Introduction to Neuropharmacology Flashcards
What is the main difficulty with the pharmacology on the CNS ?
- Billions of neurones
- Complex circuits
- Measurement of effects
- Compensations
What are the criteria for a molecule to be a NT ?
- Presence in nerve terminal
- Stored in vesicles
- Released
- Effect on postsynaptic neuron/cell
- Termination of effect
What are the properties of transmitters in the CNS ?
- Always agonists
- Can produce fast or slow events
- Can excite or inhibit
- Determined by receptors
- Ion channel - fast - neurotransmission
- 2nd messengers - slow - neuromodulation
What are the major excitatory/inhibitory transmitters in the brain ?
Glutamate - major excitatory transmitter
GABA - major inhibitory transmitter
Which NT have mixed effects ?
ACh, NA, DA and 5-HT
Is substance P excitatory or inhibitory ?
What about opioids ?
What kinds of molecules are these ?
Peptides
- substance P –> excitatory
- opioids –> inhibitory
Is NO excitatory or inhibitory ?
What about adenosine ?
Both NTs are inhibitory.
Which receptors do Glu and substance P bind ?
How do these differ in their properties ?
AMPA - Fast Kainate - Fast NMDA - Delayed Metabotropic - Slow SP --> Neurokinin 1 - Slow
Which receptors do GABA, NA (inhibitory) and adenosine bind ?
How do do these differ ?
GABA(A) – > Fast
GABA(B) –> Slow
Alpha-2AR –> Slow
A1 –>Slow
What are the main characteristics of Glu ?
- Major excitatory transmitter in CNS
- Most neurones respond to glutamate
- Often found in long pathways
- Point to point transmission
- Can cause long term changes
Which 2 NTs are present in small amounts in the Nervous System ?
SP and opioids.
Name of few processes in which Glu plays a crucial role.
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
What are the 2 different GABARs ?
What are the different roles of GABA ?
- GABA-A R = fast Cl channel
- GABA -B R = slow GPCR
- Sleep
- Anxiety
- Epilepsy
- Muscle relaxation
- Disinhibition
What are the characteristics of ACh ?
- Important transmitter in CNS
- Often found in specific pathways
- Excites through nicotinic R - CNS variants
- Excites and inhibits through slow muscarinic receptors - modulation
Which areas of the brain are affected in AD ?
What are the symptoms of this disease ?
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
Give examples of neuro-degenerative disorders.
- Stroke - non specific
- Parkinson’s disease
- Dopamine - treatable
- Alzheimer’s disease
- ACh - poorly controlled
What are the monoamine NTs ?
What do they do ?
• 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
What are the roles of MOA NTs ?
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
NA and 5HT have similar a similar type of distribution.
True or false ?
True.
What are the symptoms ?
What is the most common treatment for PD ?
What are the risks of this therapy ?
PD = motor disorder –> tremor, rigidity
Increase DA activity (L-DOPA + block DA breakdown)
Too much DA –> nausea, psychosis
Can peptides be NTs ?
How do they differ from other NTs ?
- 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
Give examples of families of peptides that act as NTs.
Name members of each family.
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
What are peptide NTs different from classical NTs ?
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)
What are the different aspects of pain ?
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.
Give examples of disorders of the NS there is excessive/insufficient activity ?
Excess activity : • Pain • Epilepsy • Anxiety • Schizoprenia +ve symptoms Insufficient activity : • Depression • Parkinson’s • Alzheimer’s • Schizoprenia -ve symptoms
What tactics can we employ to (in terms of synaptic pharmacology) to treat disorders of the NS ?
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
What are the main problems of CNS drug therapy ?
- 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
What is prozac ?
How does it work ?
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).
If opioids cause dependance, why are they used as therapeutics to treat pain ?
Because pain blocks the rewards/dependence associated with dopamine.
How are specific genes linked to neuropharmacology and the treatment of neurodegenerative diseases ?
- 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
