Cholinergic Neurotransmission and Cholinergic Drugs Flashcards
Important sites for ACh
Cells in nucleus basalis which project to cortex
Cells in septum which project to hippocampus
Cells in striatum (short interneurons)
Synthesis, storage, release, termination & metabolism of ACh
- Choline is taken into neuron via carrier mediated transport
- Choline is acetylated by choline acetyltransferase using Acetyl CoA as a source of acetyl groups
- ACh is actively packaged into vesicles by an amine transporter
- Release is via classical Ca2+ mediated exocytosis
- Termination/metabolism is via enzymatic degradation by acetylcholinesterase (treatment for alzheimers)
How does ACh exert its effects
NICOTINIC
- ligand gated ion channel receptors
- For fast excitatory synaptic transmission
MUSCARINIC
- GPCRs
- For slow excitatory OR inhibitory synaptic transmission
M1, M3, M5 are excitatory and Gq linked ⇒ act via DAG and IP3 as 2nd messengers
M2 & M4 are inhibitory and Gi linked ⇒ reduce cAMP in the cells
M1, M3 and M5
excitatory
Gq linked
⇒ act via DAG and IP3
M2 & M4
Inhibitory
Gi linked
⇒ reduce cAMP in the cells
Nicotinic receptors
Where are they located in the brain
What do presynaptic allow
What do postsynaptic facilitate
Widespread in brain
Located both presynaptically and postsynaptically
Presynaptic receptors facilitate the release of other NTs ⇒ facilitatory presynaptic receptors
Postsynaptic receptors facilitate excitation of postsynaptic neurons
Muscarinic receptors
Where are they located in the brain
effects on pre and postsynaptic neurons
Widespread in brain
Located both presynaptically and postsynaptically
Inhibitory & excitatory effects on presynaptic and postsynaptic neurons e.g. muscarinic ACh receptors can be presynaptic inhibitory autoreceptors suppressing release of ACh from cholinergic neurons
What is ACh required for
Arousal - via cells in nucleus basalis that project to cortex
Learning and memory - via cells in the septum that project to the hippocampus
Motor control - via cholinergic interneurons in the striatum
D2 antagonists used to treat
IMODIUM
Schizophrenia
pathophysiology of Alzheimer’s disease
Loss of cholinergic nucleus basalis neurons (projecting to cortex - hippocampus and basal forebrain) and septal neurons (projecting to the hippocampus) underlies the learning and memory deficits typical of Alzheimer’s disease
brain shrinkage
⇒anticholinesterases are used in treatment of this disease
pathophysiology of Parkinson’s
loss of dopaminergic substantia nigra neurons (projecting to striatum) underlies the motor deficits typical of Parkinson’s
striatal cholinergic interneurons oppose the effects of dopamine in the striatum and hence exacerbate the deficits
⇒ cholinergic antagonists are used in the treatment of this disease
trihexyphenidyl, benztropine
drugs used to treat Parkinsons
MOA
trihexyphenidyl
benztropine
→ cholinergic antagonists
normal vs Alzheimer’s brain
5% of the population over 65
up to 90% of population over 95 have Alzheimer’s
Characteristic features of Alzheimer’s
Neuritic plaques - containing the β amyloid peptide
Neurofibrillary tangles - containing the abnormally phosphorylated tau protein
drug treatment for Alzheimer’s
drugs used
MOA
provide relief from Alzheimer’s symptoms - no cure and cannot slow the degeneration of cholinergic neurons
- Tacrine
- Donepezil
- Rivastigmine - CNS selective so fewer peripheral side effects
- Galantamine - also acts as a positive allosteric modulator of nicotinic receptors
(will eventually lose their efficacy)
NMDA receptor antagonists e.g. memantine
