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Assessable Tasks
By the end of this lecture you will be able to:
• Describe the epidemiology and differences between recreational drug use and the diagnosis of addiction
• Describe the underlying mechanisms and site of action for commonly used recreational drugs
• Identify their main wanted/unwanted effects
[blank_start]OK[blank_end]
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Drugs ordered by overall harm scores and weights after normalisation (0–100) (Lancet, 2010)
1. [blank_start]Alcohol[blank_end] - 72/100
2. [blank_start]Heroin[blank_end] - 55/100
3. [blank_start]Crack Cocaine[blank_end] (smoked) - 54/100
4. [blank_start]Meth[blank_end] - 33/100
5. Cocaine - 27/100
6. Tobacco - 26/100
also cannabis - [blank_start]20[blank_end]/100, benzodiazepiones - [blank_start]15[blank_end]/100, methadone - [blank_start]14[blank_end]/100
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Alcohol
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Heroin
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Crack Cocaine
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Meth
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20
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15
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14
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DSM-5 Criteria for Substance Use Disorders:
The 11 criteria for substance use disorder are divided into four categories of behaviour related to the substance use:
1. impaired [blank_start]control[blank_end]
2. [blank_start]social[blank_end] impairment
3. [blank_start]risky[blank_end] use
4. pharmacological indicators ([blank_start]tolerance and withdrawal[blank_end]).
The severity of the substance use disorder is determined by the number of criteria the person meets:
Mild - [blank_start]2 or 3[blank_end] criteria
Moderate: [blank_start]4 or 5[blank_end] criteria
Severe: [blank_start]6[blank_end] or more criteria
Within the last 12-month period,
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control
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social
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risky
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tolerance and withdrawal
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2 or 3
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4 or 5
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6
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Probability of dependence when you have tried a drug once
[blank_start]Tobacco[blank_end] - 32%
[blank_start]Heroin[blank_end] - 23%
[blank_start]Cocaine[blank_end] - 17%
[blank_start]Alcohol[blank_end] - 15%
Stimulants - 11%
Anxiolytics and Cannabis - 9%
[blank_start]Analgesics[blank_end] - 8%
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Tobacco
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Heroin
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Cocaine
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Alcohol
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Analgesics
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Speed of drug entry into brain dictates the intensity of the ‘high’.
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Tolerance
• Can and often occurs in the absence of [blank_start]dependence[blank_end] – reduced response after repeated administration
• Usually due to receptor/[blank_start]second messenger[blank_end] desensitization and [blank_start]down[blank_end]-regulation
• [blank_start]Cross-tolerance[blank_end] – repeated use of a drug in a given category confers tolerance to the drug being used AND others within the same pharmacological category.
• Metabolic or [blank_start]pharmacokinetic tolerance[blank_end] - increased metabolism requires increasing doses to produce the same pharmacological effect.
• [blank_start]Pharmacodynamic tolerance[blank_end] – increasing doses required to produce the same effect (learned behaviour)
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Neurocircuitry of impulsive-compulsive behaviuor:
• Associated with [blank_start]anticipation of the reward[blank_end] associated with drug, noy reward of drug
• Impulsivity and compulsivity are hypothetically drives that are “[blank_start]bottom[blank_end]-up,” ie controlled by suppression of higher drives.
1 - impulsivity comes from the [blank_start]ventral striatum[blank_end] (NAc)
2 - compulsivity comes from the [blank_start]dorsal striatum[blank_end]
3 - different areas of [blank_start]prefrontal cortex[blank_end] act “[blank_start]top[blank_end]-down” to suppress these drives.
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Addiction - shifts from [blank_start]impulsive to a compulsive[blank_end] drive, that comes with migration from [blank_start]ventral[blank_end] to [blank_start]dorsal[blank_end] circuitry. With chronic drug use, compulsivity develops, as the drive changes from [blank_start]seeking pleasure[blank_end] (impulsive) to seeking r[blank_start]elief from the withdrawal symptoms[blank_end] (compulsory) and anticipation of obtaining/consuming the drug.
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Choose the incorrect statement.
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Psychotropics bypass neurotransmitters and directly stimulate receptors causing DA release and the high.
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Withdrawal of CNS depressants usually involves neuronal hypo-excitability with varying degrees of severity – anxiety, possible hallucinations, seizures etc.
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Withdrawal of CNS depressants causes significant activation of the autonomic nervous system: sweats, tremors, GI disturbances
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Inhibition of the mesolimbic DA release commonly occurs in withdrawal
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Which of these is not a CNS stimulant/depressant?
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Nicotine
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Methamphetamine
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Cocaine
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Caffeine
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Alcohol
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Benzos
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Opioids
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Cannabis
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Heroin
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Effects of Alcohol on reward:
Alcohol either acts directly upon µ [blank_start]receptors[blank_end] or releases endogenous opiates such as [blank_start]encephalin and endocannabinoids[blank_end].
