PCL389 Study Notes
SUBSTANCE USE DISORDER (SUD)
-Addiction: chronic relapsing disorder, persistent drug-seeking + drug-taking behaviours
-physical/psychological dependence, craving/relapse, activation of reward pathway
THEORIES OF MECHANISMS UNDERLYING SUD
-factors that play a role: activation of brain reward system, physical dependence, genetic, environmental cues
Dopamine Theory of Addiction
1. VTA/A10 Pathway: projection of dopamine neurons in VTA activates NA
-GABA and glutamate neurons regulate phasic dopamine released in VTA
2. Reward Prediction Error: drugs always overvalued by nervous system - abnormal phasic DA release
-DA increase greater when: one expects it + self-administered
-addictive drugs exaggerate DA reward signal (always induce RPE + phasic DA release)
3. Wanting/Liking: motivational salience motivates behaviour towards/away from particular things
-incentive salience (wanting) = reinforcement, pleasure; aversive salience = harmful effects
-drug sensitization + dopamine system enhance wanting, very hard to avoid + very strong urges
-neutral stimuli are learned as triggers for drug use, may induce relapse/craving
4. Inappropriate Learning: Hebbian learning/synaptic strength of certain connections is stronger in VTA
1
, -LTP: persistent increase in synaptic strength following high-frequency stimulation of chemical synapse
-↑ neurotransmitter release = ↑ glutamate receptors = future excitatory stimuli generate longer
response; may be changes in gene transcription (long-term stabilization of synaptic changes)
-LTD: activity-dependent reduction in efficacy of neuronal synapses following prolonged stimulation
5. Impulsivity: drug use often reduces with age (youth more prone to impulsive behaviour)
6. Receptors: substance users have reduction in D2R + hypofunctioning DAR
-D2 + D3 reductions precede SUD; inability to delay gratification
Physical Dependence = change in signalling cascade/neural circuitry; tolerance = right-shift
1. Metabolic Tolerance: repeated exposure to drug induces enzyme activity (ex. alcohol)
-large dose required for therapeutic effect; actual amount of drug that makes it to target is reduced
**no alterations in dose-response curve (equivalent to taking less drug)
-Cross-Tolerance: induction of P450 by phenobarbital, alcohol, phenytoin
2. Learned Tolerance: non-drug factors of tolerance
-sensitivity of individual (greater first response = more likely to develop tolerance)
-activity at time of drug (tolerance develops quickly if individual is alert)
-user’s previous history (previous tolerant state = more likely to revert back)
-environment (conditional response)
3. Pharmacological Tolerance: adaptive changes within signalling cascade
-receptor downregulation, altered gene/protein expression, receptor-signalling uncoupling
Ex. opioid tolerance - less likely for tolerance when used to treat pain
-with repeat exposure: desensitization, endocytosis, down-regulation, uncoupling cAMP
COMMON DRUGS
Prescription Medications: Opioids
-inhibitory actions, change neuronal excitability, activate reward pathway
1. Morphine + Derivatives: increase threshold+tolerance for pain, respiratory depression/sedation
2. Opioid Derivatives: hydrocodone, codeine, oxycodone, fentanyl
-route of administration key to misuse (faster access to brain = more addictive)
3. Heroin: synthetic, 3X more potent than morphine; highly addictive, strong tolerance+withdrawal
Psychostimulants
Amphetamine: induce fight/flight response, ↑ NE + DA; suppress appetite, may cause cardiac arrhythmia
Methamphetamine: ↑ release of amines, pronounced CNS effects (lipid soluble), neurotoxic
Cocaine: highly addictive + high cravings, blocks reuptake of DA, often taken with alcohol; cause psychosis
-Crack: vapour from heated crystal rock is inhaled; faster absorption, more cardiotoxic
Ecstasy (MDMA): hallucinogen, ↑ alertness/energy then induces calmness + empathy; releases amines
Ketamine: analgesic/anaesthetic, NMDA receptor antagonist; hallucinations at high doses
Benzodiazepines: anxiolytic, sedative, anti-seizure medication; positive allosteric modulator of GABA
receptor; often used in speedballs with cocaine
Nicotine: can increase dopamine release
POLYPHARMACY -Drug-Drug Interactions
Additive Interactions
-pharmacological: target same receptor (ex. BZDs + alcohol act on GABA receptor)
-physiological: target same “system” (ex. Opioids + Venlafaxine are anti-depressants)
2
SUBSTANCE USE DISORDER (SUD)
