B3: Drug Addiction

Question 1

What is ‘addiction circuitry’?

Answer 1

Where drug-evoked synaptic plasticity outlasts the presence of the drug in the brain.
This contributes to neural circuit reorganization and is the proposed basis of addiction

Question 2

What is the common target zone of addictive drugs?

Answer 2

All target the Mesocorticolimbic Dopamine (DA) System

This system originates in the Ventral Tegmental Area (VTA) and projects mainly to the Nucleus Accumbens (Nac) and to the Prefrontal Cortex (PFC)

So addictive drugs all increase dopamine (DA) concentration in the projection areas of the VTA, as well as within the VTA itself

Question 3

How does cocaine increase DA levels?

Answer 3

Increases amount of DA at synapses by directly inhibiting DA transporter (and thus preventing reuptake of DA from synaptic cleft)

Question 4

How do amphetamines increase DA levels?

Answer 4

Amphetamines are transporter substrates. They are taken up into the cell and enhance the nonvesicular release of DA into synapse

Question 5

How does nicotine increase DA levels?

Answer 5

Nicotine binds to Nicotinic Receptors on DA neurons

Stimulates presynaptic release of DA in the Nuc (nucleus Accubens(( by stimulating presynaptic cholinergic receptors

Question 6

How do opioid agonists (e.g. opioids, cannabinoids, GHB etc) increase DA levels?

Answer 6

Opiod agonists target GABAergic interneurons in the VTA that normally inhibit DA release in the Nuc (nucleus accubens)

Loss of GABAergic suppression of DA release from DA neurons = increased DA release into VTA and Nuc

Question 7

What is interesting about alcohol addiction?

Answer 7

Can occur in the absense of DA mechanisms

Question 8

Main indications for medical use of benzodiazepines

Answer 8

Anxiety
Sleep Disorders
Sometimes in Epilepsy

Chronic use can lead to addiction

Question 9

How do Benzodiazepines increase DA levels?

Answer 9

Benzodiazepines bind to GABAa receptors on Interneurons

This prevents normal inhibition of DA release from DA neurons

This there is increased DA release

Question 10

What is zolpidem and what is it usually used for?

Answer 10

A non-benzodiazepine hypnotic, that works in the same way as benzodiazepines:

Binds to GABAa receptors of Interneurons

This prevents their normal inhibitory action on DA neurons

Thus leading to increased DA release

Usually used for insomia and various brain disorders

Question 11

What were the warning alerts about Zolpidem released in 2008 and 2013?

Answer 11

May be associated with complex sleep-related disorders: sleep walking, sleep driving and other bizarre behaviours

In 2013, recommended that zolpidem dosages be reduced by 20% due to next-morning alertness impairments

Question 12

Describe cocaine and amphetamine neuroplasticity changes

Answer 12

Found to increase dendritic sine density, and increase dendritic branching

Found to affect medium spiny GABAergic neurons in the Nuc (nucleus accubens)

And Glutaminergic pyramidal neurons within the PFC

These changes were evidence within 24 hours of drug administration, and persisted for 3-4 months

Question 13

What is the outcome of repeated exposure to methamphetamine?

Answer 13

Causes long-lasting presynaptic corticostriatal depression (LTD)

-> i.e. affects forebrain functioning

This is relieved by readministration of methamphetamine

Question 14

Describe the LTD that occurs with long-term methamphetamine use

Answer 14

Synaptic changes - involving alterations in DA and cholinergic receptor systems

Synaptic changes persist long after withdrawal of drug from system

Without the drug, there is long-term corticostriatal depression (depressed forebrain functioning) which is relieved by readministration of methamphetamines

Question 15

What are the chief pharmacological treatments for alcohol addicion?

Answer 15

Acamprosate

Naltrexone

Disulfiram

Question 16

Describe the use of Acamprosate in alcohol withdrawal

Outcomes of this therapy in people?

Answer 16

Acamprosate: mixed antagonist of NDMA and mGluR5 glutamate receptors

Thus, it helps to reduce the neuronal hyperexcitability associated with alcohol withdrawal

In some, it redces alcohol craving - some of these people remain abstinent, while others drink less alcohol

Question 17

Neuronally, what occurs with alcohol withdrawal

List the drug which is used to deal with each of these effects, in the treatment of alcohol addiction

Answer 17

Neuronal hyperexcitability (Acamprosate)

Release of endogenous opioids - enkaphalins and endorphins (Naltrexone)

Question 18

Guidelines for Acamprosate therapy: initiation of treatment, contraindications, adverse effects

Answer 18

Should be initiated 1 week after cessation of drinking

Contraindicated if significantly impaired hepatic or renal impairment

Diarrhoea, rashes, abdo pain, vomiting, nausea

Long-term benefits/adverse events unclear

Question 19

Describe the use of Naltrexone in alcohol and opioid withdrawal

Answer 19

Naltrexone competitively inhibits all opioid receptors

remembering that alcohol causes release of endogenous opioids enkaphalins and endorphins

Question 20

What will happen if drinking alcohol whilst on naltrexone?

Answer 20

Patient will feel less pleasurable effects: naltrexone blocks opiod receptors, thus preventing endogenous opioids released by alcohol (enkephalins and endorphins) from having effect

But alcohol induced impairment remains

Question 21

Efficacy of Naltrexone?

