6/18- Neurobiology of Addiction 3: Stimulants and Opiates Flashcards
__ of physicians known to abuse drugs as known to their colleagues are not reported
2/3 of physicians known to abuse drugs as known to their colleagues are not reported
Pharmacotherapy for opiates include?
- Methadone
- Buprenorphine
- Naltrexone
- Lofexidine
- Clonidine
Pharmacotherapy for alcohol include?
- Naltrexone
- Disulfiram
- Acamprosate
Stimulants include what?
- Cocaine
- Amphetamines
Effects of stimulants (mechanism and disease associations)
- DA and reward
- Amino acid reuptake carriers
- Receptor down-regulation (Parkinson’s)
- Cerebral vasoconstriction (stroke)
- GABA down-regulation
Effects of addictive drugs on NT levels?
Relative amounts? (comparing morphine, cocaine, amphetamine, and nicotine)
Increase DA levels
Amphetamine > cocaine > nicotine > morphine
How does cocaine alter the brain?
Inhibits DA reuptake
- D2 R loss
- Hypodopaminergic state -> DA damage and Parkinsonism
Chronic stimulants reduce DA receptors and transporters
- Indirect effect on frontal cortical projection areas of DA neurons
- DA Rs do not recover; even after 4 mo of abstinence
Parkinsonian (PD) Brain Abnormalities are seen with which drugs of abuse?
- Amphetamine
- Cocaine
Stimulant abusers can also experience cerebral perfusion deficits.
- Pathophysiology?
- Results in what?
Stimulant abusers can also experience cerebral perfusion deficits.
Pathophysiology:
- Abnormally adherent platelets
- Vasoconstriction
Results:
- Affective/sensory dysregulation: occipital brain perfusion defects and fMRI abnormalities in occipital and temporal lobes
- Cognitive impairment: frontal/striatal brain perfusion defects; correlate with degree of neuropsych deficits
What are the cardiovascular effects of cocaine?
- Vasoconstriction leads to 30% blood flow reduction during human cocaine administration and cortex flow most reduced
- Chronic cerebral perfusion defects are evident even after sustained abstinence
- Platelet adherence and vasoconstriction together may contribute to the sustained perfusion defects
- Reduced cognitive functioning correlates with defects in perfusion
Difference in response to video of sad person for cocaine abusers vs. others?
- Healthy normal people: substantial brain activation when watching video of sad people
- Cocaine abusers: do not perceive emotions such as sadness in other people; poor blood flow
- Cocaine abusers pay attention to reminders of cocaine use, but ignore emotions in other people such as sadness (so brain not completely dysfunctional, but very selectively functional)
How does cocaine affect GABA and CBF?
- GABA deficiency after chronic cocaine
- Cortical CBF (cortical blood flow) reflects mostly GABA inter-neuronal activity
- GABA activity reduced during visual activation to usual cues like sadness compared to normals
- Cocaine cues lead to over-arousal in users, but are irrelevant to normals, so little visual cortex activity in normals
- Brain activation to ____ is reduced by recent cocaine use
- Brain activation in cocaine abusers is reduced in _______ areas that are used to _________
- Brain activation to visual events is reduced by recent cocaine use
- Brain activation in cocaine abusers is reduced in visual association areas that are used to understand, judge, and decide about things the cocaine abuser is seeing
What does reduced brain activation mean?
- Cocaine abusers cannot understand complex emotional events that they are seeing
- Cocaine abusers cannot decide quickly to use their relapse prevention cognitive skills when they see cues that stimulate their craving
Conclusions:
Brain abnormalities in stimulant abusers:
Pathophysiology
- ___ deficiency - ___
- _____
- ___ -> ____
Affective/sensory dysregulation
- _____
- fMRI abnormalities: _____
Conclusions:
Brain abnormalities in stimulant abusers:
Pathophysiology
- DA deficiency- Parkinson’s
- Abnormally adherent platelets
- Vasoconstriction -> multi-infarct dementia
Affective/sensory dysregulation
- Occipital brain perfusion defects
- fMRI abnormalities: occipital and temporal
What are the different types of opioid receptors mainly distributed in the brain? Functions?
