3.

PHARMACOLOGY: Common Neurotransmitter/ Receptor Targets

- Understand commonly targeted neurotransmitters/receptors, and names of
commonly used drugs that target these neurotransmitters/receptors.
- Understand the central nervous system and other effects of drugs that target
neurotransmitter/receptors (including adverse effects).
- Discuss common clinical situations where medications that target
neurotransmitter/receptors are required.

Neurotransmitters = for cell to cell communication

Other types:
- Endocrine = messenger released into bloodstream
and travels to distant cell
- Paracrine = messenger diffuses to other cells in
vicinity and binds to receptors on this cell
- Contact-dependent = both cells physically in
contact with each other
- Neuronal = travels via synapse

Neurotransmitter receptors:
- Excitatory/ inhibitory
- Binding of neurotransmitter to an excitatory receptor-> open Na / Na + K channel ->
depolarisation of post synaptic plasma membrane
- Bind to inhibitory receptor -> open K or Cl channel -> hyperpolarisation inhibits
generation of action potential
- Same neurotransmitter can produce an excitatory response in some post synaptic
cells and an inhibitory response in others

Type of receptors:
1. Ionotropic / ligand gated
a. 2 functional domains: extracellular site binding neurotransmitter, and a
membrane spanning domain that forms ion channel -> causes membrane
potential change in <2ms (quick acting)
2. Metabotropic/ g- protein coupled
a. Affect channels by activation of intermediate molecules ( g proteins)
response slower and longer lasting -> seconds to min
Drug effects:
Agonistic (increase synaptic transmission)
Drug increase synthesis of neurotransmitter
molecules (increase amount of precursor)
Increase number of neurotransmitter
molecules by destroy degrading enzymes
“” release of neurotransmitter molecules
from terminal buttons
Drug binds to auto receptors and block
their inhibitory effect on neurotransmitter
release
Bind to postsynaptic receptors and either
activate them/ increase effect on them of
neurotransmitter molecules
Block the deactivation of neurotransmitter
molecules by blocking degrading or
reuptake
Antagonistic (decrease transmission)
Block synthesis of neurotransmitter
molecules (destroy synthesising enzymes)
Cause neurotransmitter molecules to leak
from vesicle and be destroyed by degrading
enzymes
Block release of neurotransmitter
molecules from terminal buttons
Activate auto receptors and inhibit
neurotransmitter release
Drug is receptor blocker -> bind to post
synaptic receptor and block effect of
neurotransmitter

Agonistic drug -> bind to receptor -> channel OPENS

Agonistic -> channel CLOSES

Allosteric modulation = do not bind to neurotransmitter receptor (different site); increase or

decrease effect of NT binding to binding site; they act like dimmers
- GABAa positive modulators:
a. Alcohol
b. Benzodiazepines (lorazepam)(anxiolytic and antiepileptic)
c. Barbiturates (phenobarbital) (antiepileptic)

Neurotransmitters:
- Acetylcholine
- Dopamine
- GABA
- Glutamate
a. Major excitatory neurotransmitter; most abundant
b. 3 types of inotropic receptors (NMDA, AMPA, Kainate)
c. Metabotropic GPCRS
d. Not manipulated for therapeutic benefit
- Noradrenaline
a. Major concentration of noradrenergic neurons is in locus coeruleus of caudal
pons
b. Fibres from locus coeruleus form par of reticular activaiting system,
responsible for behavioural arousal and levels of awareness
c. GPCRS: alpha1,2; beta 1,2,3
i. A2 receptor = inhibitory
ii. A2 agonist clonidine = anxiolytic and sedative (for anxiety)
 - Serotonin

*acetylcholine and noradrenaline play important roles within ANS

Ach is the neurotransmitter at neuromuscular junction

Parkinson’s disease:
- Slowness of initiating and executing movements
- Degeneration of dopamine- secreting neurones within substantia nigra
- Dysfunction of nigrostriatal pathway

- Receptors = all GPCR

- D1 like receptors (D1,D5) = excitatory
- D2 (D2,3,4) = inhibitory

L-DOPA = precursor for dopamine

How to manipulate:
- Give more levodopa (dopamine does
NOT cross blood brain barrier)
- Give amantadine = increase release of
dopamine into synaptic cleft
- Give D2 receptor agonist -> stimulate
post synaptic receptor directly
(commonly used)
- Give MAO inhibitor -> inhibit enzymes
breaking dopamine; hang around
longer and activate
- Give COMT inhibitor (catechol-o-
methyltransferase)
Aim = INCREASE dopaminergic transmission

Schizophrenia:
- Dopamine
- Mesolimbic-mesocortical pathways are involved in emotions and organisation of
thoughts ; implicated in such illness
- D2 receptor antagonists used in treatment

Clinical depression:
- Serotonin or 5-hydroxytryptamine (5-HT)
- 7 receptor families 5-Ht1 to
- From Raphe nuclei of brainstem -> cotex,
thalamus, limbic system, spinal cord

Treatment:
- SSRI: inhibit reuptake of serotonin; last longer in
synaptic cleft
Epileptic seizure
- Gamma-aminobutyric acid (GABA)
- Chief inhibitory neurotransmitter in CNS: plays principal role in reducing neuronal
excitability throughout nerv system
- Involved in inhibitory motor control in spinal cord and regulation of muscle tone
- GABAa receptors = ligand-gated; responsible for most inhibitory action in CNS
- GABAb = GPCR, inhibitory motor control in spinal cord and regulation of muscle tone

Treatment:
- Vigabatrin inhibit enzyme which breaks up GABA
- Tiagabine; inhibit reuptake of GABA
- Positive ALLOSTERIC MODULATORS: Diazepam and barbiturates: act on post
synaptic receptor
Alzheimer’s
- Acetylcholine; dramatic loss of cholinergic neurons in cortex
- Receptors in brain: 95% are muscarinic GPCR: rest nicotinic ligand gated
- Cholinergic projection from nucleus basalis of Meynert (in basal forebrain) to
forebrain neocortex and associated limbic strucutres involved in learning and
memory

Drug effects:
- Give acetylcholine-esterase inhibitors (not very effective); prevent break down of
Ach