In whom is it most effective?

Answer 21

Reduced cravings for alcohol, and reduced consumption and relapse rates in some not all patients

Some evidence suggests naltrexone most effeective when used in combination with acamprosate

Most effective in:
Patients with history of binge drinking
Those drinking heavily for 20 years or less
Those with stable social support and living situation

Question 22

When is Naltrexone contraindicated?

Answer 22

Some states of chronic/acute pain -> as blocks opioid receptors, opioid analgesics will be ineffective. However, NSAIDS and other non-opioid analgesics can still be used to treat pain

Question 23

How is Disfulfiram used to treat alcohol addiction?

Answer 23

Prevents the metabolism of alcohol by blocking acetaldehyde breakdown

This causes unpleasant and potentially serious effects if alcohol is consumed:
intense flushing, sweating, palpitations, tachycardia, dyspnoea, nausea, vomiting, hyperventilation, pounding headache, chestpains, restlessness, sense of impending doom

Associated steep rise in BP followed by hypotension

Severe reactions may affect the hears, or cause convulsions of LOC

Occasionally death from cardio-respiratory failure -> treatment of the interaction = intensive supportive therapy

Question 24

Efficacy of and indications for Disulfiram treatment

Commencement

Answer 24

Used only in highly motivated, compliant patients whom understand fully the dangers of taking alcohol during treatment with disufiram

There is marked variation in the extent of resposne to alcohol

Alcohol must not have been consumed for 24 hours prior to commencement of disufiram

After cessation, should remain abstinent for at least 1 week

Doses should be dispensed under supervision of clinic or trusted person

Question 25

Drugs used to treat Opioid Addiciton

Answer 25

Naltrexone
Methadone
Buprenorphine

Question 26

Describe naltroxine use in opioid withdrawal

Answer 26

If used on someone physically dependent, will precipitate severe withdrawal reactions -> because is pure opioid receptor blocker

Thus, patients must first go through a gradual withdrawal program, and undergo a ‘naloxone challenge; to confirm abstinence from opioids

I.e. if try to take opioids after that -> they won’t feel the effects of them, because they will be blocked

Question 27

Why can naltrexone precipitate risk of overdose after cessarion of treatment?

Answer 27

Naltrexone can accelerate the loss of tolerance that occurs with absinence from opioids

Thus, if person tries to take opioids like the used to, after cessation of treatment, they can OD because they will have lost their tolerance

Question 28

Withdrawal signs associated with opiates?

Answer 28

Sweating, restlessness, vomiting, Pilerection, Rhinorrhoea

Question 29

How is methadone used for opioid addiction

Answer 29

Methadone = orally active opioid designed to remove the need for IV administration

Idea: take opioid administration from ‘street-scene’ to clinical scene

Question 30

Indications for methadone use

Answer 30

Short-term use in opioid withdrawal
Long-term substitution for heroin and other opiods

*Thought to be easier to wear addict from methadone compared with heroin or morphine

Question 31

Advantages of methadone treatment, compared with other treatments for opioid addiction?

Answer 31

High acceptibility, especially in comparison to withdrawal and abstinance-based approaches

Proven effectiveness in reducing illicit opioid use

Question 32

Features of Methadone Drug

Answer 32

S8
Can be as dangerous as heroin
Variable half life: 15-60hrs
Active for ~4-6 hours. With repeated dosing can extend to 72 hours, but takes several days to reach this steady state

Question 33

Describe Buprenorphine use in opioid withdrawal

Answer 33

Partial opioid agonist
Effective in reducing illicit opioid use

Dose administered depends on recent opioid use of individual: May precipitate ithdrawal syndrome if have had recent large dose of opioid and buprenorphine dose not properly matched

Question 34

Benefits of buprenorphine compared with methadone

Answer 34

Lower overdose risk
Less dependence

(by virtue of it being a partial opioid agonist)

Effects can be reersed with high doses of naltrexone -> will block effects of opioid analgesics

Question 35

Aims of pharmacological nicotine addiction therapy

Answer 35

Reduce severity of tobacco withdrawal symptoms

To increase likelihood of smoking cessation

Question 36

Drugs used for nicotine addiction

Answer 36

Bupropion

Varenicline

Question 37

Use of Bupropion in nicotine addiction

+ a contraindication

Answer 37

Possible action due to its inhibition of neuronal reuptake of dopamine (DA) and noradrenaline (NA)

Can worsen psychiatric conditions

Question 38

Varenicline for nicotine addiction

+ a contraindication

Answer 38

Blocks nicotine from binding to ACh nicotinic receptors
This prevents pleasurable effects of smoking

Has partial agonist activity which reduces symptoms of withdrawal

Post-marketing reports of worsening psychiatric conditions

Question 39

Describe the steps of the approach to addiction

Answer 39

Precontemplation: no thoughts about changing behaviour

Contemplation: Thoughts about the need/desire to change but no action yet taken

Preparation: Ready to take action

Action: Attempts made to change behavious and avoid environmental ‘triggers’

Maintenance: Behaviour has been changed and the person is adjusting to these changes and working to prevent relapse