Lecture 2: SUD

• Agonists bind to the receptor and have an effect. Therefore they have affinity and efficacy
• Antagonists bind to the receptor but don't have an effect. They stop other things from binding to the receptor. Therefore, they have affinity but not efficacy.
• Daily and weekly alcohol consumption is going down

  • More people deciding not to drink at all (increase in 'never drinker' category)
• 18% of Indigenous Australians drink alcohol at harmful levels
• • Significant decrease in daily smoking
  • And the 'never smoked' category is increasing
• 43% of Indigenous Australians smoke
• 17% of Australians have used an illicit substance in last 12 months. 23% of Indigenous people have used an illicit substance in the last 12 months.
• Amphetamine use has been stable between 2016-2019
• Every drug except pain killers and opioids, as well as other new and emerging psychoactive substances is going up in both recent and lifetime use.
• Why do ‘we’ take substances? They make us feel good! This 'good' feeling is related to the reward pathway and dopamine (DA)
• If you take any substances, they'll cause a release (directly or indirectly) of dopamine.
• Reward pathway

  • From ventral tegmental area (VTA) in midbrain TO the nucleus accumbens
  • The above is the main reward pathway, but dopamine neurons can also go straight up to the prefrontal cortex
  • Why is it called the mesolimbic dopamine system?
  • VTA is in midbrain = meso = middle
  • Nucleus accumbens is in limbic system = limbic

  
• How does cocaine increase dopamine?

  • USUALLY, you have neurotransmitter (dopamine) that gets released and binds with receptors. This has powerful rewarding effect post-synaptically. Then dopamine unbinds and it goes up through transporters to be repackaged
  • WITH COCAINE
  • The molecule will come into the synapse and block the transporters. So the dopamine levels go up because there's no re-uptake.

  
• How does ecstasy and meth increase serotonin/dopamine?

  • They don't just block the transporters. They reverse the transporters. So any dopamine sitting in the vesicles of the presynaptic membrane gets spat out into the synapse.
  • Depleting all stores of dopamine (if meth) and serotonin (if ecstasy)

  
• What is it called when you have a major problem with drugs of abuse?

  Addiction or Substance Use Disorder. You should not label someone an addict.
• Animal model of Addiction

  • Common animal model of drug addiction is the drug ‘self-administration’ technique
  • Animals (mice, rats, monkeys) will lever press to receive intravenous infusions of most drugs abused by humans (esp. cocaine, amphetamine, heroin, nicotine, but not LSD or THC)
  • Hard to get animals to take LSD and THC
  • Because of strong serotonin --> hallucination in animals which they don't like
  • Rats will self-administer alcohol orally
  • But they'll only drink the alcohol with some sugar (sugar-fading)
• Drug Self-Administration

  • Rats will self-administer cocaine until death (90%)
  • Cocaine is a stimulant and you can get stereotypies (repetitive behaviours). Stereotypies can be fixated on the lever for rats and they keep pressing it
  • Heroin ‘less’ toxic at 36% deaths
  • Heroin makes them fall asleep - hard to overdose for rats
• Cocaine is rewarding as it causes an increase in dopamine levels in the brain (blocks the dopamine transporter = “endocytosis”)

  • Endocytosis = re-uptake
• Rewarding effect of cocaine is blocked by:

  • Dopamine receptor antagonists... but people are non-compliant. Hard for those with addiction.
• What is Addiction/ Substance Use Disorder?

  A state characterized by:

  • Compulsion to take drugs continuously or periodically
  • Experience rewarding effects
  • Avoid the discomfort of its absence
• Physical vs. Psychological Dependence

  • Physical dependence
  • Stop taking the drug produces withdrawal symptoms
  • Heroin - abrupt cessation causes sweating, goosepimples, diaorrhea, muscular spasms, aches and pains
  • Alcohol and benzodiazepines - hypersensitivity to sound and light, anxiety, convulsions, coma and even occasionally death (if withdrawal is too abrupt)
  • Psychological dependence
  • Craving of the drug during abstinence (produces a high level of relapse)
  • This is what we're trying to target
• Symptoms arising from drug addiction can include

  • Anxiety
  • Depression
  • Psychosis
• Addiction may be treated with available pharmacotherapies.
• Are we trying to stop people from taking the drug or craving the drug? Which answer is more correct?

