BMD225 mcq 3- week 8,9,11

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How many people aged 4-17 years old have a current diagnosis of ADHD?
5.1 million
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How many people in the Uk have autism?
1/100
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How many people in the UK are treated for alcoholism?
100,000
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How many people in the uk are treated for opiate addiction?
250,000
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How many people in the uk in 2012 are treated for smoking?
1/6
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How much do genes account for the variance in smoking maintenance?
up to 70%
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How much do genes account for the variance in cessation success?
50% of
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How much do genes account for of the variance in withdrawal symptoms?
30-50%
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To find genetic variations what are the two studies that need to be conducted?
Human genome wide association and Mutagenesis.
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What do mutagenesis studies entail?
Screening families for the behaviour/disease marker of interest.
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For scientific purposes, why do we use zebrafish?
Fish are vertebrates- highly conserved DNa sequence with humans. Have the same neural pathways. Can make more mutations in fish than can in mice or rats.
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For ethical purposes, why do we use zebrafish?
Using fish reduces the number of rodents used
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For practical purposes why do we use zebrafish?
They are cheap and easy to house - reducing costs makes drugs cheaper
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What are some advantages of zebrafish that allow us to utilise it?
They are genetically amenable, a cost effective vertebrate system for pharmacological/genetic screening. They are able to minimise variation. Transparent larvae facilitating developmental analysis and allowing in vivo correlations.
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What is the first approach?
Screen mutant families to find genes influencing behaviours assocaited with addiction and psychiatric disease: drug seeking, impulse control, sensorimotor gating
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What is the second approach?
Determine cellular processes affected, screen chemicals for ability to treat
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How do you test if fish like drugs?
A conditioned place preference assay
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What does a conditioned place preference assay entail day by day?
Day 1: Find basal preference, Day 2: restrict to preferred side for 20 mins with no drug, restrict to non-preferred side for 20 mins with drug. Day 3 + 4 repeat, Day 5 - find new preference
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What drugs can be used in a conditioned place preference assay?
Nicotine, ethanol, cocaine, amphetamine
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What is the result of a conditioned place preference assay for zebrafish?
They show CPP responses to most classes of commonly abused drugs. Cocaine had the greatest the higher the concentration
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In the genetic screening for facotrs affecting drug seeking what is the sign for homozygous, heterozygous, homozygous wildtype?
(-/-), (+/-), (+/+)
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In a classic F3 screen, in the third generation, what is the percentage of offspring that will be homozygous for any specific allele?
25%
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In a classic F3 screen, in the third generation, what is the percentage of offspring that will be heterozygous?
50%
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In a classic F3 screen, in the third generation, what is the percentage of offspring that will be homozygous wildtype?
25%
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If there is a dominant major effect and a recessive major effect in a population based screen what do you do?
Screen family
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If there is a multi-allelic minor effect what do you do?
A disequilibrium map.
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what did population-based screening of ENU families identify?
Novel alleles associated with nicotine preference
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What are some points that can be identified from the data in the graphs?
The QM2 mutant at the lowest frequency caused the greatest change in placebo preference. Of the QM2 strin the mutant SNP carriers caused the greatest change in place preference vs wt. Of the sa202, the sa103 dominant effect had the greatest result
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What is QM2?
A loss of function mutant, implicated in axon guidance
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In a conserved exon structure what are the conserved protein domains and what is the percentage of identical amino acid sequence?
Conserved protein domains: LRR, EGF, LAMG. 69% identical amino acid sequence.
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What can be said from the prediction of QM2 variants in smoking consumption?
around 10 and 11 SNP's (single nucleotide polymorphisms), the relative smoking/cigarettes per day was at its lowest
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What can be said from the prediction of QM2 variants on quit rate?
Around 10 and 11 SNPs again there was a higher OR (a greater chance of a minor allele increasing the chances of quitting)
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What is the point of using zebrafish to predict genes affecting human drug seeking behaviour?
Finding the gene helps identify cellular processes involved such as in the nerve growth and generation of new neurons. It also helps towards personalise therapies by tailoring treatments to individuals.
