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Title: Neuroscience - Pharmacology of Reward Pathways - Lecture 7
Description: My notes from my module 'Neuroscience' made in my second year at the University of York. They're in the format of the presentation on the left with small powerpoint slides, and the transcript of what was said during that slide on the right.
Description: My notes from my module 'Neuroscience' made in my second year at the University of York. They're in the format of the presentation on the left with small powerpoint slides, and the transcript of what was said during that slide on the right.
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Slide 1
Module BIO00009I
Neuroscience
Lecture 7
Pharmacology of reward pathways
interaction with dependence-producing drugs
Sangeeta Chawla
sangeeta
...
ac
...
Neuronal cell signalling
Intracellular signalling
- GPCR and Ca2+ signalling
- Modulation of synaptic transmission
L6
...
Pharmacology of reward pathways
-The reward pathway
-Synaptic targets of dependence-producing drugs
L8
...
Understand how intracellular signalling contributes to
neurotransmission and its modulation
...
Relate major anatomical regions of the brain to their function
and neural circuits to behavioral responses
...
Understand how small molecules can interact with
neuronal proteins to modify connectivity within neural
circuits and alter behaviour
...
Appreciate the mechanisms by which behaviour is
synchronized to day-night cycles
...
Explain and evaluate how our understanding of behaviour
and neural circuits has been inferred from particular
experiments
...
Anatomy and neural circuits
The reward pathway
Dopamine project to forebrain called nucleus
succumbus, this is the part of brain modifed by addictive
drugs either directly or indirectly
...
Pharmacology of reward pathway
Overview
VTA sends
dopaminergic
projections
to the Nucleus
Accumbens and,
Amygdala
(mesolimbic pathway)
VTA dopaminergic
projections to
Prefrontal cortex
( mesocortical
pathway)
(plans how to get
stimulus again)
Feder et al, 2009 Nature Reviews Neuroscience 10, 446-457
...
Blue lines represent glutamatergic connections; green
lines represent; red lines represent dopaminergic
connections; the orange line represents a GABA (aminobutyric acid)-ergic connection
...
Doesn’t just
project to nucleus accumbens
...
Amount of stimulus gives it a level of reward- the more
there is activity in NA, the more likely you are to seek
the behaviour again
...
Pharmacology of reward pathway
The Dopaminergic synapse
Synaptic transmission at
Dopaminergic synapses
Note D2 autoreceptors on presynapse!
VMAT: Vesicular monoamine transporter
Dopamine loading into vesicles
MAO: Monoamine oxidase
Dopamine degradation
Degradation
MAO
DAT: Dopamine transporter
on plasma membrane
Dopamine reuptake
VMAT
DAT
Int J Biol Sci 2010; 6(2):133-150
On presynaptic site, Dopamergic axon terminal
...
Some neuropeptides are synthesised in the cell body,
packaged into vesicles that are quite large
...
Smaller
aa derived NT are synthesised locally, enzymatic
conversion of dopamine at synapse, makes load vesicles
with dopamine
...
On
post is GPCRs which are dopamine receptors (D1),
coupled to Galpha S turn on adenyl cycase increases
activity to make more cAMP
...
Dopamin is then taken back by presynaptic terminal via
transporter, some degraded by enzyme, some recycled
into vesicles
Drugs act on the proteins involved in recycling
...
Pharmacology of reward pathway
Cocaine
Some drugs of abuse interact with Dopamine transporters
in the reward pathway (increasing synaptic dopamine)
Cocaine blocks DAT
acutely increasing
Dopamine
-DAT knockout mice show no
behavioral activation after
Cocaine or amphetamine
Giros et al, Nature
...
Mice behavioral activation after cocaine: increased in
stereotypic locomoter activity- sniffing grooming,
rearing
...
Cocaine blocks dopamine transporter, therefore its not
taken back up into synapses so more dopamine hanging
around
...
How do we know this?
-knockout mice for dopamine receptor
How to tell mice is addicted? How measured?
-mice show behaviour sterotypes,
-stereotypical sniffing grooming etc same as humans
(nail bitinge etc)
-but knockout don’t show any behavioural activation
Reward pathway make seek out reward again
-seeking the drug, activating NA again
But all drugs have side effects, have other effects on
other parts of the brain
Slide 8
L7
...
This circuit is important for fine tuned movement,
affected in diseases such as parkinsons
Slide 9
L7
...
Amphetamines: Similar but slightly different
Also increase synaptic dopamine enter presynaptic
terminals via dopamine transporter (amphetamine is
structurally similar to dopamine)
Taken up by presynaptic terminals and accumulates
there , eventually taken up by VMAT out of vesicles
...
Then concentration gradient increases, so
Dop receptors detects this, so reverses, so dopamine
moved out of cell
...
Cocaine and amp are examples of direct action at the
synapse
Slide 10
L7
...
