Overdose leads to mild respiratory depression with confusion and dizziness
• In rodents, THC is teratogenic BUT evidence for this in humans is lacking
• Tolerance and physical dependence is seen in a small proportion of heavy users
• Abstinence leads to symptoms similar to alcohol withdrawal
• Psychological dependence
• Increased likelihood of schizophrenia (?) Not proved but increases dopamine which can lead to schizophrenia-like state. But you may be closer to schizophrenia than others, a mix of genes and things not just on/off
• Ladder of drug use/abuse (?)

Question 15

How does cannabis work?

Answer 15

High lipid solubility originally suggested an action like general anaesthetics on “membranes” HOWEVER
Now known to act on specific membrane bound receptors, coupled to G-proteins – CB1 (cannabanoid receptor 1) and CB2 subtypes (CB = cannabinoid).

Receptors are part of a system using ENDOGENOUS cannabinoid substances – the endocannabinoids (EC’s)

Question 16

Where do cannabonoids bind?

Answer 16

Cannabonoid receptor 1 and 2
Cb1= primarily central
Cb2= primarily peripheral

Question 17

What are the two major endogenous cannabinoids? (found naturally in body)

Answer 17

Anandamide and 2 Arachinodonoyl glycerol (2-AG)

Question 18

Biosynthesis/Inactivation of Endocannabinoids describe

Answer 18

two separate pathways occuring in post synpatic neurone.
Post synaptic neurone can make 2-ag using phospholipase C, which is associated with nauronal membrane. A similar enzyme called phospholipase D can make anandamide. Both of these when made are not stored in vesicles, they’re too lipid soluble. They’re pumped out of post synaptic cell by a endocannabinoid transporter (EMT).
CB1 receptors are present usually in presynaptic terminals, often glutaminergic terminals.

Question 19

What are the important points about Biosynthesis/Inactivation of Endocannabinoids

Answer 19

1. These are usually made in postsynaptic neurone
2. made on demand not in vesicles
3. and act in retrograde manner on pre-synaptic terminal
   (also these enzymes are calcium dependent)

Question 20

Biosynthesis/Inactivation of Endocannabinoids

List of important stuff from slide

Answer 20

-Both AG and anandamide are synthesized from membrane
lipids by enzymes which are activated ‘on demand’

-The key is probably post-synaptic Ca2+ levels (acts as switch) The more calcium coming into neurone, the more active it is

-Not vesicular release (so levels released variable?)
Uptake by transporter, degradation locally

-Produced postsynaptically but acts on presynaptic terminals
= RETROGRADE signal

Question 21

Where is the endocannabinoid system present?

Answer 21

Peripheral AND central
Periphery mainly through CB2
CNS mainly through CB1
Amongst the most abundant receptor in the brain (with GABA and Glu)!
Not homogeneously distributed – more in “higher” CNS, not brainstem, (but can be (up)regulated)
Can act within excitatory and inhibitory synapses to reduce transmitter release – complex overall actions!

Question 22

Summary of how cannabinoids work?

Answer 22

Ca2+ influx post-synaptically induces formation of EC’s by activating phospholipase C or D. ECs are free to leave/ transported into the synaptic space because they are lipid soluble so not stored in vesicles.
Feedback- Taken up by presynaptic cell, they cause (amongst other things) decrease in Ca2+ influx, reducing transmitter release – whichever transmitter is involved.