Stimulants (Test 2) Flashcards
Monoaminergic stimulants
Increase synaptic levels of monoamine transmitters (especially dopamine and norepinephrine) to mediate stimulant and rewarding properties
Some of the earliest reasons that people would routinely take amphetamines/cocaine in the early days?
Increased attention and mood at low doses
○ Used to give amphetamines to people to get them to do boring and tedious tasks and stay attentive. Increased arousal and vigilance.
Effects of amphetamines/cocaine at higher doses
Get decreased activity and mood, can lead to schizophrenia like state (positive symptoms)
How do amphetamines/cocaine have a biphasic effect
Early stimulant, later depressant effect when looking at locomotion
Why is there a decrease in the “biphasic” effect
- Dopamine used to initiate motor sequences.
- Used to measure activity with mice in a box with IR lasers, counted how many beams the mouse broke while running around.
- A decrease in locomotion because you activated motor movements to the point where you can’t activate a full sequence and you’re stuck in one movement chain
How is decrease in activity due to stimulants related to schizophrenia?
- Also common in people with schizophrenia because they have too much dopamine activation.
- Small, repeated movements didn’t break enough laser beams, made people think that it was a depressant effect when really it’s stimulation to the extreme.
Do stimulants eventually become sedatives?
Decreased activity, but not sedative. Too much stimulation.
What happens with repeated administration of amphetamines/cocaine at postsynaptic sites?
Reinforcing effects gain tolerance. This means your doses get progressively bigger due to down-regulation at postsynaptic sites.
What happens with repeated administration of amphetamines/cocaine at presynaptic sites
Motor and psychosis effects sensitize and get bigger each time you take the drug due to downregulation at presynaptic autoreceptors.
Less sensitive autoreceptors, less inhibition of NT release. Causes excessive release of dopamine.
stereotopy
small, repeated movements.
How are amphetamines usually taken?
Usually orally or inhaled
Amphetamine pharmacokinetics
- High lipid solubility
- Weak base, best absorbed in the small intestine
- Huge half-life, from 1/3 of a day to a day and a half
What is amphetamine metabolized by?
Metabolized in the liver by cytochrome P450, shows cross tolerance with other drugs
TI for amphetamine?
rough TI is 7-15
Cocaine pharmacokinetics
- Poorer absorption than amphetamine, less lipid soluble.
- Half-life of about 60 minutes. Has a much shorter effect than amphetamine
What is cocaine metabolized by?
Metabolized by cytochrome P450
What is the TI for cocaine?
TI is roughly 15, double digits. On border of what we’d define as a very dangerous drug. Want TI to be in at least double digit domain. Potentially lethal consequences.
Amphetamine pharmacodynamics
- phosphorylates dopamine transporters so DA is pumped out of the cell into the synapse.
- With amphetamine, you don’t need Ca for exocytosis. DA is pumped into the synapse anyways. It’s Calcium independent and doesn’t need action potentials.
Cocaine pharmacodynamics
- Only blocks monoamine transporters (doesn’t reverse transportation). esp. 5-HT and dopamine
- This means that cocaine needs action potentials to work.
- local anesthetic by blocking voltage-gated ion channels including (voltage gated sodium channels)
monoamine transporter
Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters
How was cocaine used originally?
Doctor friend realized that it’s a local anesthetic and blocks conduction of pain. Analogues are now used for this (lidocaine for dentistry)
Primary reinforcing effects over time
Primary reinforcing effects usually diminish over time and become less important the more that people take a drug.
what is a primary reinforcer?
a primary reinforcer is a stimulus that does not require pairing to function as a reinforcer and most likely has obtained this function through the evolution and its role in species’ survival. Examples of primary reinforcers include sleep, food, air, water, and sex.
Does stress raise dopamine levels?
Stress increases dopamine – for this reason, perhaps, people who are stressed take drugs. Increase in dopamine might lead to the user having more reinforcing thoughts/behaviors
Tolerance
addicts come to experience pleasure less
Sensitization
addicts crave the experience more
What is an example of the resiliency of monoaminergic neurons?
Monoaminergic neurons are resilient – in parkinson’s you don’t see symptoms until about 50% of the neurons are gone
What is Ibogane?
Ibogane – a new psychotropic, this drug is an oneirogen, a drug that leads to an altered state of consciousness in which a person is amenable to behavioral modification via some form of cognitive therapy.
Incentive-motivation model of addiction
The incentive salience [incentive-moitvation] theory of addiction suggests that “liking” (hedonic value) of a drug may be dissociated from “wanting” the drug due to increased incentive salience.
amphetamines and ADHD
amphetamine and related stimulants reduce the symptoms of ADHD by increasing the “signal-to-
noise” ratio at synapses.
“noise” as in signal-noise
by blocking the DAT, “noise”
is reduced by a cAMP alteration in ion channels, primarily K+ channels.
“signal” as in signal-noise
by blocking the NeT, “signal”
is increased at synapses in the PFC as NE increases the effect that transmitters like GLU have at their synapses.