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What are some facts about QM2?
It is an axon guidance molecule. The zebrafish version is expressed in floorplate and roofplate and neuronal clusters.
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What is the role of CHRNa5 in mammals?
Its signalling regulates activity in the IPN-habeluna projection to modify nicotine intake
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What is the effect of QM2 +/- on CHRNa5 expression?
It increases it.
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Define endophenotype?
A quantifiable core component of a complex behaviour trait
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To figure out the endophenotype of a larva what do you do?
Sensorimotor gating; habituation/pre-pulse inhibition
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To figure out the endophenotype of an adult what do you do?
Drug seeking/reward sensitivity, impulsivity: impulsive action,impulsive choice, attention: sustained, selective. Behabioural flexibility: reversal learning, set shifting
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What does ASR stand for?
Acoustic startle response
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What does PCP do to startle habituation?
Its exposure decreases habituation.
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How does QM2 affect acoustic habituation and PPI?
It reduces both.
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What are defects in habituation associated with?
Disrupted Dopaminergic signalling: DR1ko
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What have larval habituation screens been able to identify?
Genes involved in sensorimotor gating meaning potential roles in schizophrenia and addiction.
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What are the steps in screening that Fish and Pfizer came up with?
Target validation, high throughput screen, hit to lead, lead optimization, preclinical, clinical
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during target validation what can happen and what do you do?
Gene knockdown/ genetic mutant. Screens identify mutations affecting learning, impulse control and drug seeking
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In 'Hit to Lead' what can happen and what do you do?
Lead series prioritization. Screen chemical libraries for possible therapeutic effects.
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In Lead optimization what can happen?
Therapeutic Window, efficacy assays.
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In the preclinical what can happen and what do you do?
Safety liability. All new drugs must be assessed for their addictive potential. Assays in fish are a cost effective means of assessing reward potential
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In the clinical what can happen?
Reprofiling. New Indication Screening.
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What are NSAIDS inhibitors of?
cyclooxygenase
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Give examples of non -selective NSAIDs
Aspirin, Ibuprofen, Diclofenac
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Give examples of selective NSAIDs
Paracetamol, Coxibs
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What does modulation result in?
Descending inhibiton of nociception through the release of neurotransmitters: serotonin norepinephrine and ENDOGENOUS OPIOIDS
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Describe what causes peripheral transmission?
The travelling of nociceptive impulses along peripheral nerves to the dorsal horn of the spinal cord
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What causes synaptic transmission?
The synapsing of the dorsal horns with the second order neurons
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What causes central transmission?
The further transmission of nociceptive impulses via neurons which ccross the spinal cord and ascend to the thalamus, and branches to the brainstem nuclei
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Whih fibres involved in the conduction of action potentials are myelinated/unmyelinated?
a delta fibers are thinly myelinated, C fibres are unmyelinated
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What is lamina II?
Substantia gelatinosa
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Which two components in the pain pathway are rich in opioid receptors?
Periaqueductal grey matter (PAG) and Lamina II
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What are the two classes of opioid endogenous peptides?
Enkephalins, Endorphin and Dynorphins
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What is the role of opioid receptors?
To inhibit adenylate cyclase, reducing cAMP
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What are the classical terminology of the opioid receptors
u, delta, kappa, orl
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What are the recommended new terminology of opioid receptors?
MOPr, DOPr, KOPr, NOPr
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What is morphine?
An alkaloid extracted from opium
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What are the actions of morphine?
Analgesic, Antidiarrhoeal, Antitussive
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What are some other actions of morphine?
Euphoria, stimulation of ctz, miosis (decreased pupil)
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Between the time when morphine treatment begins and you withdraw morphine what are the mechsnisms that occur
Acute morphine causes an initial reduction in CAMP generation, that single dose can then cause a single detection of tolerance, dependence occurs next, when morphine is removed the graph shoots back up due to rebound increase in cAMP.
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What are some other opiates?
Codeine, Diamorphine (heroin)
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Which of the opiates is a pro-drug?