Indirect modulation of a reward pathway
There are also local GABAergic neurones inside the VTA
that are modulated by drugs
...
VTA- also recives GABergic from drug
Local GABergic + NAc projections inhibit VTA
Slide 11
L7
...
Slide 12
L7
...
Pharmacology of rewards pathway
Opiates cellular effects
Inhibit neurotransmitter release (GABA)
by reducing the excitability
of the presynaptic membrane
1
...
Open GIRKs- G protein-gated inwardly rectifying
K+ channels (hyperpolarize neurons)
GIRKs regulated directly by Gbg subunits
L7
...
We have opiate receptors in the brain (endogenous
receptors)
...
We made natural
ligands for these, the endorphins etc
Involved in pain/mood
Inhibit GABAergic neurones How?
Opiate receptors are GPCRs, theres 3 types including
mu,
Substances (morphine, heroin, methadone) trigger tis
receptor, they have different distribution about the CNS
...
This reduces NT release
(GABA)
...
This causes direct
modulation of beta/gamma subunits
...
Addictive behaviour is difficult to assess
Expose rodents to drug
...
Measure time in either compartment
...
Give saline/drug injections in one compartment, then
record now how long spent in each compartment and
look at difference
...
Scores calculated as the
difference between postconditioning and
preconditioning time spent in the compartment
associated with morphine
...
Pharmacology of reward pathway
Opiates in Behavioral paradigm
Conditioned place preference
WT
D2R KO
Scores calculated as the
difference between
postconditioning and
preconditioning time spent in the
compartment associated with
morphine
...
Mice don’t show the same
morphine induced place preference
...
Dopamine D2 receptor
KO mice show
no morphine-induced
place preferenceMaldonado et al, 1997, Nature 388:586
Slide 16
L7
...
Nicotine also acts on presynaptic channels on
glutamatergic axons from cortex and amygdala
that project to VTA and Nac neurons
...
Some
nicotine can act directly on NA neuron
...
Niccotine can also act on presynaptic terminals on
glutamatergic terminals (indirect modulation) it
increases excitability so more glutamate is released to
VTA
...
Pharmacology of rewards pathway
Schematic overview
Drugs and the reward pathway-summary
Cocaine/amphetamine increase dopamine by acting on
dopamine transporters, it hangs around for long
...
Purves
Slide 18
All make you seek the reward circuit again, these drugs
are similar to endogenous compounds
...
Side effects
L7
...
Cannabis- affects pre synaptic transmission,
normally only released when there’s high frequency
firing overactivity, to modulate the activity- feedback
inhibition! But when taken has access to receptors
in an uncontrolled manner!
Ethanol- addictive but not sure why?
Slide 19
L7
...
Pharmacology of reward pathway
Side effects
Dopaminergic projections
From substantia nigra to
The dorsal striatum
(caudate and putamen):
MOTOR FUNCTION
Vta projecting to NA and prefrontal cortex (rewrad
circuit) and this synapse is modulated by drugs typically
but they have side effects on other circuits such as
substantia nigra, resulting in effects like uncontrolled
movements
THINK ABOUT SIDE effects!
Drugs of abuse- Side effects
Drug
Side effects
Basal ganglia
Increased motor activity,
insomnia, euphoria
Amphetamine
Basal ganglia
Increased motor activity,
insomnia, euphoria
Morphine
Spinal cord
Analgesia, drowsiness
Cannabis
Hippocampus, Cerebellum
Impaired Memory, loss of
coordination and balance
Nicotine
Hippocampus, Cortex
Increased arousal and
vigilance
Ethanol
Slide 21
Targets outside reward circuit
Cocaine
Cerebellum, temporal
lobe/cortex
Sedation, slurred speech,
Motor incoordination, effects
on mood
L7
...
Pharmacology of reward pathway
Summary
3
...
Dependence-producing Drugs act to alter synaptic transmission by
acting on
a
...
enzymes involved in NT synthesis/degradation, - probably
ethanol
c
...
NT receptors
5
...
Behavioral experiments show important of
a
...
Dopamine Transporters
Mechanism is activation of reward pathway- induces
drug seeking behaviour
Nucleus accumbens neurons- all addictive stimuli
activate this
...
After
interaction with circuit get homeostatic changes,
compensative changes, eg too much dopamine in
synapse, post synaptic neurones will adapt, start
spreading less dopamine receptors leading to long term
chages resulting in lowered sensitivity- therefore drug
user uses higher and higher amount- as not getting
same reaction
Title: Neuroscience - Pharmacology of Reward Pathways - Lecture 7
Description: My notes from my module 'Neuroscience' made in my second year at the University of York. They're in the format of the presentation on the left with small powerpoint slides, and the transcript of what was said during that slide on the right.
Description: My notes from my module 'Neuroscience' made in my second year at the University of York. They're in the format of the presentation on the left with small powerpoint slides, and the transcript of what was said during that slide on the right.