Stimulants Flashcards
What types of transmitters do amphetamine & cocaine effect?
all monoamines!
DA, NE, EPI, 5-HT
What happens when stimulants are used at low doses?
Increased attention / mood
What happens when stimulants are used at higher doses?
Decreased activity / mood
What happens with chronic high doses of stimulants?
Schizophrenia-like state
What are the differences between schizophrenic brains and chronic stimulant brains?
Schizophrenic brains have lower DA concentrations in some parts
How long does it take to remove symptoms with antipsychotics in stimulant-induced psychotic states?
Schizophrenia-induced?
Stimulant-induced: Hours
Schizophrenia-induced: Weeks
What effects will tolerate with stimulants? Why?
Reinforcing effects
Due to regionally specific receptor downregulation at postsynaptic sites
What effects will sensitize with stimulants?
Why?
Motor and psychosis-inducing effects
Due to downregulation of presynaptic autoreceptors
What breaks down monoamines?
MAO (monoamine oxidase)
What is the ED50 of amphetamine?
10mg (narcolepsy)
20-30mg (adhd)
250mg (abuse)
What is the LD50 of amphetamine?
200mg
What is the TI of amphetamine?
7-15
What is TI?
LD50 / ED50
What is the half-life of cocaine?
60min
What is the ED50 of cocaine?
~3mg dose
What is the LD50 of cocaine?
~50mg
What is the TI of cocaine?
~15
What are the effects of amphetamine?
Increase release of newly-synthasized DA
Cause vesicles to release DA into cytoplasm
What does amph do to DT (dopamine transporter)?
Phosphorylates it
DA is then pumped out of the cell
What does Amphetamine block?
MAO
What is MAO?
monoamine oxidase
Degradation enzyme responsible for inactivating monoamines
What does cocaine do?
Blocks transporter (compared to amphetamine, which reverses it)
What is the crucial difference between cocaine / amphetamine?
You need action potentials with cocaine
What does cocaine do if near a sodium channel?
Blocks it (local anesthetic)
What does cocaine do if near a 5-HT transporter?
Blocks it (and other monoamine transporters)
Why doesn’t cocaine always block ion channels, so that it doesn’t have an effect at the synapse?
You need much higher concentrations of cocaine to block ion channels
What is the medial forebrain bundle?
Axons from the midbrain to the forebrain
mesoaccumbens axons
mesocortical axons
mesolimbic axons
Monoamine projections to the forebrain
How (generally) do amphetamines help with ADHD?
Interaction between NE and DA
What are synapses en passante?
Synapses ‘in passing’
Swelling in the middle of an axon containing voltage-gated Ca2+ channels
Cause release sites in the axon itself
What is Volume Conduction?
Communication not specific to a synapse
Release neurotransmitter into extracellular space, making a ‘gradient’ of changed activation
What are the most diverse group of ion channels?
K+ channels
What is a current shunt?
Na+ shunt, K+ shunt
As quickly as Na+ comes in, K+ goes out (K+ driving force affected by Na+)
Keeps membrane voltage stable
What are EPSPs in relation to shunts?
Overwhelming the ability of the leak channels to compensate for Na+
What is the general rule for D1/D2 receptors?
D1 = excitatory D2 = inhibitory
What is the effect of blocking shunt for NE/DA in relation to ADHD?
Signals better able to come in
Noise blocked
What is a metaphor for increasing NE release for a state-change?
Increase volume: make signal stronger, noise weaker
What’s happening in the neuron when you change signal-to-noise by adding amphetamine?
Less random activation (shunts, DA)
Cell is more excitable (state-change, depolarization)
Higher likelihood of action potential, but less random noise
How addictive are psychostimulants?
Among the most readily addictive substances known
What happens when you have low levels of D4 receptors?
‘need the buzz you get from seeing what’s over the next mountain’
More apt to explore, more apt to desire novel experiences
How do NE transporters relate to DA?
They’re great at picking up DA - can reduce DA levels
Only one enzyme away from NE
How to DA transporters relate to NE?
Not great at picking up NE
NE is already farther along in the cascade chain than DA, so you can’t synthesize DA from NE
How much caffeine does a 6-oz cup of coffee have?
74-83mg/5-oz cup (tall is 12-oz)
What might help in infant sleep apnea?
Caffeine
Which receptors does caffeine antagonize?
A-1 and A-2Aa adenosine receptors
Where are the adenosine receptors we’re interested found?
Terminal boutons
But they’re there all over the nervous system
Where is adenosine released?
Postsynaptically, propagates BACKWARD to terminal bouton
What do A-1 receptors do when activated?
2nd messenger
Increase K+ efflux
Decrease Ca2+ influx
(decrease exocytosis)
Where are there lots of A1 receptors?