Mu:
- analgesia
- euphoria
- respiratory depression
- addiction
Kappa:
- analgesia
- dysphoria
- diuresis
- addiction?
Delta
- analgesia?
- addiction?
Example of and mechanism involved in opiate agonist activity?
Ex) Morphine
- Bind to receptor
- Activate G protein
- Affect adenyl cyclase
- Increase or decrease conversion of ATP -> cAMP
Example of and mechanism involved in opiate antagonist activity?
Ex) Naltrexone
- Bind to receptor
- No activation of G protein
- Expose “spare or hidden Rs” - traffic effects (Rs transported from ER, vesicles,…); makes them very useful for reversing receptor abnormalities from the use of chronic agonists
Example of and mechanism involved in opiate partial agonist activity?
Ex) Buprenorphine
- Bind to receptor
- Partial coupling to G protein
Adventitious properties of Buprenorphine in treatment?
Partial agonist, so:
- High safety profile/ceiling effect
- Low dependence
Tight receptor binding:
- Long duration of action
- Slow onset mild abstinence
[Expose “spare or hidden Rs” - traffic effects (Rs transported from ER, vesicles,…); makes them very useful for reversing receptor abnormalities from the use of chronic agonists]
Relative effects of full agonist, partial agonist, and antagonist on opioid receptors (chart)
- Full agonist = Methadone
- Partial agonist = Buprenorphine
- Antagonist = Naloxone
Mu efficacy and opiate addiction (graph)
- Super agonist = Fentanyl
- Full agonist = Mophine/heroin, Hydromorphone
- Partial agonist = Buprenorphine
- Antagonist = Naltrexone
(With cancer treatments, may get to point where any more would kill them, so must take them off and start over)
What is the underlying mechanism of positive opiate effects?
With full agonists (morphine)?
With partial agonists?
2nd messenger: cAMP (cyclic adenosine monophosphate)
- Opiates bind to mu opiate Rs and INHIBIT cAMP formation
- Chronic opiates up-regulate cAMP, leading to withdrawal symptoms (increased converting enzyme made due to mu opiate R inhibiting cAMP formation)
- Partial opiate agonists like buprenorphine inhibit cAMP less than full agonists
- Less inhibition produces milder withdrawal when inhibition is removed by stopping Buprenorphine
Morphine:
- Morphine binds mu Rs, inhibiting cAMP formation
- Chronic opiate inhibition of cAMP formation -> more enzymes synthesized to make cAMP
- When opiate removed, more cAMP than normal is produced due to increased amt of enzyme
- Increased cAMP levels lead to increased activity in adrenergic neurons and withdrwawal symptoms
Buprenorphine inhibits cAMP ____ (more/less) than morphine
Buprenorphine inhibits cAMP less than morphine
- Producing less dependence
- Milder withdrawal
- Less effective relief of severe dependence
What are the implications of reduced activity of Buprenorphine at mu opiate Rs?
- Buprenorphine reduces cyclic AMP levels less than morphine or methadone
- Less opiate effects as buprenorphine dose is raised
- Less compensatory enzyme synthesized to make cyclic AMP - When buprenorphine removed, less cyclic AMP than when methadone removed
- Less activity in adrenergic neurons and less withdrawal symptoms after stopping buprenorphine than methadone
What are some opioid withdrawal symptoms?
- Dysphoric mood
- Nausea/vomiting
- Muscle aches/cramps
- Lacrimation
- Rhinorrhea
- Pupillary dilation
- Sweating, piloerection
- Diarrhea
- Yawning
- Mild fever
- Insomnia
- Craving
- Distress/irritability
“Everything runs”
- Like a bad case of the flu
What is used to treat opioid withdrawal?
What characteristics allow it to do so well?
Buprenorphine
- High affinity and slow dissociation from mu opioid receptor
- Less withdrawal symptoms during detoxification
Equivalent opioid withdrawal severity
Summary:
- Buprenorphine is mu opioid, partial agonist due to action at cyclic AMP second messenger, not poor receptor binding
- Profile of effects similar to other mu agonist opioids, but less respiratory depression, lower physical dependence, easier withdrawal
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