lecture 35: emerging treatments for drug dependence: preclinical evaluation Flashcards
1
Q
What is the prevalence of drug use?
A
- alcohol and tobacco use (ONS, UK):
- more 13 year olds have drunk alcohol than not
- that’s 350,000 13-year-old drinkers in england and wales alone
- illicit drug use (AIHW)
- cannabis: 34% ages 14+ have used in lifetime
- opioids (inc heroin): 2.3%, or 384,800 people
- amphetamines: 9.1% (or, 1 in 5 of those aged 20-29)
2
Q
Is drug use protracted?
A
- estimates those aged 50+ seeking drug abuse help will rise from 1.7m in 2000/01 to 4.4m by 2020
- 2010 cost of drug and alcohol abuse to australia = $56 billion
- when you can stop you don’t want to, and when you want to stop, you can’t - Luke Davies
3
Q
What is addiction?
A
- Nikki Sixx: when you can give up something any time, as long as it’s next tuesday
- a chronic relapsing disorder which consists of a compulsive pattern of drug-seeking and drug taking behaviour
- takes place at the expense of other activities
- persists despite adverse consequences
- almost 10% of the global burden of disease comes from the use of alcohol, tobacco, and illicit drugs (WHO, 2002)
- WHO estimates that 12.4% of death worldwide can be attributed to addiction and costs ~3.5% of GDP in western countries (US$500b in 2008)
- for every dollar spent on treatment, seven are saved in related healthcare costs
- addiction receives less than 2% of the public and private funding of cancer
4
Q
What is a scheme for potential therapeutic interventions?
A
- primary prevention
- initial use of drug
- sporadic intermittent use → possible use of vaccines and selected medications
- regular use
- addiction → medications useful and needed
- early withdrawl → more than 80% relapse to addiction (with no medication)
- protracted abstinence → less than 20% sustained abstinence (with no medication)
- short-acting opiates: 1 in 3 to 1 in 4 individuals who ever self-administer progress to addiction
- cocaine: 1 in 10 to 1 in 20 individuals who ever self-administer progress to addiction
- alcohol: 1 in 10 to 1 in 20 individuals who ever self-administer progress to addiction
5
Q
What are imaging substrates for relapse propensity?
A
- cue-induced activation in the anterior cingulate (BA32) and medial prefrontal cortex (BA10)
- cue-induced activation of the putamen
- if we want targeted therapies for relapse have to understand what is going on in their brain
- looked at abstinent alcoholics and looked at cues
- had to rate self-rated craving
- imaged
- cue induced activation in the striatum
- followed them up on the study to see when they relapsed and how much
- self-rated craving had no kind of value whatsoever
- neither did cue induced activation in striatum
- BA10 (medial prefrontal cortex) was very strong indicator of propensity to relapse and how much they would consume
- decision making networks are being hijacked
- alcohol or drug related cues have exaggerated salience compared to non drug cues
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6
Q
What is a circuitry model of drug-seeking?
A
- stress: extended amygdala
- central amygdala nucleus, bed nucleus of the stria terminalis, nucleus accumbens shell
- cue: ventral tegmental area and basolateral amygdala
- final common pathway:
- prefrontal cortex
- nucleus accumbens core
- ventral pallidum
7
Q
What is alcoholism?
A
- polymodal disorder, but a significant number of alcoholics present with some type of psychiatric co-morbidity
- genetic factors - still awaiting definitive marker genes (controversial e.g. A1 allele of D2R). there is a region on chromosome 1 associated with vulnerability to both alcoholism and depression
- environmental factors - peer pressure (binge) to self-medication of underlying psychological disturbance
- diagnosis is critical for selection of appropriate therapy
8
Q
What are physicians’ opinions about medications to treat alcoholism?
A
- average%’s of patients prescribed:
- naltrexone 13% (only small to medium effect)
- disulfiram 9%
- benzodiazepines 11%
- antidepressants 46%
- what is needed?
- improved education of physicians
- better therapeutics
9
Q
What can be used to treat alcoholism?
A
- disulfiram - ALDH inhibitor, largely not useful. needs high motivation and compliance, signficant adverse side-effects
- naltrexone - non-selective opioid receptor antagonist, tolerance an issue
- acamprosate - mixed pharmacology, tolerance and non responders (we have just shown it is not actually an active molecule, but counter ion dictates efficacy)
- antidepressants (largely not useful)
- benzodiazepines (largely not useful)
- baclofen (ongoing trials)
- topiramate, lamotrigine (anticonvulsants, used in withdrawal)
- CRF1 receptor antagonists (under development)
- others e.g. orexin ligands?
