lecture 35: emerging treatments for drug dependence: preclinical evaluation

Question 1

What is the prevalence of drug use?

Answer 1

• 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)

Question 2

Is drug use protracted?

Answer 2

• 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

Question 3

What is addiction?

Answer 3

• 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

Question 4

What is a scheme for potential therapeutic interventions?

Answer 4

• 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

Question 5

What are imaging substrates for relapse propensity?

Answer 5

• 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
  *

Question 6

What is a circuitry model of drug-seeking?

Answer 6

• 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

Question 7

What is alcoholism?

Answer 7

• 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

Question 8

What are physicians’ opinions about medications to treat alcoholism?

Answer 8

• 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

Question 9

What can be used to treat alcoholism?

Answer 9

• 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?

Question 10

What is naltrexone?

Answer 10

• 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

Question 11

What is modeling drug-seeking behaviour?

Answer 11

• 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

Question 12

What is modelling relapse in animals?

Answer 12

• 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

Question 13

What does naltrexone do in primates and rodents?

Answer 13

• 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

Question 14

Will animals reinstate alcohol-seeking following extinction and protracted abstinence?

Answer 14

• 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

Question 15

What are activated during cue-induced reinstatement to alcohol seeking?

Answer 15

• orexin containing neurons
• cues that previously indicated drug availability

Question 16

What are potential anatomic loci of OX1R?

Answer 16

• PFC
• NAc
• VTA
• Amy
• DA
• GABA
• prelimbic cortex

Question 17

What is modelling the development of alcoholism in animals?

Answer 17

• 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

Question 18

What is implicated in dependent rats?

Answer 18

• 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

Question 19

What is MTIP?

Answer 19

• 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

Question 20

What can be used to treat smoking addiction?

Answer 20

• nicotine replacement (patches, gum, etc)
• buproprion - amine uptake inhibitor
• modafinil - amine uptake inhibitor
• memantine - partial NMDA R antagonist
• varenicline - partial agonist at nicotinic Rs
• vaccine
• GW468816 (antagonist at glycine site on NMDA receptor, recruiting for CT)

Question 21

What are partial agonists of a4b2 nACh receptors?

Answer 21

• 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

Question 22

What about nicotine vaccination?

Answer 22

• 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)

Question 23

What are treatments for marijuana addiction?

Answer 23

• none approved
• selegeline - MAO inhibitor
• venlafaxine - SNRI
• atomoxetine - NRI
• gabapentin - Ca channel blocker /GABA_B agonist
• dronabinol - THC analogue

Question 24

What are treatments for cocain addiction?

Answer 24

• none yet approved - under development
• modafinil - stimulant used to treat narcolepsy
• topiramate
• baclofen (GABA_B agonist)
• antidepressants
• vaccine
• aripiprazole atypical antipsychotic (D2 partial agonist (recruiting for CT)
• vigabatrin GABA transaminase inhibitor (recruiting for CT)
• N-acetylcysteine (restores GLT1 function) (recruiting for CT)

Question 25

What are treatments for opiate addiction?

Answer 25

• 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

Question 26

summary

Answer 26

• effective therapeutics should be safe, well tolerated and efficacious
• combination with CBT and other behavioural strategies
• major issues - non-compliance and co-morbidity
• episodic Rx for relapse prevention may possibly provide wider windows of opportunity for Rx
• poly-pharmacy i.e. combination Rx and lower doses