  Craving the drug
• Addiction Treatments

  • There are few pharmacological treatments for drug addiction
  • Dopamine receptor antagonists don’t work
  • Compliance is a HUGE problem!
  • So far best pharmacotherapies are for heroin, alcohol and nicotine addiction - not for the psychostimulants or cannabis
• There is some research done on vaccines as a treatment for addiction.

  • Vaccines would be an anti-cocaine antibody. It stops cocaine from having any effect on the body. What is the problem with vaccines?


  The people selling it will just alter it and the vaccine will end up ineffective.
• Several lines of evidence suggest that craving involves increased

  glutamate release (from prefrontal cortex to nucleus accumbens)
• Glutamate Transmission Triggers Craving Study

  • Abstinent cocaine addicts shown two videos. noe of nature and one of crack paraphenalia/taking of the drug (craving)
  • What did the PET scan show?

  The amygdala and anterior cingulate lit up for the cocaine video, but not for the nature video. The amygdala regulates cues so if you have a cue (not the actual drug, but a cue), it, as well as the anterior cingulate, will light up.

  
• Associations With Drug-taking Stimulates Glutamate Transmission to Nucleus Accumbens

  • Anterior cingulate cortex and amygdala neurons contain glutamate which signals to neurons in the nucleus accumbens
  • Glutamate is involved with learned associations with the drug-taking environment
  • When shown a cue (e.g. picture of drug paraphernalia), it triggers glutamate release. Then the glutamate goes into the nucleus accumbens which causes cravings!

  
• Treatments for Addiction

  • Glutamate in the nucleus accumbens triggers craving in abstinent individuals
  • Future treatments may involve specific glutamate receptor antagonists or agents that normalise glutamate levels
• Example of glutamate receptor antagonist that may help lessen glutamate in the nucleus accumbens, and thus, lessen cravings

  • N-acetylcysteine (NAC)
• N-acetylcysteine (NAC), which is a glutamate antagonist, helps regulate glutamate levels so that there are no ups or downs, or triggers.

  It is not effective for smokers, but may be effective for cocaine users.
• Treatments for Heroin/Morphine Addiction

  • Methadone
  • Brand names: Biodone Forte, Methadone Syrup, Physeptone
  • Buprenorphine
  • Brand names: Subutex, Buvidal, Sublocade
  • Naloxone & Naltrexone
  • Naloxone brand names: Narcan, Naloxone Minijet (prefilled syringe)
  • Naltrexone brand names: ReVia, Naltrexone QP
  • Buprenorphine + Naloxone together
  • Brand name: Suboxone (sublingual film)
• Treatment for Heroin/Morphine Addiction

  • Methadone
  • is also a mu opiate receptor agonist (like heroin)
  • binds to the mu opiate receptor for longer than heroin - reduces the ability for heroin to work (receptors are already bound - so prevents other opiates like heroin from binding)
  • due to slow mechanism of action, less “rush” associated with methadone use
• Treatment for Heroin/Morphine Addiction

  • Buprenorphine
  • binds to receptors but has less efficacy (partial agonist) than methadone
  • Partial agonists have affinity but lower efficacy than full agonists. But they're also not antagonists. They have both agonist and antagonist properties.
  • They bind to the receptor and stop other drugs from binding there as well. They don't have much of an effect themselves but they're not antagonists.
  • replacement therapies
  • Buprenorphine with naloxone is Suboxone
• Treatment for Heroin/Morphine Addiction

  • Naloxone & Naltrexone
  • Mu receptor antagonist
  • compliance is a problem
  • Used for emergency in OD (eg. Naloxone Minijet – prefilled syringe)
• Treatments for Heroin/Morphine Addiction

  • Buprenorphine + Naloxone (Suboxone – sublingual film)
  • Sublingual = under the tongue
• Methadone acts at mu opiate receptors but has less addictive potential than fast-acting heroin. It reduces heroin from acting at mu receptors.

  • Blue dots = mu opiate receptors
  • Methadone is essentially replacing heroin

  
• Naloxone is an antagonist at mu opiate receptors. It blocks heroin from increasing dopamine.

  Comparison of treatments for heroin addiction

  • Methadone acts like heroin and stops it from having an effect. VS Naloxone is a true antagonist as it binds (affinity) but has no efficacy - just blocks heroin from binding to mu opiate receptors.

  
• Treatments for Alcoholism

  • Acamprosate
  • Brand name: Campral
  • Naloxone & Naltrexone
  • Naloxone brand name: Narcan
  • Naltrexone brand name: ReVia, Generic
  • Disulfiram
  • Brand name: Antabuse