Introduction to Neuropharmacology

Question 1

What is the main difficulty with the pharmacology on the CNS ?

Answer 1

• Billions of neurones
• Complex circuits
• Measurement of effects
• Compensations

Question 2

What are the criteria for a molecule to be a NT ?

Answer 2

• Presence in nerve terminal
• Stored in vesicles
• Released
• Effect on postsynaptic neuron/cell
• Termination of effect

Question 3

What are the properties of transmitters in the CNS ?

Answer 3

• Always agonists
• Can produce fast or slow events
• Can excite or inhibit
• Determined by receptors
• Ion channel - fast - neurotransmission
• 2nd messengers - slow - neuromodulation

Question 4

What are the major excitatory/inhibitory transmitters in the brain ?

Answer 4

Glutamate - major excitatory transmitter

GABA - major inhibitory transmitter

Question 5

Which NT have mixed effects ?

Answer 5

ACh, NA, DA and 5-HT

Question 6

Is substance P excitatory or inhibitory ?
What about opioids ?
What kinds of molecules are these ?

Answer 6

Peptides

• substance P –> excitatory
• opioids –> inhibitory

Question 7

Is NO excitatory or inhibitory ?

What about adenosine ?

Answer 7

Both NTs are inhibitory.

Question 8

Which receptors do Glu and substance P bind ?

How do these differ in their properties ?

Answer 8

AMPA - Fast
Kainate - Fast
NMDA - Delayed
Metabotropic - Slow
SP --> Neurokinin 1 - Slow

Question 9

Which receptors do GABA, NA (inhibitory) and adenosine bind ?
How do do these differ ?

Answer 9

GABA(A) – > Fast
GABA(B) –> Slow
Alpha-2AR –> Slow
A1 –>Slow

Question 10

What are the main characteristics of Glu ?

Answer 10

• Major excitatory transmitter in CNS
• Most neurones respond to glutamate
• Often found in long pathways
• Point to point transmission
• Can cause long term changes

Question 11

Which 2 NTs are present in small amounts in the Nervous System ?

Answer 11

SP and opioids.

Question 12

Name of few processes in which Glu plays a crucial role.

Answer 12

Pain - wind-up, LTP in spinal cord
Memory - LTP etc in hippocampus
Epilepsy - forebrain
Development - neuronal contacts
Cell death - excessive activation of glutamate receptors
(NMDA) - xs influx of calcium - osmotic pressure - activation of enzymes - NO - free radicals - death

Question 13

What are the 2 different GABARs ?

What are the different roles of GABA ?

Answer 13

• GABA-A R = fast Cl channel
• GABA -B R = slow GPCR
• Sleep
• Anxiety
• Epilepsy
• Muscle relaxation
• Disinhibition

Question 14

What are the characteristics of ACh ?

Answer 14

• Important transmitter in CNS
• Often found in specific pathways
• Excites through nicotinic R - CNS variants
• Excites and inhibits through slow muscarinic receptors - modulation

Question 15

Which areas of the brain are affected in AD ?

What are the symptoms of this disease ?

Answer 15

Areas affected :
- Limbic system
- Association cortex
- ACh pathways in subcortex
Symptoms :
- Recent memories go first –> hippocampus
- Alert and responsive at first
- Meaning of words and use of objects starts to fail
- Confusion, agitation, delusions, social disinhibition
- Language failure and amnesia

Question 16

Give examples of neuro-degenerative disorders.

Answer 16

• Stroke - non specific
• Parkinson’s disease
• Dopamine - treatable
• Alzheimer’s disease
• ACh - poorly controlled

Question 17

What are the monoamine NTs ?

What do they do ?

Answer 17

• Noradrenaline, dopamine, 5-
hydroxytrptamine (5HT) aka serotonin
• Found in specific pathways - small numbers
• Excite and inhibit through slow receptors
- modulation
• Only exception is 5HT3 - fast ionotropic

Question 18

What are the roles of MOA NTs ?