Diamorphine
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Which of the opiates is metabolised to morphine?
codeine
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Which opiate is semi-synthetic?
Diamorphine
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What are the other agonists of opioid recceptors?
Pethidine, Fentanyl, Methadone
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Of the other agonists of opioid receptors which are longer acting than morphine and which are short acting?
Methadone - long. Pethidine, Fentanyl - short.
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Which of the other agonists of opioid receptors interact with monoamine oxidase inhibitors?
Pethidine.
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What is buprenorphine and what does it produce?
A partial agonist which produces strong analgesia.
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Give example of the antagonists at the opioid receptors?
Naloxone, Naltrexone
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Out of the opioid antagonists, which is an antagonist at all three receptor sub-types?
Naloxone.
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Out of the opioid antagonists, which has a longer duration of action i.e longer half life?
Naltrexone.
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What is amitriptyline?
A tricyclic antidepressant, which has an effect on the inhibition of central noradrenaline reuptake, possibly increasing spinal inhibition.
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Give examples of anticonvulsants that inhibit calcium channel opening?
Gabapentin, Carbamazepine.
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When neurons become damaged or die can they reproduce/ replace themselves?
No
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What are some examples of neurodegenerative diseases?
Parkinson's, Alzheimer's and Huntington's disease
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What is Parkinson's disease?
A progressive disorder mainly arising from a a massive loss of dopamine neurons in the SUBSTANTIA NIGRA
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What is the main manifestation of PD?
loss of movement control
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What are the two interacting neurotransmitters that control movement?
Dopamine and Acetylcholine
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What does the loss of dopaminergic neurons in PD produce?
A reduction in dopamine, the effects of acetylcholine become dominate.
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What are the four major dopamine pathways?
Nigrostriatal tract, mesolimbic pathway, mesocortical pathway, pituitary gland path
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Of the three major dopamine pathways which ones have cell bodies that lie in the ventral tegmental area/ VTA?
Mesolimbic and mesocortical
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In the mesolimbic pathway where do the fibres project to and via what?
They project via the medial forebrain bundle to the mesolimbic system
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In the mesocortical pathways where do the fibres project to and via what?
via the medial forebrain bundle to the frontal cortex
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Where do the short neurons in the pituitary path run from and run to?
from the vegmental hypothalamus to the pituitary gland
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How many types of dopamine receptors are there?
Five
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What does the D1 family of dopamine receptors include? what is their role?
D1 and D5. Increase adenylate cyclase (Gi). Excitatory.
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What does the D2 family of dopamine receptors include? what is their role?
D2, D3, D4. decreases adenylate cyclase and IP3, and increases potassium while decreasing calcium. Inhibitory.
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What is the effect on D1 receptor activation when D2 receptors are activated?
Opposing effect.
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What type of coupling do all 5 types of dopamine receptors go through?
G-protein coupled.
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Where are the three places that dopamine takes action?
Corpus striatum (nigrostriatal pathway), pituitary gland, mesolimbic/mesocortical pathways
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In the pituitary gland what action does dopamine take?
It inhibits prolactin release
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In the ML/MC pathways what action does dopamine take?
Invovled in emotion, excess dopamine implicated in psychosis/schizophrenia
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In the corpus sstriatum what action does dopamine take?
Acts on the D1 and D2 receptors, inhibits cholineric interneurons: important in motor control. D2 receptors induce vomiting
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What causes the deterioriation in PD?
Loss of dopaminergic neurons - which occurs gradually over several years
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Which pathway; directt/indirect facilitates movement?
Direct
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Which pathway; direct/indrect inhibits movement?
Indirect
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What does the direct pathway do?
Disinhibits motor thalamus, activates thalamo-cortex, activates motor cortex, facilitates movement
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What does the indirect pathway do?
Inhibits motor thalamus, inhibits thalamo-cortex, inhibits motor cortex, inhibits movement.
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Where do dopamine neurons release dopamine?
In the basal ganglia, reducing the inhibitory bias of the basal ganglia
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What does a loss of dopamine neurons result in?