It causes increased [blank_start]DA[blank_end] release in [blank_start]NAc[blank_end]. Reinforcing effects also theoretically mediated by enhancing [blank_start]GABA[blank_end] inhibition and reducing [blank_start]GLU[blank_end] excitation.
Factors Associated With Alcoholism
• Environmental Factors
1. family or peer [blank_start]group[blank_end] behavior
2. availability of other reinforcers (e.g. recreational resources)
3. job/educational opportunities
4. conditioned stimuli ([blank_start]environmental cues[blank_end] paired with drug use)
5. [blank_start]Cost/ease of availability[blank_end] of alcohol
• Host Factors - Genes:
1. + and - for alcohol (reduced gene expression for alcohol dehydrogenase reduced
sensitivity to alcohol phenotype in alcoholics);
2. Antisocial or [blank_start]anxious[blank_end] traits; risk-taking
3. Prior experience/expectations
Tx: Naltrexone on the [blank_start]VTA[blank_end] reduces reward.
Naltrexone - µ [blank_start]opiate antagonist[blank_end]: blocks [blank_start]pleasurable[blank_end] effects of alcohol, decreases cravings. [blank_start]Long acting benzodiazepines[blank_end] used to mediate ‘withdrawal’ over a few weeks to prevent symptoms like life threatening seizures.
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receptors
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encephalin and endocannabinoids
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DA
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NAc
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GABA
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GLU
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group
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environmental cues
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Cost/ease of availability
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anxious
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VTA
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opiate antagonist
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pleasurable
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Long acting benzodiazepines
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Cannabis - THC and cannabidiol
• ‘normal’ dose - sense of well-being, relaxation, friendliness, loss of [blank_start]temporal[blank_end] awareness, slows [blank_start]thought[blank_end] processes, impairs [blank_start]short[blank_end]-term memory
• ‘high’ doses - can induce [blank_start]panic, toxic delirium[blank_end] and rarely [blank_start]psychosis[blank_end]
• “[blank_start]amotivational syndrome[blank_end]” in frequent/heavy users characterized by the emergence of decreased drive and ambition, thus “amotivational.”
Cannabidiol = [blank_start]allosteric[blank_end] negative modulator of [blank_start]CB1 and CB2[blank_end], potentially used to treat addiction, anxiety, psychosis and epilepsy
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temporal
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thought
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short
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panic, toxic delirium
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psychosis
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amotivational syndrome
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allosteric
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CB1 and CB2
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Cannabinoids in the mesolimbic pathway:
• [blank_start]GABAergic[blank_end] interneuron feedback projections provide tonic [blank_start]inhibition[blank_end] of [blank_start]VTA dopaminergic[blank_end] neurons
• [blank_start]CB1[blank_end] receptors mediate marijuana’s reinforcing properties
Opioids in the mesolimbic pathway:
Act on [blank_start]opioid neurons[blank_end] which arise in the [blank_start]arcuate nucleus[blank_end] and project to the [blank_start]VTA and NAc[blank_end]. Opioids bypass the enkephalins and [blank_start]directly[blank_end] stimulate receptors causing [blank_start]DA[blank_end] release = high.
Nicotine & dopamine release:
Nicotine - full agonist at α4,β2 [blank_start]nicotinic[blank_end] receptors on [blank_start]DA neurons in the VTA[blank_end] – cause prolonged channel [blank_start]opening[blank_end] until desensitization → prolonged burst of action potentials and consequently [blank_start]prolonged DA release[blank_end]
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GABAergic
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inhibition
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VTA dopaminergic
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CB1
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opioid neurons
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arcuate nucleus
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VTA and NAc
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directly
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DA
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nicotinic
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DA neurons in the VTA
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opening
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prolonged DA release
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The ‘amphetamines’
• Increase [blank_start]synaptic[blank_end] conc. of DA, by"
• inducing release of newly synthesized [blank_start]stores of intraneuronal DA[blank_end]
• and inhibiting NA, 5-HT and DA [blank_start]reuptake transporters[blank_end] and VMAT
• [blank_start]Methylphenidate[blank_end] is an uptake inhibitor only
• Methamphetamine - similar to cocaine but [blank_start]longer[blank_end] lasting effects with less euphoria, associated with [blank_start]schizophrenia[blank_end]-like psychosis
• Ecstasy - [blank_start]serotonergic[blank_end], dependence rare/debatable
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The amphetamines ‘undesirable effects’
- change in [blank_start]structure and function[blank_end] of the human brain
- ability to cause [blank_start]cerebral and/or myocardial[blank_end] infarcts ([blank_start]dead[blank_end] tissue from oxygen deprivation)
Overdose treatment is with non-selective or [blank_start]Ca2+[blank_end] or ß-blockers, [blank_start]diazepam[blank_end] for seizures