Lecture 2: Substance Use

• Cocaine blocks reuptake transporters, increasing the amount of dopamine in the synapse.
• Animals will lever press to receive intravenous infusions of most drugs abused by humans (esp. cocaine, amphetamine, heroin, nicotine, but not LSD, THC?)
• Rats will self-administer cocaine until death (90%),

  Heroin ‘less’ toxic at 36% deaths
• Cocaine is rewarding at it causes an increase in dopamine levels in the brain (blocks the dopamine transporter “endocytosis”)
• Rewarding effect of cocaine is blocked by: Dopamine receptor antagonists
• What is the problem with dopamine receptor antagonists as a treatment for addiction?

  Compliance
• Several lines of evidence suggest that craving involves increased glutamate release (from prefrontal cortex to nucleus accumbens)
• What are the two regions of the brain that have strong glutamate projections to the nucleus accumbens, causing craving?

  The amygdala and anterior cingulate
• Glutamate is involved with learned associations with the drug-taking environment
• Glutamate in the nucleus accumbens triggers craving in abstinent individuals.

  Future treatments may involve specific glutamate receptor antagonists or agents that normalise glutamate levels
• NAC regulates glutamate levels
• Acamprosate = glutamate NMDA receptor antagonist
• Bupropion = dopamine reuptake inhibitor
• Varenicline is a nicotine receptor partial agonist
• Nicobrevin contains camphor, eucalyptus oil, Menthyl valerate, and quinine.
• Clonidine

  • agonist at alpha2- adrenoceptors (noradrenaline)• helps to reduce withdrawal effects of opioids, cocaine and nicotine

  • noradrenaline cell bodies in the locus coeruleus are thought to produce withdrawal symptoms

  • not widely used - intolerable side effects (low blood pressure, drowsy)
• Psychostimulant replacement therapy (benztropines)?

  • Similar to methadone but aimed at blocking the dopamine transporter

  • Prevents cocaine from having it’s effect at the DAT

  • Drugs bind slowly to DAT and stay there for a long time
• Oxytocin may be effective in treating which two substance use disorders?

  Alcohol and methampethamine
• Medicinal cannabis may be effective for methamphetamine addiction.