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Disease in the brain > Drugs of abuse, addiction & reward (finished) > Flashcards

Drugs of abuse, addiction & reward (finished) Flashcards

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The Brain flashcards
1
Q

Where do most DA neurons originate?

A

In the Substantia nigra & VTA area

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2
Q

Where do DA pathways project to?

(Projecting from SN & VTA)

A

Nucleus accumbens, then into striatum & frontal cortex

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3
Q

What is the function/outcome of DA pathways?

A
  • Reward
  • Pleasure
  • Euphoria
  • Motor function (Parkinson’s)
  • Compulsion
  • Preservation
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4
Q

Where do serotonergic & DA pathways converge?

A

The nucleus accumbens

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5
Q

Where do serotonergic pathways originate?

A

In the raphe nucleus

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6
Q

Where do serotonergic pathways act on?

(Originate in the raphe nucleus)

A

Project primarily into the nucleus accumbens

Also goes on to hippocampus, striatum & frontal cortex

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7
Q

What is the function of serotnerigc signalling pathways?

A
  • Mood
  • Memory processing
  • Cognition
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8
Q

Where does the mesolimbic DA pathway run?

A

From the midbrain VTA area

To the nucleus accumbens (DA neurons innervate this)

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9
Q

What system is the nucleus accumbens part of & what does that system control?

A

The Limbic system (reward)

Controls emotion, pleasure, reward & goal-directed behaviour

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10
Q

What happens if there is overactivity in the mesolimbic dopamine pathway?

A

It contributes to the +ive symptoms of SZ:

  • Psychosis
  • Delusions
  • Hallucinations
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11
Q

What is the role of the mesolimbic DA pathway?

A
  • Involved in producing reward & pleasure to encourage to do
  • DA pathways are responsible
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12
Q

Where do drugs act on in the brain?

A

On the mesolimbic dopamine pathway (reward)

Generally act on the nuc Acc

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13
Q

What are the 3 actions drugs can have on in the mesolimbic DA pathway?

A

1 - Many inc DA release in the nuc Acc

2 - Others enhance serotonin (5-HT) function (innervates the nuc Acc)

3 - Some block N-Methyl-D-Aspartate receptors (NMDA antagonists)

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14
Q

What drugs act by inc DA release in the nuc Acc?

A
  • Opiates (naturally occurring e.g. morphine & heroin)
  • Opioids (synthetic e.g. fentanyl)
  • Amphetamine, cocaine, cannabis etc (even coffee & barbiturates
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15
Q

What drugs act by enhancing serotonin (5-HT) function (innervating nuc Acc)?

A
  • LSD –> a hallucinogen
  • Ecstacy (aka MDMA)
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16
Q

What drug are NMDA antagonists?

A
  • Phencyclidine (PCP)
  • Ketamine

Both are hallucinogens –> similar to LSD but activates different receptors

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17
Q

Where do all the routes which drugs can act of converge to?

(e.g. DA pathways, 5-HT & NMDA antagonists)

A

They all converge & impact on the nucleus accumbens

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18
Q

What did the study on rats show about the reward pathways in the brain?

A
  • Activity in VTA DA neuronal pathways is associated w reward
  • Rats will self-administer rewarding drugs & using micro-electrodes, activity can be recorded from DA neurons in VTA
  • By pushing level rat gets reward feeling in response to cocaine
  • Shows action of reward via cocaine works well in mammalian system
  • Press-reward-learn-repeat
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19
Q

Describe another method to show brain reward in rats + results

A
  • Brain Reward Pathways in mammals and predictability- can also measure activity from neurons by insertion of electrode into brain of rat
  • Once rat self administered cocaine = strong increase in activity = which causes dopamine release = reward feeling (red graph)
  • Neuron activities can be mapped within the brain
    Activity is a combination of expectation of reward and what you actually get as a reward
  • Induce a suppression of these neurons by giving less cocaine/no cocaine than the rats expected = leads to reduction in firing = results in a worse reward + fully predicted reward produces no response = negative error response (blue graph)
  • A reward that is better than predicted elicits stronger neuronal activation = positive prediction error response (red graph)

When you have worse experience than you expect after taking the drug- makes you want to take a higher dose so it makes a bigger impact = addiction phenomenon

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20
Q

What effect does all drugs have?

