Lecture 35 - Drug Addiction - Pre-clinical Evaluation Flashcards
1
Q
Describe the prevalence of drug use, and the importance in terms of public health
A
- Drug use is prevalent
- Alcohol & tobacco are most prevalent
- Cannabis
- Amphetamines
- Opioids
- Accounts for 10% of global burden of disease
- Economics
- Costs ~3.5% GFP for developped countries
- Receives <2% the funding of cancer (public & private)
- Every dollar spent on treatment is 7 saved in healthcare costs
- Sucks up a significant portion of GDP
2
Q
Characterise drug addiction
A
- “A chronic relapsing disorder which consists of a compulsive pattern of drug-seeking and drug taking behaviour*
- Persists despite adverse consequences”*
3
Q
Describe the possible therapeutic strategies for drug addiction
A
- Primary prevention
- Before initial drug use
- During intermittent use
- ? medications, vaccines
- Addiction
- Medications are useful and needed
4
Q
Describe the aetiology of alcoholism
A
- Polymodal
- Usually + psychiatric co-morbidity
- Genetic factors
- Still controversial, polygenic
- There is no one gene
- Region on **chromosome 1 **associated with vulnerability
- Environmental factors
- Peer pressure
- Self medication of psychiatric disorders
- Panic disorders, anxiety, schizophrenia
5
Q
List medications that are commonly prescribed for alcoholism
Briefly state their efficacy
A
-
Baclofen
- Shown to be beneficial
- Still ongoing clinical trials
-
Naltrexone
- Non-selective opioid antagonist
- Tolerance an issue
- Small to medium effect
-
Antidepressants
- Largely not useful
-
Benzodiazepines
- Largely not useful
- Only useful for mental disturbances encountered in withdrawal
-
Disulfiram
- ALDH inhibitor
- Acetaldehyde dehydrogenase inhibitor
- Cannot metabolise acetaldehyde, it builds up
- Nausea, flush etc.
- Largely not useful
- Need strong compliance and motivation
- Significant adverse effects
- ALDH inhibitor
6
Q
What is needed in terms of alcoholism therapy prescription?
A
- Better education of physicians
- About which drugs are beneficial and which aren’t
- Better therapeutics
- The field of drug discovery & research
7
Q
Describe the use of Naltrexone
A
- Non-selective opioid receptor antagonist
- FDA approved for treatment of alcohol dependence
- Clinical trials showed variable outcomes
- Many of the end points were abstinence, which is unrealistic
- Better would have been reduction in consumption (harm-minimisation)
- Positive response found in:
- Family history of alcoholism
- Early onset
- Co-morbid use of other drugs
- “Double the odss of following abstainer trajectory”
8
Q
Describe the final common circuit for drug seeking
A
- PFC → NAc → ventral pallidum
- Interfering with signalling along this pathway can interrupt relapse, no matter whether it is a cue or a stress.
- Other structure in the brain are of course being incorporated.
9
Q
Describe the mouse model that has been used to investigate drugs for alcohol relapse
A
Mouse model, operant responding
- Mouse in cage
- Lever results in delivery of 10ml of alcohol
- Mouse will quickly learn to press lever
- Mouse will do this repeatedly until intoxicated
- Paradigm:
- Acquisition
- Mouse learns the behaviour of drinking
-
Extinction
- Operant task no longer delivers the drug
- Mouse learns that the task no longer has benefit
-
Reinstatement
- Reinstatement of a cue, stress or priming stimulus
- Mouse returns to the previous behaviour, even though the mouse has learnt the new behavious
- Acquisition
10
Q
Describe empirical evidence of Naltrexone in preventing alcohol relapse in mouse experiments
A
- When naltrexone is administered to the mice, there is reduced reinstatement of behaviour after exposure to the alcohol-cue
- This happens even after protracted abstinence
- ie after 5 months (quarter of mouse’s lifetime)
11
Q
Describe the role of orexin and its receptors in cue-induced alcohol seeking
A
- There is empirical evidence that orexin neurons are active during reinstatement (relapse)
- Orexin releasef from the LH
- The orexin receptors are located:
- VTA
- NAc
- PFC
- Amygdala
12
Q
Describe the vapourised ethanol model of alcohol relapse
Describe what this model showed about CRF involvement in relapse
A
- Model:
- Mice exposed to ethanol vapour for 15 hrs per day
- Then, ethanol is removed, mice suffer acute physical withdrawal, then recover
- After extinction (10 days), alcohol is then made available
- Post-dependent mice drink considerably more alcohol than normal mice
- Use of CRF receptor antagonist
- Use of this antagonist reduced the post-dependent consumption of alcohol in a dose dependent manner
- No effect on the non-post-dependent mice
13
Q
Describe the action of MTIP
A
- Receptor antagonist at the CRFR
- Corticotropin releasing factor receptor
- Reduces ethanol consumption in post-dependent mice in a dose dependent manner
- Potential therapeutic for alcohol addiction
14
Q
List & describe the action of therapeutics for smoking addiction
A
- Nicotine replacement therapy
- Bupropion
- Amine uptake inhibitor
- Novel:
- Vaccine
- Nicotine conjugated to a Pseudomonas antigen
- Results in reduced intake of nicotine in mouse models
- Vaccine
- nAChR partial agonist
- eg Varenicline (Champix)
- Inhibits dopamine spike upon nicotine consumption
15
Q
List some therapeutics for cannabis addiction
A
- None approved
- Gabapentin
- Ca channel blocker
- etc.
