4-DA and glu Flashcards
when given Ritalin, did people with lots of D2 receptors or little D2 receptors react pleasantly to the experience?
low levels of D2 causes euphoria
when given Ritalin, did people with lots of D2 receptors or little D2 receptors react negatively to the experience?
high levels of D2 causes dysphoria
what levels of D2 receptors may be protective against addiction?
high levels
how can you naturally increase D2 receptor levels?
exercise
what does social stress do to D2 receptor levels?
decrease
where are D2 receptors most affected in the brain?
nucleus accumbens (that is where you feel pleasure due to dopamine)
what G protein do D1 receptors use?
Gs
what G protein do D2 receptors use?
Gi/Go
what are the 3 steps in Gs pathway?
adenylyl cyclase stimulated, increases cAMP levels, activates kinases to phosphorylate
what are the 3 steps in Gi pathway?
inhibit adenylyl cyclase, inhibit Ca+ channels, activates potassium channels
what does the activation of potassium channels do to neuronal firing (Gi)?
decreases probability that neuron will fire
where are D1 receptors
on postsynaptic receptors
where are D2 receptors
on presynaptic and postsynaptic receptors
what does D1 receptors do to neurotransmission(excitatory or inhibitory)?
excitatory
what does D2 receptors do to neurotransmission(excitatory or inhibitory)?
inhibitory
what kind of pathways are associated to D1 type receptors
reward
what kind of pathways are associated to D2 type receptors
aversion
what is D1 affinity to dopamine and at what concentrations
low affinity (only active at high concentrations)
what is D2 affinity to dopamine and at what concentrations
high affinity (1000X higher, active at much lower dopamine concentrations)
love who?
FROG
which dopamine receptors respond to tonic levels of dopamine
D2 (D1 cant, it needs high concentrations)
which dopamine receptors respond to high levels of dopamine (bursts)
D1`
if D1 and D2 receptors have different effects, why doesn’t dopamine cancel itself out when it activates the receptors?
they are found on different neuronal populations that form different pathways (reward vs. punishment)
what 3 things happen once D2 receptors are activated
1-increase K+ channel and decrease Ca++ channel (hyperpolarization)
2-increase DAT
3-inhibits TH enzyme
what is TH enzyme and what does it do
tyrosine hydroxylase which helps synthesis DA
what is DAT
dopamine transporter (brings it inside the presynaptic neuron from the cleft
why does D2 decrease Ca++ channel
because you need Ca++ to release NT from vesicles
AND it helps make the neuron more negative (hyperpolarized)
why does low D2 cause a predisposition to likelyhood of addiction
because D2 are autoreceptors that help inhibit further dopamine release
what happens when you knock out D2 receptors in mice and then give them cocaine
they become more sensitive to cocaine
which type of neurons are D2 receptors on
the majority aren’t on DA releasing neurons
how can D2 receptors affect glutamate release
because there are D2 receptors on glutamate releasing neurons, so if there is DA released and leaks out near another D2 receptor, it can inhibit glutamate release
how can communication between diff. parts of the brain via glu or GABA be affected by DA? (ex:PFC communicating with amygdala)
DA influences the DA or GABA releasing neurons if they have D2 receptors on it, so it influences the excitability of the striatum
how is dopamine release and expectation related
they are related because expectation drives the response-dopamine release can change (even with the same dose) depending on the expectations
how would DA be released if the animal was given a dose smaller than expected
small - they ANGY (shuts down activity of neuron)
how would DA be released if the animal was given a dose larger than expected
big - they HAPI
what did the picture and dose experiment teach us about DA
not only reward, but also works with anticipation (and comparison of reward received to what was expected)
what is the dopamine signalling in pre-reward caused by
due to learned behaviour from cues and expectations (like a pic associated to a dose)
what is the dopamine signalling in post-reward caused by
summation of pharmacological properties of drug and expectation
what is the role of glutamate in the brain (associated to how drugs affect the brain)
neuroplasticity, over-learning of behaviours and relapse
what does glutamate signalling do to drug-related behaviours
it may “lock in” some of the behaviours
where are 2 locations that glutamate is released
presynaptic terminals and glial cells
where does/what causes the phasic/acute level of glutamate release
presynaptic terminals
where does/what causes the tonic/basal level of glutamate release
glial cells
what are mGluR (simple definition)
presynaptic metabotropic glutamate receptors
what activates mGluR
glutamate release from glial cells
what is the role of mGluR cells
to control sympathetic glutamate release (make sure there isnt excess release)
what does the cystine-glutamate exchanger do
releases (approx. 60%) glutamate from the glial cells
What does chronic drug use do to TONIC glutamate release
reduce it
how does chronic drug use reduce the level of tonic glutamate release
inhibits the cystine-glutamate exchanger (decreases activation of presynaptic glutamate autoreceptors)
why is more glutamate released during stress/ cue/drug stuff?
because cystine-glutamate exchanger is inhibited, which decreases activation of presynaptic glu autoreceptors, which turns off negative feedbacl
what does excess glu do to the brain (2)
induces neuroplasticity and impairs communication between the PFC and nucleus accumbens
what happens when both dopamine and glutamate are released on neurons in the nucleus accumbens
(ERK!) change in gene expression causing structure and function of neurons to change
what is ERK stand for
extracellular signal-related kinase
what causes the activation of ERK
only activated when dopamine and glutamate are released simultaneously on a signal neuron
what does activation of ERK cause
changes in neuronal structure and proliferation
-long term changes
where does ERK activation happen
postsynaptic side of a neuron, like the spiny neuron that receives both DA and glu input
what are the steps in the ERK pathway(4)
- D1 activation leads to stimulation of glu receptor
- D1 causes adenylyl cyclase and cAMP (Gs)
- glu causes increase Ca2+
- ERK gets phosphorylated and can cause gene transcription (only happens if BOTH DA and glu pathways are activated)
can ERK happen if D1 is activated but not NMDA
no
is ERK activation increased or decreased with most drugs of abuse
increased
what is a key role of ERK when it comes to drug abuse
neuronal plasticity
what NT plays a role in transient neuroplasticity
dopamine
what NT plays a role in stable neuroplasticity
glutamate and dopamine
what is stable neuroplasticity
when your brain has already changed-it is very hard to turn back the effects of drugs
how can you turn around compulsive relapse
behavioural intervention and pharmacology
-abstinence may not be enough