-Addiction: chronic relapsing disorder, persistent drug-seeking + drug-taking behaviours
-physical/psychological dependence, craving/relapse, activation of reward pathway
THEORIES OF MECHANISMS UNDERLYING SUD
-factors that play a role: activation of brain reward system, physical dependence, genetic, environmental cues
Dopamine Theory of Addiction
1. VTA/A10 Pathway: projection of dopamine neurons in VTA activates NA
-GABA and glutamate neurons regulate phasic dopamine released in VTA
2. Reward Prediction Error: drugs always overvalued by nervous system - abnormal phasic DA release
-DA increase greater when: one expects it + self-administered
-addictive drugs exaggerate DA reward signal (always induce RPE + phasic DA release)
3. Wanting/Liking: motivational salience motivates behaviour towards/away from particular things
-incentive salience (wanting) = reinforcement, pleasure; aversive salience = harmful effects
-drug sensitization + dopamine system enhance wanting, very hard to avoid + very strong urges
-neutral stimuli are learned as triggers for drug use, may induce relapse/craving
4. Inappropriate Learning: Hebbian learning/synaptic strength of certain connections is stronger in VTA
1
, -LTP: persistent increase in synaptic strength following high-frequency stimulation of chemical synapse
-↑ neurotransmitter release = ↑ glutamate receptors = future excitatory stimuli generate longer
response; may be changes in gene transcription (long-term stabilization of synaptic changes)
-LTD: activity-dependent reduction in efficacy of neuronal synapses following prolonged stimulation
5. Impulsivity: drug use often reduces with age (youth more prone to impulsive behaviour)
6. Receptors: substance users have reduction in D2R + hypofunctioning DAR
-D2 + D3 reductions precede SUD; inability to delay gratification
Physical Dependence = change in signalling cascade/neural circuitry; tolerance = right-shift
1. Metabolic Tolerance: repeated exposure to drug induces enzyme activity (ex. alcohol)
-large dose required for therapeutic effect; actual amount of drug that makes it to target is reduced
**no alterations in dose-response curve (equivalent to taking less drug)
-Cross-Tolerance: induction of P450 by phenobarbital, alcohol, phenytoin
2. Learned Tolerance: non-drug factors of tolerance
-sensitivity of individual (greater first response = more likely to develop tolerance)
-activity at time of drug (tolerance develops quickly if individual is alert)
-user’s previous history (previous tolerant state = more likely to revert back)
-environment (conditional response)
3. Pharmacological Tolerance: adaptive changes within signalling cascade
-receptor downregulation, altered gene/protein expression, receptor-signalling uncoupling
Ex. opioid tolerance - less likely for tolerance when used to treat pain
-with repeat exposure: desensitization, endocytosis, down-regulation, uncoupling cAMP
COMMON DRUGS
Prescription Medications: Opioids
-inhibitory actions, change neuronal excitability, activate reward pathway
1. Morphine + Derivatives: increase threshold+tolerance for pain, respiratory depression/sedation
2. Opioid Derivatives: hydrocodone, codeine, oxycodone, fentanyl
-route of administration key to misuse (faster access to brain = more addictive)
3. Heroin: synthetic, 3X more potent than morphine; highly addictive, strong tolerance+withdrawal
Psychostimulants
Amphetamine: induce fight/flight response, ↑ NE + DA; suppress appetite, may cause cardiac arrhythmia
Methamphetamine: ↑ release of amines, pronounced CNS effects (lipid soluble), neurotoxic
Cocaine: highly addictive + high cravings, blocks reuptake of DA, often taken with alcohol; cause psychosis
-Crack: vapour from heated crystal rock is inhaled; faster absorption, more cardiotoxic
Ecstasy (MDMA): hallucinogen, ↑ alertness/energy then induces calmness + empathy; releases amines
Ketamine: analgesic/anaesthetic, NMDA receptor antagonist; hallucinations at high doses
Benzodiazepines: anxiolytic, sedative, anti-seizure medication; positive allosteric modulator of GABA
receptor; often used in speedballs with cocaine
Nicotine: can increase dopamine release
POLYPHARMACY -Drug-Drug Interactions
Additive Interactions
-pharmacological: target same receptor (ex. BZDs + alcohol act on GABA receptor)
-physiological: target same “system” (ex. Opioids + Venlafaxine are anti-depressants)
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