10
Q
What is naltrexone?
A
- approved by FDA for treatment of alcohol dependent patients
- variable outcomes of clinical trials - why?
- rubio et al - 2005 - predictors of a positive response to NTX treatment were family history of alcoholism, early age at onset of drinking problems and co-morbid use of other drugs
- o’malley et al (2007) - extended release NTX prolongs abstinence and decreases both number of drinking days and number of heavy drinking days (dose-related)
- gueorguieva et al 2007 - naltrexone doubled the odds of following the abstainer trajectory instead of the consistent drinker trajectory but did not significant;y change the odds of following the abstainer trajectory as contrasted with the sporadic drinker trajectory
- naltrexone may have a clinically meaningful effect for alcohol-dependent patients with a high chance of consistent drinking
11
Q
What is modeling drug-seeking behaviour?
A
- self-administration
- continual access
- restricted access
- operant responding
- e.g. self administration of alcohol in rats - operant responding
- conditioned place preference (pavlovian conditioning)
- extinction/reinstatement - “relapse”
- sensitization (drug-induced plasticity)
- withdrawal syndrome
12
Q
What is modelling relapse in animals?
A
- acquisiton → animal learns that under a certain contingency, enjoy taking it, 100% voluntary, let them administer for an extended period of time
- extinction → operant task doesn’t give them the drug, stop doing it, coming out of rehab
- reinstatement
- Reinstatement→ cue, stress or prime
- use that paradigm (operant responding) to see if any drugs can’t prevent relapse
- thought to be a craving and seeking that has to precede the using
13
Q
What does naltrexone do in primates and rodents?
A
- reduces responding for ethanol
- reduced self-administration of drug in primates
- without affecting food
- cue induced seeking
- S+ condition reinstate
- prevented by pretreatment with opioid receptor antagonist naltrexone
- drugs have to work in these paradigms
14
Q
Will animals reinstate alcohol-seeking following extinction and protracted abstinence?
A
- i) early reinstatement straight after extinction
- ii) late reinstatement, 5 months withdrawal after extinction
- yes, they do, and OX1 receptors implicated at both time points
- in humans there is an enduring relapse propensity months, years, decades after they have become abstinent
15
Q
What are activated during cue-induced reinstatement to alcohol seeking?
A
- orexin containing neurons
- cues that previously indicated drug availability
16
Q
What are potential anatomic loci of OX1R?
A
- PFC
- NAc
- VTA
- Amy
- DA
- GABA
- prelimbic cortex
17
Q
What is modelling the development of alcoholism in animals?
A
- use → abstinence → relapse → heavy use → abstinence → relapse → early dependence → abstinance → relapse → late dependence → neuroadapted state
- impulsive stage
- binge intoxication → pleasureable effects → abstinence neutral effect → reward craving → binge intoxication
- compulsive stage
- prolonged intoxication → relief → protracted abstinence negative effect → relief craving → prolonged intoxication
- post dependent dysphoric state
- will consume heaps
18
Q
What is implicated in dependent rats?
A
- CRF
- i.e. CRF receptor antagonism blocks the enhanced responding for alcohol observed in withdrawing dependent rats - ineffective in non-dependent rats
- locus of action: CeA
19
Q
What is MTIP?
A
- 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]Pyridazine
- a novel brain-penetrant
- orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
- plus other small molecule compounds from Koob lab/san diego
21
Q
What are partial agonists of a4b2 nACh receptors?
A
- rational, pharmacology and clinical efficacy of partial agonists of a4b2 nACh receptors for smoking cessation
- but has been linked to precipitation of manic episodes and worsening of schizophrenic symptoms
22
Q
What about nicotine vaccination?
A
- effects of a nictone conjugate vaccine on the acquisition and maintenance of nicotine self-adminstration in rats
- active immunisation - nicotine conjugated via a succinic acid linker to recombinant pseudomonas protein A (4 injections)
25
Q
What are treatments for opiate addiction?
A
- methadone
- LAAM (L-alpha-acetylmethadol) - discontinued due to adverse cardiac events
- heroin prescription (Europe/Canada)
- buprenorphine
- naltrexone
- clonidine (recruiting for CT)
- memantine/naltrexone (recruiting for CT)
- 24% of LAAM vs 12% of MM abstinent for more than 12 weeks, no adverse events in this trial, authors argue against withdrawal of Rx
