Cocaine and Amphetamines Flashcards
What are drug free periods known as?
Remission ⇒ followed by relapse (aspect difficult to control)
What is substance use disorder?
- Maladaptive pattern of substance use for at least 12 months leadins to significant impairment or distress by clinical standards
What is the conditioned place preference test (CPP)?
(3 marks)
- Relies on conditioned association between drug effect and environment
- drug rewarding, stays within the environment associated with it
- drug aversive, stays within the other environment
What is the best way of measuring drug reinforcement?
Investigating HOW animl self administered the drug
How can you measure how an animal self administers a drug?
- Use infusion pump attatched to animal and can use lever to inject drug
- At higher doses, number of reinforcers can decline due to satiation, aversive reactions/ behaviourally disrupted side effect
How can you use progressive ratios to measure breaking point of animal?
(4 marks)
- Animal is trained to press lever with frequency ratio (FR) of 5 - drug every 5 responses
- Breaking point = number of responses animal is willing to do to get the drug
- Correlation between motivation of animal and addictive condition
- Breaking point is higher with higher motivation - increases with higher doses
How is relapsed modelled in self administration studies?
What does this show?
(3 marks)
- Deliver small dose of drug
- Subject animal to stress
- Put in environmental cues previously paired with drug delivery
People may be free of addiction for years but single dose can start it all over again
What is abstinence syndrome?
Attempts at abstience that lead to unpleasant withdrawal symptoms to motivate user to use the drug again
Assuming circuitry of VTA-NAc parallels that of SN-DS in basal ganglia system, what receptor class should be activated by psychostimulation of NAc-VTA to enhance locomotor function?
Dopamine D1
What is the reward circuit?
- Neural circuit responsible for acute rewarding and reinforcing affects of abused drugs
- Uses GABAA receptors and dopamine pathways
Which one is synthetic and which one is a natural compound:
Cocain or Amphetamines?
Cocaine - natural compound
Amphetamines - synthetic
What is cocaine?
(2 marks)
- Alkaloid
- Coca leaves used to relieve fatigue and maintain fitness at high altitudes
What two cocain drugs are used experimentally?
(2 marks)
- WIN 35,428 (aka CFT)
- RTI-55 (aka B-CIT)
What are some of the characteristics of Cocain HCl?
(3 marks)
Water soluble
Injected/orally digested
Normally snorted nasally
What methods are used to create crack cocaine?
(4 marks)
- Dissolve in water and add alkaline solution i.e. ammonia
- Extract cocaine base with organic solvent typically ether
- (Freebasing: refers to cocaine smoked in this manner)
- Mix dissolved HCl with baking soda, heat mixture then dry it
- Chunks of dry or hardened mixture known as ‘crack’ cocaine
What properties of cocaine allow it to be absorb very efficiently?
(2 marks)
Lipophilic - (fat soluble) readily passes through blood brain barrier
Smoking - undetectable in blood and goes straight to brain
Why does cocaine tend to be taken repeatedly throughout the day?
Very short half life
What breakdown product of cocaine is detectable in urine for several days?
Benzoylecgonine
What is created when you mix alcohol and cocaine?
Unique metabolite called cocathylene - longer half life and much stronger
Explain the mechanism of cocaine action.
(6 marks)
- Cocaine binds to transporters of DA, NE and serotonin (5-HT)
- Blocks transporter and increases time of NT in synaptic cleft and increases transmission
- Cocaine preferntially binds with high affinity to DAT transporter, followed by NE transporter and then 5-HT receptor
- Most action of cocaine exerted through dopamine transporter
- Remove transporter - lose most cocaine response
- At v high concentrations cocaine able to inhibit voltage gated Na+ hcannels in axons blocking nerve conduction
What are the effects of cocaine if applied locally?
Works as local anaesthetic by preventing transmission of signals along sensory nerves
What are the typical feelings of the high associated with cocaine?
