Reward/Drugs of abuse/Legal highs Flashcards
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What does the WHO recommend drug dependence to be referred to as?
- Abuse
- Dependence
»> NOT addiction, habbituation
What is dependence syndrome?
- Strong desire or sense of compulsion to take substance
- Difficulties in controlling use (amount, onset, termination)
- Physical withdrawal state (?)
- Tolerance (?); seen w/long term abuse
- Progressive neglect of other interests, increasing time spent obtaining and taking substance
- Persistence w/substance despite detrimental effects: social, cognitive, physical
What are the parallels between Social Attachment and Substance Abuse?
- Social Attachment
• Substance Abuse - Dating = ‘smitten’
• Time set aside for getting and using substance - Sensation of time flying w/partner
• Time increase; drug seeking behaviour, recovering - Loss of time with friends
• Social, occupational and recreational activities reduced - Euphoria to contentment
• Development of tolerance; reduced intensity - More time spent with partner
• Dependence; induced increased in drug use - Separation anxiety
- Physical or emotional abuse
• Withdrawal; continued use despite recognition of problems - Anhedonia (inability to feel pleasure) and depression induced by loss or separation
• Withdrawal-induced anhedonia and depression
What is the rat experimental model for brain reward pathways?
- Rat is hooked up to tube w/indwelling catheter
- Has access to a lever
- Which is connected to programming + recording equipment and the infusion pump to administer the dose
»> Learned behaviour, keeps pressing lever instead of grooming themselves etc.
Describe the brain reward pathway for dopamine, and where drugs of abuse act.
- Many drugs of abuse increase DA release in the nucleus accumbens, NAC
- Cell bodies of the (mesolimbic) DA pathway in the ventral tegmental area (VTA; in the midbrain, neurons run up and) terminate in the NAC
What drugs of abuse are involved DA increase in the NAC?
- Opiates
- Nicotine
- Amphetamine
- Cocaine
- Cannabis
- Ethanol
- Ecstasy
- PCP
- Barbiturates
- Caffeine
Which brain reward pathway do LSD (lysergic acid diethylamide) and Ecstasy (MDMA - 3, 4-methylenedioxymethamphetamine) act on?
- Enhance serotonin (5-HT) function
- Hallucinogenic
Which drugs of abuse are NMDA antagonists?
- Phencyclidine (PCP)
- Ketamine
»> Hallucinogenic
»> Blocking excitatory mechanism
What is meant by the disinhibition of GABAa receptors by morphine/cannabinoids?
- GABAa normally triggers downstream signalling to dampen down DA release from ventral tegmental area (VTA) to nucleus accumbens (NAC); GABA is inhibitory
- However, morphine/cannabinoids (and endogenous enkephalins)
Describe how various drugs of abuse enhance the release of DA from VTA (ventral tegmental area) neurones.
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Cocaine:
- Prevents reuptake of DA, thus more DA in cleft activating receptors = reward
Amphetamine:
- Same site of action as cocaine (end of VTA next to NAC)
- Taken up into the nerve ending and ‘kick out’ DA
»> NA is induced instead in PNS = tachycardia (same w/cocaine)
Morphine/cannabinoids:
- Disinhibition of GABAa receptors
- GABA normally results in dampening down DA release from VTA to NAC; inhibiting an inhibitor
What kind of studies were conducted to demonstrate how drugs of abuse affect DA release?
- Microdialysis of the brain
- Isotonic fluid perfused; ECF equilibrates through dialysis membrane = excess DA(?) transferred into dialysate
- Can be examined upon collection from outlet tube
What does a faster and higher peak in brain DA levels mean for the person taking the drug of abuse? How does this affect ‘formulation’?
- Faster and higher peaks in DA = greater the ‘rush’ (euphoria)
Formulation:
• IV heroin ‘better’ than methadone PO
• Snorting/inhaling cocaine better than chewing cocoa leaves
• Smoking cigarettes better than chewing tobacco
What is bromocriptine and what is it used for?
DA agonist:
- Stopping breast milk production on medical grounds
- Problems usually caused by not having the right amount of prolactin
- Treating non-cancerous tumours in the brain (prolactinomas)
- Treating Parkinson’s Disease (increases DA)
Why must special care be taken for DA agonists such as Bromocriptine and Ropinirole? (used for PD, stopping breast milk production, against prolactinomas etc.)