A

All drugs enhance DA in the VTA innervating the nuc acc

Leads to reward

e.g. ethanol (alcohol) the more drank = the greater the DA hit (reward feeling)

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21
Q

How is activity in the VTA balanced?

A

Drugs of abuse enhance DA in the VTA innervating the nuc acc

Balanced = GABA neurons inhibit VTA neuronal activity (by feedback inhibition)

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22
Q

Describe another method to show brain reward pathways in mammals + what does this show?

A

Can also measure activity from neurons by insertion of electrode into brain of rat
Once rat self administered cocaine = strong increase in activity = which causes dopamine release = reward feeling (red graph)
Neuron activities can be mapped within the brain
Activity is a combination of expectation of reward and what you actually get as a reward
- induce a suppression of these neurons by giving less cocaine/no cocaine than the rats expected = leads to reduction in firing = results in a worse reward + fully predicted reward produces no response = negative error response (blue graph)
- A reward that is better than predicted elicits stronger neuronal activation = positive prediction error response (red graph)

When you have worse experience than you expect after taking the drug- makes you want to take a higher dose so it makes a bigger impact = addiction phenomenon

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23
Q

Name a method that enables neurotransmitter levels to measured in a conscious animal brain

A

Microdialysis

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24
Q

Describe how microdialysis works in a mouse

A

Tube inserted into mouse brain which is perfused with cerebral spinal fluid (CSF)- outflow of perfusion can be collected and analysed the quantity and quality of neurotransmitters
Shows not only activity changes but also quantity of neurotransmitter changes in response to rewards

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25
Q

briefly descibe how cocaine works?

A

Cocaine directly binds to DAT which inhibits it- induces an increase of dopamine in synaptic cleft = reward feeling

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26
Q

briefly descibe how nicotine works?

A
  • Nicotine activates dopaminergic neurons which increases dopamine
  • Also activates glutamatergic inputs into dopaminergic neurons = indirectly activating activity of dopaminergic outputs + also effects inhibitory neurons
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27
Q

briefly descibe how ethanol works?

A

Ethanol = increases directly the activity of dopaminergic neurons by activation- specifically by these Ih and GIRK potassium channels

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28
Q

briefly descibe how morphine works?

A

acts indirectly by binding to the Mu opioid receptor (MOR) on GABAergic interneurons (=inhibitory neurons)

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29
Q

What is the usual function of MOR on GABAergic interneurons?

A
  • Their usual function = continuously inhibiting dopaminergic neurons = brings dopaminergic activity down- but activation of MOR = reduced inhibition = increased activity of dopamine
30
Q

How does alcohol affect GABAergic interneurons?

A

Alcohol leads to release of beta endorphins onto GABAergic interneurons = inhibition via activation of MOR which is negatively coupled to cAMP production and inhibits the terminals which results in less inhibition onto dopaminergic neurons
= more dopamine activity

31
Q

What are the differences between acute and long term effects of drugs?

A
  • Drugs of abuse enhance release of dopamine from VTA neurones innervating the nuc. Acc = cause of addiction –
  • Acute- give you a high (positive reward)
  • Long-term effects = opposing effects- changes gene expression of transmitter receptors + transmitter production as changes proteins- development of genetic changes overtime partly counteracts acute effects as every neuron is plastic
  • Drug usage often increases over the long term as genes change in response to drug activity- which changes receptor activity = feedback loop
31
Q

Name one organism that can be used to study the exact reward effect

A

drosophila

32
Q

Describe the method used to study brain reward pathways in drosophila

A

odour rewarded learning and memory:
Larvae placed on agar plate that is rewarding (contains fructose) and this is associated with a smell- flies are trained to make this association- Test to see how many larvae remember the association to assess learning

Then can establish which neurons are involved for dopamine release and how they interact with mushroom bodies (= learning + memory centres)- can now investigate how dopamine and reward work together

33
Q

Outline one key feature associated with drugs of abuse + what does this depend on?