Answer 18

Dopamine :
- Motor control 
- dependence 
- reward 
- nausea 
- psychosis
5HT :
- Pain 
- migraine 
- anxiety
- depression
- hallucinations
- fear
- temperature
- anorexia
- attention
NA :
- Mood
- Sleep-wake cycle
- Stress
- Autonomic control

Question 19

NA and 5HT have similar a similar type of distribution.

True or false ?

Answer 19

True.

Question 20

What are the symptoms ?
What is the most common treatment for PD ?
What are the risks of this therapy ?

Answer 20

PD = motor disorder –> tremor, rigidity
Increase DA activity (L-DOPA + block DA breakdown)
Too much DA –> nausea, psychosis

Question 21

Can peptides be NTs ?

How do they differ from other NTs ?

Answer 21

• Not only hormones
• Found and act in CNS
• Different life cycle from other NTs
• Important long term changes in activity
• A peptide will only excite or inhibit, not both

Question 22

Give examples of families of peptides that act as NTs.

Name members of each family.

Answer 22

Gastrins : Gastin, cholecystokinin
Insulins : Insulin, insulin-like growth factor
NPYs : Neuropeptide Y, pancreatic polypeptide
Opioids : Enkephalin, dynorphin, endorphin
Secretins : Secretin, vasoactive intestinal peptide,
pituitary adenylate cyclase-activating polypeptide
Tachykinins : Substance P, neurokinin A, neurokinin B

Question 23

What are peptide NTs different from classical NTs ?

Answer 23

Nuclear synthesis as large precursor
Transport down axon - slow + processing en route
Release
No uptake - enzyme breakdown
Often coexist with: 
- Glu (Sub P)
- NA (NPY)
- DA (CCK)

Question 24

What are the different aspects of pain ?

Answer 24

Sensory aspects of pain : threshold, intensity and location (cortex)
Psychological aspects of pain : unpleasant, threatening, aversive (limbic system)
Social, economic issues : depression, anxiety, sleep disorders etc.

Question 25

Give examples of disorders of the NS there is excessive/insufficient activity ?

Answer 25

Excess activity : 
•  Pain
•  Epilepsy
•  Anxiety
•  Schizoprenia +ve symptoms
Insufficient activity : 
•  Depression
•  Parkinson’s
•  Alzheimer’s
•  Schizoprenia -ve symptoms

Question 26

What tactics can we employ to (in terms of synaptic pharmacology) to treat disorders of the NS ?

Answer 26

Increase NT function :
•  Precursor, block uptake or metabolism
•  Receptor activation - agonist
Decrease NT function : 
• Receptor antagonism
Can act on : 
- Synthesis --> PD
- Release
- Effects --> Pain, SCZ, heroin, nicotine, LSD, cannabis
- Removal --> depression (uptake blocked), cocaine, MDMA

Question 27

What are the main problems of CNS drug therapy ?

Answer 27

• Multiple receptors for NTs
• Receptor up/down regulation to drugs
• Actions at multiple sites
• Blood brain barrier
• Circuits - disinhibition
• Long term changes
• Co-existence of NTs

Question 28

What is prozac ?

How does it work ?

Answer 28

Prozac is an antidepressant. It is mainly used to treat major depression, obsessive-compulsive disorder, and panic disorder. Also known by its generic name, fluoxetine, Prozac is a selective serotonin reuptake inhibitor (SSRI).

Question 29

If opioids cause dependance, why are they used as therapeutics to treat pain ?

Answer 29

Because pain blocks the rewards/dependence associated with dopamine.

Question 30

How are specific genes linked to neuropharmacology and the treatment of neurodegenerative diseases ?

Answer 30

• Certain genes an be induced/suppressed by NTs
• Ca influx - NMDA R as example
• Mouse strains
• Genes for R, enzymes, transporters
• Basis for individual differences
• Protect or predispose
• Ca channel mutation - migraine