An increased amount of activity coming out of the indirect pathway?
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How is the thalamus kept?
In an overly inhibited state. By subduing the thalamus the signal to the motor cortex is imbalanced.
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What is the aetiology of parkinson's disease?
No obviousious causes, mainly environmental factors and rare type of hereditary PD, the damage is associated with protein misfolding/aggregation, mitochondrial dysfunction leads to oxidative stress, inflammation and apoptosis, use of some drugs
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When are symptoms of PD noticeable?
until over 60-80% of the neurons are lost
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What are the PD symptoms?
resting tremor, slowness (bradykinesia, hypokinesia), muscle rigidity
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What are some signs of PD?
patients walk with a shuffle, difficult to get going and difficult to stop, visible degree of cognitive impairment.
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What are some drugs that can mimic parkinson's like symptoms?
Neurotoxins: MPTP, Dopamine antagonists: chlorpromazine, Deletion Reserpine blockage of vMAT
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What event coined the term 'frozen addict' syndrome?
In California, 1982, there was an impurity in illicit opioid (heroin substitute)
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Which dopamine neurons are particularly sensitive?
nigrostriatal
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What are the four main aims of pharmacotherapy of Parkinson's disease?
replacement of dopamine, reduced metabolism of dopamine, direct dopamine agoniss, release dopamine, block cholinergic effects
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What is the first line treatment for parkinson's disease?
L-Dopa and DOPA-decarboxylase inhibitor
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Why is L-DOPA rapidly decarboxylated in the brain?
b/c DDC does not cross the blood brain barrier
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What are the adverse effects of L-DOPA?
Dyskinesia, On/off effects, nausea, hypotension, psychoses
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What is the role of COMT inhibitors?
It acts in the periphery to reduce peak/trough fluctuations of L-DOPA, and indirectly elevates CNS levels of dopamine
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Is Selegiline a selective/non selective MAOb inhibitor?
selective
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Where can MaoB be found?
In central DA neurones
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What is the effect of selegiline on MaOa
no effect on MAOa in peripheral noradrenergic nerves
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Which dopamine agonists are better than bromocripitine and pergolide?
Pramipexole, Ropinirole
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What is the role of amantadine?
Increases dopamine release, inhibits amine uptake, directly acting on dopamine receptors
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What does activation of opiates cause?
A reduction in neuronal excitability and neurotransmitter release?
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Which receptor is the most important in terms of abuse potential and development of tolerance?
The u receptor.
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What are the two in vivo methods for assessing mechanisms of reinforcement?
Drug self administration, conditioned place preference
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Which system is the common reward pathway for many drugs of abuse?
The mesolimbic system
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what does intra-VTA morphine do?
Increases level pressing and also increases dpaminergic cell firing in VTA and dopamine release in nucleus accumbens
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What decreases lever pressing as well as dopamine release?
Blockade of u receptors in the VTA
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What can block lever pressing?
Blockade of dopamine receptors
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What are the effects of psychostimulants?
euphoria, behavioural excitement, reduced fatigue, anorectic
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What are the neurochemical effects of cocaine and amphetamine?
Indirect sympathomimetics with a main effect upon dopaminergic nerve terminals
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What are the effects of cocaine and amphetamine?
Tolerance to euhoric effects develops rapidly, withdrawal symptoms, highly addictive with strong reinforcement properties, can cause a psychotic reaction as dose is increased to overcome tolerance to euphoric effect
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What are the general effects of cocaine and amphetamine on the mesolimbic system?
Increased lever pressing when administer into the ML system.
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Where is the main effect of amphetamine seen, in the mesolimbic system?
When administered into nucleus accumbens
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Where is the main effect of cocaine seen, in the mesolimbic system?
When administered into the frontal cortex
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When alcohol gets to the GABA and NMDA receptor where does it go to then in the brain?
Hippocampus, Cerebellum
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When cocaine gets to the monoamine transporters where does it go to in the body?
Heart, Cortex
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When morphine gets to the opioid receptors where does it go to then in the body?
Brainstem, spinal cord
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