A

dose dependency- The faster and higher the drug delivery occurs = more reliable the elevation in brain dopamine levels = the greater the reward (euphoria) and more likely addiction will occur as reward-feeling wants to be repeated

Higher and faster intake depends on the mode of delivery and absorption rate which varies with different drugs so reach brain at different speeds

34
Q

Name a factor that affects the absoption rate of a drug and how does this affect addiction

A

Formulation’ is a factor affecting absorption rate – kinetics- direct faster intakes result in much higher risk of addiction as reward feeling is much stronger

35
Q

Outline 3 ways that show that certain methods of absorption result in a greater reward

A
  • Intravenous heroin ‘more addictive’ than methadone by mouth as has to go via gut before it gets into blood stream
  • Inhaling cocaine greater reward than chewing coca leaves
  • Smoking cigarettes greater reward than chewing tobacco
36
Q

What happens to the brain when there is a physical dependence?

A

= altered physiological state produced by repeated drug administration- drug removal leads to withdrawal

36
Q

Define: physical dependence

A

= when brain requires these drugs

37
Q

Name some drugs with varying degrees of dependence

Categories = narcotic analgesics, general CNS depressants, anxiolytic, psychomotor/psychostimulants & psychedelic drugs

A
38
Q

What affects the different dependencies of drugs?

A

activation of different pathways in different brain regions = results in graded response of addiction despite all the drugs increasing dopamine

39
Q

What is the difference between opiates and opioids? + examples

A

Opiates = naturally occurring- morphine, heroin, opium, codeine
Opioids = produced by humans- methadone, fentanyl

40
Q

What is the predominant method in which opiods/opiates act?

A

All act by same mechanisms predominantly by activating G-protein-coupled opioid receptors (GPCR, µ-opioid receptor, MOR) which inhibits cAMP = Reduce neurotransmitter release in GABAergic inhibitory neurons = increase in dopaminergic signaling

41
Q

Name some acute effects of opioids / opiates

A
  • Euphoria
  • tranquility
  • miosis (pupillary constriction)
42
Q

Name some chronic effects of opiods / opiates

A
  • Constipation, depression, insomnia, dependence
  • Anhedonia and tolerance
43
Q

Describe the withdrawal symptoms associated with opioids/opiates

A
    • Craving, restlessness, insomnia, diarrhoea
  • Cold flashes with goose bumps (“cold turkey”)
  • Major withdrawal symptoms peak 48 - 72 hours after the last dose and subsides after about a week- but craving and dependency is still present
44
Q

What is cocaine?

A

Alkaloid extracted from the coca tree (Erythroxylum coca)

45
Q

Outline methods of cocaine intake

A
  • Leaves chewed in Peru, cocaine hydrochloride
  • Snorted or smoked with tobacco
46
Q

In terms of neurobiology, what does cocaine consumption result in?

A
  • Increases catecholamine (DA) neurotransmitter function by preventing DA re-uptake as blocks DAT transporter
47
Q

What does higher doses of cocaine result in?

A
  • Overactivity of sympathetic system (Noradrenaline + adrenaline uptake blockade) at higher doses: hypertension, tachycardia, dilated pupil, palpitations = negative outcomes
48
Q

What does tolerance refer to?

A

Higher doses are required to maintain the same effect

49
Q

How can you assess tolerance?

A

through a binding assay

50
Q

What is this graph showing?

A
  • Find that amount of cocaine required to inhibit DAT is much higher in self-administered conditions (blue bar) = more cocaine needed to have same effect
  • Controls require certain amount of cocaine which blocks 50% of DAT activity but w long-term use u need more cocaine to cause the same effect
51
Q

What is this graph showing?

A

blue is long-term usage and black is control

  • Give same amount of cocaine = small increase in dopamine release in long-term usage rates but larger increase in controls
  • Long term build up of tolerance is reflected in the lack of dopamine increase following cocaine administration
  • = suggests long-term users need more cocaine in order to achieve same reward
52
Q

What is the active agent of cannabis and how does it work?

