6/18- Neurobiology of Addiction 3: Stimulants and Opiates Flashcards Preview

Term 5: Behavioral Science > 6/18- Neurobiology of Addiction 3: Stimulants and Opiates > Flashcards

Flashcards in 6/18- Neurobiology of Addiction 3: Stimulants and Opiates Deck (28):
1

__ 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

2

Pharmacotherapy for opiates include?

- Methadone

- Buprenorphine

- Naltrexone

- Lofexidine

- Clonidine

3

Pharmacotherapy for alcohol include?

- Naltrexone

- Disulfiram

- Acamprosate

4

Stimulants include what?

- Cocaine

- Amphetamines

5

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

6

Effects of addictive drugs on NT levels?

Relative amounts? (comparing morphine, cocaine, amphetamine, and nicotine)

Increase DA levels

Amphetamine > cocaine > nicotine > morphine

7

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

8

Parkinsonian (PD) Brain Abnormalities are seen with which drugs of abuse?

- Amphetamine

- Cocaine

9

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

10

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

11

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)

12

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

13

- 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

14

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

15

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

16

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? 

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17

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

18

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

19

Example of and mechanism involved in opiate partial agonist activity?

Ex) Buprenorphine

- Bind to receptor

- Partial coupling to G protein

20

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]

21

Relative effects of full agonist, partial agonist, and antagonist on opioid receptors (chart)

- Full agonist = Methadone

- Partial agonist = Buprenorphine

- Antagonist = Naloxone 

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22

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)

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23

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

24

Buprenorphine inhibits cAMP ____ (more/less) than morphine

Buprenorphine inhibits cAMP less than morphine

- Producing less dependence

- Milder withdrawal

- Less effective relief of severe dependence

25

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

26

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

27

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

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28

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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