Lec 3- Drugs of absue (1)

Question 1

Categories- by action

Answer 1

• Psychostimulants- Cocaine, amphetamine, nicotine
• Depressants- Barbiturates, alcohol
• Psychotomimetic- LSD, PCP, cannabis
• Opiates- Heroin, dihydrocodiene
• Volatile intoxicants- Glue, amyl nitrate
• Legal high- many types of action

Question 2

Drug dependence

Answer 2

• Repetitive drug use because the sense of well-being has acute reinforcing effects in the brain
• Psychological dependence
  
  • Drug-seeking behaviour
  • Pleasure (Positive reinforcement)
  • Not related to the development of tolerance to a drug
  • Drug ‘habit’- environment
• Physiological Dependence
  
  • Body ‘needs’ drug for normal function
  • Tolerance (quantity of the drug that can/have to take)/sensitization (behaviour- alcoholic will show signs of being drunk earlier)- physiological processes
  • Physical withdrawal symptoms (Negative reinforcement)
  • Psychological dependence usually also present

Question 3

Drug addiction

Answer 3

• Continued use of the drug despite negative social, personal, financial, psychological consequences
• Positive and negative reinforcement usually involved
• High relapse rate
• Can be addicted even after overcoming dependence e.g. alcoholic

Question 4

Tolerance

Answer 4

• After chronic use, the same amount of drug is insufficient to cause the desired effect and thus, more drug is used
• A compensatory response
• Pharmacokinetic- e.g. drug more rapidly metabolised in the liver
  
  • Example: alcohol- inducible alcohol dehydrogenase
• Pharmacodynamic- e.g. receptor of a drug becomes desensitized, or levels of its gene expression change
  
  • Example opioid receptor internalisation, G-protein uncoupling
• Tolerance is very rapid

Question 5

Cross-tolerance

Answer 5

• Tolerance to one drug causes tolerance to another within the same class
• Examples:
  
  • Barbiturates and benzodiazepines
  • Cocaine and amphetamine

Question 6

Sensitization

Answer 6

• Increased response to a drug after long-term chronic or intermittent administration
  
  • Example: Amphetamines (last a lot longer) or cocaine, alcohol
  • Repeated administration produces enhanced effects of these drugs on the user
  • Consequent more powerful withdrawal
  • Enhances compulsive drug seeking= Negative response
• Important- pathological response may also sensitize e.g. methamphetamine psychosis
• Increased behavioural response, Long process

Question 7

Sensitization

Answer 7

• How can you tolerance and sensitization
• Tolerance occurs rapidly
• Sensitization due to brain structure changes over years of abuse
• Sensitization changes motivation >> drug response e.g. behavioural response to a drug or to its absence is augmented, not necessarily the drug-receptor effect

Question 8

Withdrawal

Answer 8

• Drug-specific syndrome that occurs when drug supply is abruptly terminated
• Symptoms usually the opposite of the effects of the drug before the abuser became tolerant
  
  • E.g. cocaine crash
  • Heroin cold turkey

Question 9

Extinction and reinstatement

Answer 9

• Extinction occurs when drug-seeking behaviour is blocked through treatment
  
  • Pharmacological e.g. naloxone- an opioid antagonist
  • Behavioural e.g. Group therapy for drug addiction
• Reinstatement occurs when drug-seeking behaviour reactivated
  
  • Pharmacological e.g. tramadol reinstating heroin abuse; cocaine reinstating heroin abuse
  • Psychological e.g. stress or habit/ location triggers drug-seeking behaviour
• Reinstatement is best characterised with opioid u-receptors e.g. heroin addict
  
  • block receptors with naloxone = extinction
  • Any drug with u-receptor activity or even indirect u-receptor activation through, say, cocaine, triggers drug seeking

Question 10

Co-abuse

Answer 10

• Polypharmacy very common
• Alcohol and recreational drugs
• Heroin and cocaine (speedball)
• Heroin and Crack (Hardball)
• Tobacco and Cannabis

Question 11

Overall

Answer 11

1.

Question 12

Where do drugs of abuse act

Answer 12

• The brain has pre-existing reward systems (Food, water, sex and social interaction)
  
  • Evolved to encourage behaviours with the positive effect on Darwinian fitness
  • Drugs hi-jacks this reward system, fooling the brain into signalling that drugs enhance fitness greatly
  • Mesolimbic dopamine pathway is directly involved nucleus accumbens, VTA (ventral tegmental area) and pre-frontal cortex (Where motivation occurs)

Question 13

Mesolimbic reward pathways

Answer 13

• VTA input to NA_c releases DA, GABA
• PFC input to NA_c/VTA releases DA
• Increase DA in NA_c is the key
• PFC- prefrontal cortex
• NA_c - Nucleus accumbens
• H/EC- Hippocampal/entorhinal area
• VTA- Ventral tegmental area
• A- Amygdala (emotional area)
• C- Caudate
• The increase of Dopamine in the Nucleus Accumbens (NAc) is key

Question 14

Mesolimbic reward pathways: evidence

Answer 14

• 1970’s- animals self-administer morphine into ventricles- close to deep nuclei such as NAc
• Non-BBB permeable opioids are ineffective
• 1980’s- Intracranial self-stimulation (ICSS) occurs when electrodes placed directly into lateral hypothalamus (LH), NA_c or VTA- blocked by dopamine antagonist
• 1980’s lesions of DA cells in these areas with OHDA (6-hydroxyDA) abolish reinforcement and ICSS
• Alcohol and cannabis activate DA release in NA_c shell (not ‘core’ region) area specific for drug abuse

Question 15

Mesolimbic reward pathways

Answer 15

• ALL addictive drugs of abuse activate dopamine release in the shell of the NA_c
• Some directly through the release of DA
• Others indirectly through suppression of GABA inhibition of DA cells (cf. later)
• Take home message
  
  • Drugs => NA_c shell Increased DA

Question 16

Mesolimbic reward system- Mechanism

Answer 16

• DA. neurones originate in the VTA and project into the NAc shell
• DA is then released
• Inhibitory GABA neurons within VTA and projecting feedback GABA neurones from NAc tonically inhibit VTA DA
• In the NAc, both D1 and D2 DA receptors mediate reward
• This system is subject to control from other neurones
  
  • Other neurones act on GABA inhibitory neurones, inhibiting them causing a reduction in inhibitory signals to the VTA thereby increasing VTA activity

Question 17

What is disinhibition

Answer 17

• (Glu/DA) neurone is excited =>
• AP potential is firing
• GABA inhibitory cell is then activated
• inhibiting next Glu/DA
• Glu/DA neurones is excited =>
• GABA inhibitory (-ve signal) =>
• Another GABA inhibitory signal =>
• Another Glu/DA causes excitation