Please enable JavaScript.
Coggle requires JavaScript to display documents.
Chemical Signalling (Neuromodulators (Serotonin (Synthesis
tryptofan
…
Chemical Signalling
Neuromodulators
diffuse systems, modulate the activity of glutamate and GABA in target areas
affect properties of neuron
do not carry information themselves
generally, effect of neurotransmiter goverened by receptor
GABA at GABAb receptor is neuromodulator
Acetylcholine (ACh) at nicotinic ACh receptors is a neurotransmitter
(obverse is usually true of these)
-
Dopamine
Cell bodies in midbrain: ventral tegmental area (VTA) and substantia nigra
projections into forebrain: striatum (reward, movement, motivation) and frontal lobe (executive function, etc.)
Nigrostriatal
SN projections to neostriatum (caudate and putamen)
role in movement
disorder:
Parkinson's - destruction of DA projections from SN to basal ganglia
Huntington's - destruction of DA target nerons in striatum
Mesolimbic
VTA projections to Nucleus accumbens (NAcc)
role in reinforcement (reward)
dysfunction - addiction
Mesocortical
VTA projections into prefrontal cortex
role in working memory & planning
dysfunction - schizophrenia, addiction
Processes
Synthesis
in synaptic terminal
- Tyrosine (essential amino acid in diet)
catalysed by tyrosine hydroxylase (TH)
rate limiting step (bottleneck)
- L. Dopa
catalysed by dopa decarboxylase
- Dopamine
loaded into vesicles
Tyrosine Hydroxylase
negative feedback
DA competes for binding with essential cofactor
too much DA lowers TH production
presynaptic autoreceptors detect DA release
leads to phosphorylation of TH
increases TH pool replenisment
prolonged activity in presynaptic neuron
increase of transcripton of TH gene
produce more enzyme
increases TH pool size
drugs
Reserpine
impairs storage of monoamines in vesicles
(vesicles remain empty, so no release)
L-DOPA
precursor of dopamine
bypasses rate limiting TH step
increases TH pool size
AMPT
inactivates TH
release
depolarisation of presynaptic membrane (through AP)
influx of Ca2+ through voltage gated channels
Ca2+ dependent vesicle docking and release
Reuptake
Transporters
once back inside reloaded back into vesicles
or degraded with enzymes MAO (Monoamine oxidase) or COMT
drugs
cocaine, amphetamine, methylphenidate (Ritalin)
block reuptake of monoamines into terminals
(amphetamine reverses transporter)
more dopamine in synaptic cleft
selegiline MAOI (MAO B)
Entacapone - COMT inhibitor
increases pool by stopping breakdown of Catecholamines
-
Serotonin
9 raphe nuclei (in brainstem) diffuse projections
each nuclei project into different regions
Descending projections to cerebellum & spinal cord
pain related
Raphe nuclei fire tonically during waking (quiet during sleep)
Function:
mood, appetite, sleep, pain, emotion
Synthesis
- tryptofan
essential amino acid from diet
rate limiting
- 5-HTP
- 5-HT (serotonin)
-
Storage
loaded into vesicles
release
Ca2+ dependent
reuptake/metabolism
uptaek through serotonin transporters (SERT)
degraded by MAO inside cell
drugs
Fluoxetine (prozac)
reuptake inhibitor
Fenfluramine
causes release and inhibit reuptake
MDMA
causes noradrenaline & serotonin transporters to run backwards
MAOI (like DA)
-
-
Glutamate
- Synthesised in neuron terminals
from glucose or glutamine
- stored in vesicles by vesicular glutamate transporters
- released by excytosis (Ca2+ influx dependent system)
- acts at postsynaptic glutamate receptors
- reuptake by excitatory amino acid transporters (EAATs) in the membrane of the presynaptic cell or by glia
-
-
GABA
- GABA synthesised from Glutamate
- stored in vesicles by vesicular GABA transporters
- released by excytosis (Ca2+ influx dependent system)
- acts at postsynaptic ionotropic GABAa and metabotropic GABAb receptors
- reuptake into the membrane of the presynaptic cell or by non-GABAergic neurons and glia
GABA made 'de novo' (from scratch rather than recycled)-
GABA
2 main families of GABA receptor
GABAa ionotropic
ligand gated Cl- channels
fast IPSPs
GABAb metabotropic
G- Protein coupled
indirectly coupled to K+ or Ca2+ channel through 2nd messengers
(opens K+ channel, closes Ca2+ channel)
Slow IPSPs (slow but remember wide reaching)
heteropentameric structure
5 subunits - 2 alpha + 3 (beta, gamma or delta)
GABA binds, allows more Cl- to flow through channel
Pharmacology
Drugs binding at GABA binding site (Competitive)
Muscimol - agonist (amanita muscaria)
Drugs binding elsewhere on the receptor (noncompetitive)
Benzodiazepine
Barbiturates
Ethanol
Neurosteroids
increase GABA activity - Anxiolytics
Agonists - alcohol, barbiturates
indirect agonists - benzodiazepines
decrease GABA activity - anxiogenics
antagonist - Flumazenil
(reversing sedation due to BDZ overdose)
all work at GABAa site
Barbiturates
- General, non-specific depression of neuronal activity
including vital functions breathing etc.
- poor therapeutic ratio
easy to overdose, small difference between active therapeutic dose and overdose
Benzodiazepines
- good fast acting anxiolytic
- large therapeutic ratio / window
- may cause dependence
- interacts with alcohol
indirect agonist, has no effect on its own, only with GABA
Evidence of GABAergic dysfunction in anxiety disorders
patients with panic disorder have less benzodiazepene binding sites
kinetics
at GABAa binding sitesBarbiturate agonist + GABA = massive hyperpolarisationBenzodiazepine indirect agonist
no action on its own + GABA large hyperpolarisationFlumazinil antagonist - no effect on its own
- GABA Less hyperpolarisation
Schizophrenia
NMDA receptors
PCP & MK801 block NMDA receptors (NMDA antagonist)
both produce hallucinations
certain antipsychotics enhance current flow (flux) through NMDA receptors
-