A
  • Active agent terahydrocannabinol (THC) mimics effects of endogenous endocannabinoids (e.g. anandamide, 2-arachidonoyl glycerol)- these are already present in the body and are released after physical activity
  • Cannabinoids work by activating the CB receptors- CB1 (predominant in brain) CB2 (predominant in the body)- THC binds to these receptors and activates them = reward feeling
  • Acts via an inhibitory GPCR cascade- CB1 and CB2 reduce cAMP signalling
53
Q

What are the effects of cannabis?

A
  • Mild euphoric effect in moderate doses; dysphoric in high doses particularly in naïve users
  • Very low acute toxicity but concerns about development of psychosis in chronic heavy users
  • Stimulates appetite through actions on feeding centres in the hypothalamus and possibly gut. Analgesic activity
54
Q

What is the common name for different forms of amphetamines?

A

speed

55
Q

Name 2 phenylethylamine drugs

A

methamphetamine, dexamphetamine

56
Q

What is the positive short term effect of taking speed?

A

produce increased wakefulness and concentration with decreased fatigue and appetite = strong stimulatory effect

57
Q

In terms of neurobiology, what does speed do?

A

Release monoamines (DA) from neuronal storage vesicles and block DAT, NET and SERT re-uptake transporters = increasing synaptic DA, NA and 5-HT

57
Q

Do you build up any tolerance after using speed?

A

Yes

58
Q

What are the more long-term effects of speed?

A
  • Effects = Euphoria, energy, self-esteem, self-confidence, aggression, excessive feelings of power, obsession, paranoia
  • With chronic and/or high doses, amphetamine psychosis can occur (akin to schizophrenia)
  • Increases cardiovascular tone; raises blood pressure, tachycardia in response mainly to NA increases
59
Q

Name one subsitute for MDMA and do they differ?

A

Mephedrone is a substitute for MDMA- structures different, effects slightly different but all have same outcome

60
Q

What do amphetamines and mephedrone have in common?

A

All work by interacting or blocking DAT, NET, SERT transporters and have similar pharmacology + psychoactive effects

61
Q

Describe a simple experiment that show mephedrone and amphetamines behave differently

A

Simple experiment to show mephedrone and amphetamines have similar structures but still behave very differently
- Measure intracellular calcium in neuronal culture- apply both drugs and get very different effects in terms of calcium responses

62
Q

What is the difference in pharmacology of cocaine and amphetamines?

A

Cocaine- Inhibits DAT transporter = more dopamine in synaptic cleft
Amphetamines- Inhibits DAT + VMAT2- cause higher dopamine release compared to cocaine

63
Q

What is one of the things thought to be the cause of different effects of drugs?

A

different affinities to different receptors and transporters

64
Q

Describe how cocaine blocks different transporters at different concentrations

A

cocaine to block noradrenergic transporters need lots but to block DAT you need less = most likely responsible for the different outcomes

65
Q

What ratio can be calculated that can determine the cause of addictio, dependency and tolerance?

A

ratio of blockage for DAT / SERT is important and held responsible for build up tolerance and addiction

66
Q

Compare the DAT/SERT ratio for MDMA and amphetamines

A
  • Ratio for MDMA is very low but for amphetamines it is very high
67
Q

If you a low ratio of DAT/SERT what does this mean?

A

= blocking more serotonin reuptake than dopamine reuptake = greater SERT inhibition may reduce abuse potential e.g. MDMA less abuse potential tnan cocaine

68
Q

What is methamphetamine?

A

= meth, structurally similar to amphetamine but is neurotoxic

69
Q

What is this PET scan showing- comparing a healthy control to a meth user

A

PET scan for DAT ligand- drug abuser has big degeneration of dopaminergic neurons
= long term usage of methamphetamine is neurotoxic
But amphetamine not neurotoxic
= different drugs do have different effects in the long-term

Disease in the brain (22 decks)

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