S/Es include potential addiction:
- Risk of impulse control disorders; can include behaviours such as addictive gambling, excessive eating/spending, abnormally high sex drive etc.
- Tell HCP if developing urgres
Name two narcotic analgesics and their degree of dependence liability.
- Morphine (V. Strong)
- Heroin (V. Strong)
Name 4 General CNS depressants and their corresponding degree of dependence liability.
- Ethanol (Strong)
- Barbiturates (Strong)
- Cannabis (Weak)
- Anaesthetics (Moderate)
Name some psychomotor stimulants and their corresponding degree of dependence liability.
- Nicotine (V. Strong)
- Cocaine (V. Strong)
- Amphetamines (Strong)
- Caffeine (Weak)
- Ecstasy (Absent ?)
Name some psychedelic agents and their corresponding degree of dependence liability.
- LSD (Weak or Absent)
- Mescaline (Weak or Absent)
- Phencyclidine (Moderate)
What is the degree of dependence liability of Benzodiazepine? What class of drug is it?
Anxiolytic (Strong)
What is the mechanism of action of opiates? General effects? Give examples.
- Agonists at GPCRs (mu receptors mainly)
- Lower NT release in brain and periphery
Resulting in: • Analgesia • Euphoria • Positive reinforcement • Respiratory depression • Dysphoria (state of unease/general dissatisfaction with life) • Sedation
E.g. morphine, heroin, methadone, codeine
What are the acute and chronic effects of opiates?
Acute: • Euphoria • Tranquility • Miosis (excessive constriction of pupil of the eye) • Drowsiness • Itching • Nausea
Chronic:
- Anhedonia (lack of pleasure in life)
- Constipation
- Depression
- Insomnia
- Dependence
- Nutritional status poor; danger of HIV and hepatitis from injecting
- Significant tolerance; need to increase dose
What are the withdrawal precipitates for opiates?
- Craving
- Insomnia
- Restlessness
- Diarrhoea
- Muscle and bone pain
- Vomiting
- Cold flashes w/goose bumps (cold turkey)
- Kicking movement (kicking the habit)
When do withdrawal symptoms peak for opiates? What other complications involving withdrawal may occur?
- Major withdrawal symptoms peak 48-72 hours after the last dose, subsiding after a week
- Sudden withdrawal by heavily-dependent users occasionally fatal; although heroin withdrawal is considered less dangerous than alcohol or barbiturate withdrawal.
Describe the mechanism of action of cocaine.
- Increases catecholamine (DA, NA etc.) NT function by preventing re-uptake
- DA most important for CNS behaviour
- High conc. has anesthetic properties
Describe cocaine’s main effects (+ effects in high doses), and the different routes of administration.
Effects:
- Euphoria
- Excitement
- Increased capacity for work
High doses: • Overactivity of the sympathetic system (reuptake blockade) • Hypertension • Tachycardia • Hyperpyrexia • Dilated pupil • Palpitations
Routes:
- Cocoa leaves chewed in Peru (cocaine HCl)
- Snorted (hydrochloride; can cause perforation of nasal septum), or smoked w/tobacco
Outline cocaine’s effect on dependence.
- Little tolerance
- Little PHYSICAL dependence
- But, strong PSYCHOLOGICAl dependence (e.g. more cocaine was required to bind same number of sites at 50% neuronal uptake in dependent rats)
»> Free base ‘crack’ can be smoked = v. rapid dependence
Describe the mechanism of action of amphetamines. Give examples.
- Release monoamines from neuronal storage vesicles
- Block re-uptake transporters
- Resulting in increased synaptic DA, NA and 5-HT
E.g. methamphetamine, dexamphetamine
What are the general effects of amphetamine use?
- Phenylethylamine drugs, produce increased wakefulness and concentration
- In association w/fatigue and appetite
- Some tolerance
- Performance enhancing (sport/war)
»> ‘Speed’ - Increases cardiovascular tone; raised BP, tachycardia (sympathetic)
What are the psychological effects of amphetamine use? What about with chronic use/high doses?