HC, striatum, septum, frontal/cingulate cortex
What brain region is affected first in Alzheimer’s?
Septum
What type of neurons mainly exist in the septum?
Cholinergic
What is a higher dose of caffeine?
~500mg+
What can caffeine do at higher doses?
Hallucinations, paranoia, mania/depression
Where in the brain is caffeine less potent?
Brainstem
2-10 cups
Where in the brain is caffeine not very potent?
Spinal cord - need 20-50 cups (tremor/seizures)
What is the LD50 of caffeine?
~200 cups of coffee (15g)
Where is caffeine metabolized?
Cytochrome p-450 in the liver, excreted in urine
Overlaps with alcohol breakdown enzymes
What are the three significant metabolites of caffeine?
Paraxanthine (lose a methyl group at the top right)
Theobromine (lose a methyl group between ketones)
Theophylline (lose a methyl group on the bottom left)
How does cocaine absorption compare to amphetamine?
It’s worse (less fat-soluble)
How is the “signal” increased in signal-to-noise by amphetamine?
Blocking the NeT
What does blocking the NeT by amphetamines do physically in the PfC to strengthen “signal”?
NE increases effect transmitters like GLU have at synapses
How is “noise” decreased by amphetamine?
Blocks DAT
How does blocking DAT decrease “noise”?
cAMP alteration in ion channels (primarily K+)
Suppresses K+ conductance that normally amplifies irrelevant inputs
How popular is nicotine?
3 most used drug in the world
What is the current therapeutic relevance of nicotine?
NO relevance
(Reduces nicotine withdrawal…)
may help tourette’s, parkinson’s, alzheimer’s, schizophrenia
Where do you lose cholinergic neurons with alzheimer’s?
Septum
What does nicotine do?
Cholinergic agonist
Differences between ACh and Glu?
Glutamate is everywhere, has refined effect of NDMA
Ach is very specific to specific parts of the brain (e.g. cholinergic neurons of the septum)
How is nicotine usually injested?
Orally or by inhalation
What is the solubility of nicotine?
Both fat and water-soluble
How fast does nicotine hit the brain with inhalation?
3 min
peak levels within 10 min
What is the ED50 of nicotine?
.5-1mg
cigarette is 8mg
What is first-pass metabolism like for nicotine?
HIGH. 90% metabolized in liver by cytochrome P450
In what medium is nicotine eliminated?
Urine
What is the half life of nicotine?
1/2 hr
Why does tolerance to nicotine develop in the liver?
hepatic enzyme activation
What is the LD50 of nicotine?
60mg
What are lethal effects of nicotine produced by?
Paralysis of respiratory muscles
Nicotinic receptors get overstimulated
What happens to quiescent (dormant) nAchRs in the presence of nicotine?
Upregulated, they’re activated
What happens in ongoing activation of nAChRs by nicotine?
Desensitizes ongoing activation
Acting as an antagonist now
How does long-term antagonistic effects of nicotine work?
Nicotine pushes receptors into an inactive state after long enough exposure
Where in the pons do you see lots of nitcotinic Ach receptors?
Locus coeruleus
Lots of NE released there
What is causing the rewarding effects of nicotine?
Stimulation of mesolimbic DA neurons by nicotinic cholinergic neurons
What is the chemical source of arousal by nicotine?
nACh activation of LC/Brainstem neurons involved in sleep/wake
Activation of cortical/thalamic neurons
What does amphetamine do to MAO?
Blocks it, this increases synaptic DA levels
Why might amphetamine and cocaine cause toleration of rewarding/reinforcing effects?
Not as many DA receptors in specific parts of the brain
What is cocaines’ solubility like?
Less lipid soluble than amphetamine
Both lipid and water soluble (facilitate entering brain)
Which monoamine transporters does cocaine block?
5-HT, DA
Cocaine acts as a local anesthetic. What does it do to ion channels that causes this?
Gets charged (+)
When it’s charged (+), gets stuck inside sodium channels, blocking Na+ from entering
What is DATKi? How is it relevant to cocaine?
A knock-in DA transporter not sensitive to cocaine
Cocaine doesn’t block it, so it recycles DA just as easily, so cocaine has less effect
How fast is the GI absorption of caffeine?
99% in 45 min (fast)
How fast is the GI absorption of caffeine?
99% in 45 min (fast)
Where are A1 and A-2a found?
presynaptically (terminal boutons)
What happens when adenosine binds to A-1 receptors?
2nd messenger signals increase K+ efflux, decrease Ca2+ influx
This decreases exocytosis
Where in the brain are A-1 receptors generally found?
Limbic + memory system:
HC, striatum, septum, frontal/cingulate cortex
The neurons of which part of the brain does caffeine have the greatest effect on?
Cortical neurons - big increase in cortical activity
