lecture 20: stimulants Flashcards
drugs of abuse def
drugs that tend to increase release of dopamine into the nucleus accumbens
- some drugs of abuse are much more likely to cause substance use disorders
examples of drugs of abuse
- stimulants
- opioids
- alcohol
- benzodiazepines
- psychedelics
- cannabis
what are stimulants
= drugs which increase locomotion, wakefulness, and cognition
- stimulants typically significantly increase the release of dopamine in the nucleus accumbens
- the strongest stimulants are dopamine releasing agents followed by NDRIs
what is tolerance
= a decrease in potency of a drug after repeated use
–> more drug is required for the same response
what are the causes of tolerance
- change in receptor function (NACh desensitisation)
- internalisation of receptors
- internalisation of transporters
- exhaustion of mediators
- increased drug metabolism
what are the mechanisms of tolerance
–> change in receptor expression
- u-opioid receptor expression is down-regulated with chronic use (fewer receptors are present on neurons)
- dopamine transporters and receptors can be down-regulated in methamphetamine abusers
–> internalisation of receptors
- prolonged exposure to agonist will cause receptors to be internalised into the cell
- over activation can trigger internalisation, so there are less receptors on the cell membrane
how does tolerance impact neurotransmission
–> receptor down regulation
- fewer receptors available on postsynaptic neurons
- neurotransmitter release results in less receptor activation
- results in decreased intracellular signalling
= if fewer D1 GPCRs are present, less cAMP will produced inside the cell
receptors involved in drugs of abuse
- dopamine
- alpha (noradrenaline)
- serotonin
- NMDA (glutamate)
- opioid
- GABA
- cannabinoid
- nicotinic (acetylcholine)
what behavioural addictions is dopamine believed to be involved in
- gambling addiction
- food addiction
- sex addiction
where is dopamine released from
ventral tegmental area
where are dopamine receptors found
nucleus accumbens
when does VTA activity (dopamine release into nucleus accumbens) increase
with the presence of an unexpected reward
- strongest release of dopamine without euphoria is by having some sort of positive event that we don’t expect
difference between tonic and phasic firing
tonic = baseline level of firing (tone)
phasic = burst of release, drastic change in firing
what is the role of dopamine in drug dependence
- most but not all drugs that cause dependence increase dopamine levels in the brain
- phasic or “burst” firing of dopamine receptors is more likely to cause drug dependence
noradrenaline and dopamine releasing agents (NDRAs)
- amphetamine and methamphetamine enter vesicles and push dopamine and noradrenaline out into the synapse
- once in the synapse these high levels of neurotransmitters will bind to dopamine and noradrenaline receptors
- methamphetamine enters the brain more rapidly than amphetamine = metamphetamine exhibits increased dependence risk compared to amphetamine
why does methamphetamine have a higher dependence risk
- because it is more lipophilic (gets into the brain faster) = pushes more dopamine and noradrenaline out of the neurons at a faster rate
serotonin releasing agents (SRAs)
- MDMA releases neurotransmitters the same way as methamphetamine
–> MDMA primarily releases serotonin rather than dopamine - MDMA is much less likely to cause dependence than methamphetamine
cocaine
–> cocaine is an NDRI
–> NET and DAT recycle dopamine/noradrenaline by removing them from the synapse
- increases noradrenaline binding to a2 receptors
- increases dopamine binding to D1 receptors in the nucleus accumbens
–> effects are not long lasting which many contribute to addictive potential
- smoking cocaine (crack) is much more addictive than intranasal cocaine
smoking or injective drugs vs snorting or swallowing
- use drugs more frequently
- spend more money on drugs
- greater loss of control over drug taking
- more likely to overdose
pharmacokinetics
how quickly drugs get into and out of the body
how does speed of administration impact dopamine
the faster it goes into the bloodstream the more of a phasic release of dopamine we get so the more euphoria we get
impacts of speed of drug absorption and use
- speed of drug delivery with NDRIs/NDRAs is more likely to imitate the phasic release of dopamine
- speed of drug delivery results in rats self administering higher total doses of drug
- mouse studies show dopamine receptor down regulation differences between rapid and slow delivery of cocaine
- speed of drug delivery has been found to alter some gene expression pathways in neurons
why does the speed of administration matter
–> D1 receptors are responsible for the dopamine “high:
- D1 receptors are lower affinity receptors than D2 receptors
- phasic (burst) firing of dopamine is required to activate D1 receptors
- rapid drug delivery increases D1 receptor activation
–> D2 receptors are occupied first before D1 receptors
- high concentrations of dopamine are needed in the synapse to activate remaining D1 receptors
affinity def
describes how tightly a drug or neurotransmitter binds to a receptor