Exhilaration and euphoria, enchanced alertness, may see increased aggresive behaviour
What did animal models show about the affects of low doses of cocaine?
- Increases locomotion, rearing and mild sniffing behaviour
What is meant when it is said that cocaine is ‘sympathomimetic’?
(3 marks)
- Can only work in post ganglionic synapses in sympathetic nervous system as it doesn’t use ACh it uses NE
- Produces sytems of sympathetic nervous activation
- Some responses if very abd are an example of cocaine infection
Why are psychostimulants sympathomimetics?
Activate catecholamine receptors in post ganglionic synapses
How are the effects of cocaine experiences if you are heterozygous (one copy) for the DAT transporter?
(4 marks)
- Suffer way less effects of cocaine
- Insensitive to cocaine
- Proves that DAT transporter is intial main site of action of cocaine
- Animals with DAT mutant still functional for DA uptake, but fail to self administer
What does the intensity of the high experienced from cocaine depend on if you have the minimum occupancy of DAT transporter?
- Depenent on rate at which DAT occupancy occurs and baseline level of DA activity in mesolimbic pathway
What is the dominant receptor implicated in cocaine action?
(3 marks)
D1 receptor
- KO mice don’t self administer cocaine - shows it has critical role
- Required for locomotor stimulating effects
What is seen in D2 and 3 KO mice after the administration of cocaine?
(2 marks)
search D3 purpose
- D2 KO mice self administer cocaine
- D3 receptors however are important for cocaine reward and reinforcement
What are cocaine binges?
Episodic bouts of repeated use lasting hours to days with little or no sleep
What can chronic exposure of cocaine lead to?
Either sensitisation or tolerance
Which one occurs is dependent on drug exposure or response measured
What are the phases sensitisation is divided into?
(2 marks)
- Induction: process by which sensitisation is established
- Expression: process by which sensitised resopnse is manifested
What was found when animals were given amphetamines directly into VTA?
- Heightened release of DA in nucleus acuumbens and increased locomotor response when challenged with other amphetamines
From PET scans what was reveleaed about the dopaminergic system in cocaine-dependent subjects?
- D2 receptor binding is reduced, there is also reduced DA activity in the striatum
What are some potential forms of treatment for cocaine addiction?
(4 marks)
- Modafinil: stimulant - mode of activation has affects on - DA, NE, glutamate and GABA systems - binds to DAT w/ low affinity and acts as weak DAT uptake inhibitor
- Disulfiram: antiabuse - used to treat alcohol dependence
- Cocaine vaccines: antibodies bind cocaine/ have catalytic activity that breaks down cocaine
- Relapse prevention therapy (cognitive behavioural therapy)
What is repeated Transcranial Magnetic Stimulation (rTMS)?
(3 marks)
- Non-invasive procedure
- Tested in dorsolateral pre-frontal cortex - stimulation prevents cocaine use in humans
- Found with this method more cocaine free urine so it works
- Most promising form of cocaine treatment
What are amphetamines and metaphetamines metabolised by?
Liver at a small rate
What neurological behaviour are amphetamines used to treat in children?
ADHD
How long can the affects of methamphetamine last?
3 to 6 days with little sleep or eating
How do amphetamines and metamphetamines affect the catecholaminergic system?
(5 marks)
- Indirect agonists
- Massive extracellular increase of extracellular DA
- Amphetamine is taken up by DAT transporter and absorbed which causes a massive release of DA via vesicles
- so lots of DA in synaptic cleft
- Facilitated by activated PKC and CamKII causing phosphorylation of transporter
What are some of the behaviorual effects of amphetamines and methamphetamines?
(4 marks)
- Heightened alertness
- Suppress appetite
- more confidence
- methamphetamine causes brain damage
How does methamphetamine cause damage to the brain and body?
(3 marks)
- Damages DA axons and terminals and serotonergic fibres in several brain areas
- DA innervation to striatum severly compromised - can be permanent
- Heavy use associated with cardiovascular problems