Psychological:
- Euphoria
- Increased libido
- Energy
- Self-esteem
- Self-confidence
- Aggression
- Excessive feelings of power, obsession, paranoia
Chronic/high dose:
• Amphetamine psychosis can occur
What are the parallels between amphetamines and pseudoephedrine?
- Work in the same way, but just in the periphery (increases cardiovascular tone, raised BP, tachycardia)
»> Banned in sport
What is the active agent of cannabis? What is its mechanism of action?
- Various preparations of Cannbis sativa
- Active agent (THC); mimics effects so small endogenous lipid messengers e.g. anandamide (like enkephalins in opioids)
- Inhibits wide range of NT release in the brain and periphery; via special Gi protein-coupled cannabinoid receptors
What are the effects of cannabis use? Munchies?
- Mild euphoric effect in moderate dose
- Dysphoric in high doses (profound unease; particularly in naive users; ‘whitey’)
- Context dependent
- Stimulates appetite through actions on feeding centre in hypothalamus and possibly gut
- Analgesic
What is the risk of toxicity w/cannabis use?
- Very low acute toxicity
- BUT, some concerns about precipitation of psychosis in chronic heavy users
What is the drug abuse cost WRT crime, social security, NHS and justice for drug offenders?
- £20 billion a year
- > £300 per person in England and Wales
How does the annual spend per drug user differ between recreational use, Class A users and problem users?
Young recreation/older regular users:
- < £20 p.a.
Class A users:
- £2,030 p.a.
Problem users:
- £11,000 p.a.
Why is treatment of drug users advantageous to the economy, as well as the drug user?
For every £1 spent on treatment, at least £5 is saved on health service and criminal justice costs.
What is the pharmacological approach to treatment of opiate abuse? How is it given?
- Agonist substitution; Methadone
- Long-acting synthetic opiate agonist (onset of withdrawal 36-72 hr compared to 8-12 hr for heroin); administered PO for sustained period at dose sufficient to prevent opiate withdrawal (used appropriately)
How does methadone work? What can it do for the user? Cessation?
- Blocks effects of illicit opiate use and decreases opiate craving
- Patient stabilised on adequate, sustained dosages can hold jobs, avoid crime and violence of street culture, reduced exposure to HIV by stopping needle sharing
- Very low rate of complete cessation of heroin use in methadone patients e.g. 2 patients in 10 years
How effective is NRT for smoking cessation?
- Relatively ineffective in long-term smoking cessation; one year quit rates stand at 17% vs 10% placebo
- No. of formulations: gum, patches, sprays etc.
- Most difficult ‘drug’ to give up
What do Champix (Varenicline) and Buprenorphine have in common?
Both partial receptor agonists:
- Champix = nicotinic ACh (smoking)
- Buprenorphine = mu-opioid (opioids)
What antagonist treatments are availible for pharmacological therapy of drug abuse, and what are their criteria? Antibody therapy? Can their effect be overcome?
Naltrexone:
- Not common (heavy addicts only)
- Therapy for opiate addiction; patients must be detoxified and opiate-free for several days before naltrexone can be taken
- Prevents precipitating opiate abstinence syndrome
Mecamylamine:
- nACh receptor antagonist (nicotinic)
- Blocks rewarding actions of nicotine and cue-induced craving
> > > Various attempts made to produce mAb (e.g. cocaine, nicotine that binds drugs of abuse in bloodstream; failed.
Antagonist effects can be overcome by increasing dose of drug
Patient non-compliance major problem
What anti-craving medicines are availible? How do they work?
Acamprosate (Ca2+ salt of N-acetyl-homotaurine):
- Registered for use as adjunct in maintaining abstinence in alcohol-dependent patients
- Reduces alcohol consumption in alcoholic rats
- Reduces neuronal excitability that occurs during alcohol withdrawal
Naltrexone:
- Can be used in addition in opioid dependence, also reduces alcohol craving by interfering with positive reinforcement and possibly alcohol-conditioned cues
- Possibly acts by blocking endogenous opioid disinhibition of GABA neurones in VTA, thereby reducing firing of DA releasing neurones
What is the official position the HCP WRT to drugs of abuse and the user?
- To help manage the condition
- Not to ‘solve’
- To not be judgemental
