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pharmacology > Neuropharmacology of drugs > Flashcards

Neuropharmacology of drugs Flashcards

1
Q

What are the brain regions involved in drug addiction?

A
  • reward centres of the brain – ventral tegmental area and nucleus accumbens
  • amygdala – involved with emotional distress
  • hippocampus – involved with memory and learning
  • cordatory pertanum (CPu) - important because it’s involved in habit formation
  • pre-frontal cortex - involved in decision making and judgment
  • Orbital frontal cortex – involved in giving value to reward
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2
Q

What is the main motivational transmitter?

A

Dopamine

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3
Q

Which pathway is always involved in drug addiction?

A

The mesolimbic dopaminergic pathway

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4
Q

What is the structure of the mesolimbic dopaminergic pathway?

A

Neurones in the ventral tegmental area project to the nucleus accumbens and the frontal cortex

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5
Q

What is the mesolimbic dopaminergic pathway usually activated by?

A

Natural rewards

  • food
  • social interaction
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6
Q

What do drugs of abuse do to the mesolimbic dopaminergic pathway?

A
  • Drugs of abuse hijack the pathway – they stimulate it at a much higher degree than other natural rewards
  • Experiments on rats showed that when rats were given drugs there was massive increase in dopamine release in the nucleus accumbens (NA)
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7
Q

How do drugs of abuse cause positive reinforcement in the first stage of addiction?

A
  • Dopamine, GABA, Glutamate, CRF and opioid peptides involved in the mechanism of action of drugs
  • All drugs of abuse stimulate the reward pathway and cause dopamine release but through different ways
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8
Q

How do the following drugs cause their reward effects:

  • opioids
  • cocaine
  • amphetamine
  • alcohol
  • nicotine
  • cannabinoids
  • phencyclidine
  • hallucinogens
A

o Opioids - Agonist at mu (and delta and kappa) opioid receptors
o Cocaine - Dopamine transporter blocker - indirect DA agonist
o Amphetamine - Dopamine releaser - indirect DA agonist
o Alcohol - Facilitates GABA-A + inhibits NMDA receptor function
o Nicotine - Agonist at nACh receptors
o Cannabinoids - Agonist at CB1 receptors
o Phencyclidine - NMDA receptor antagonist
o Hallucinogens - 5-HT2A agonists

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9
Q

Examples of amphetamine like drugs?

A

MDMA and methylphenidate

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10
Q

What is amphetamines mechanism of action?

A

Releases cytosolic monoamines/dopamine

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11
Q

Why is the prolonged use of amphetamines bad?

A

It’s neurotoxic

  • there’s degeneration of amine-containing nerve terminals
  • cell death
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12
Q

Pharmacological effects of amphetamine?

A
  • increased alertness and locomotor stimulation (increased aggression)
  • Euphoria / excitement
  • Anorexia
  • decreased physical and mental fatigue (improves monotonous tasks)
  • Peripheral sympathomimetic actions (increased blood pressure & decreased gastric motility)
  • Confidence improves/lack of tiredness
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13
Q

What is the therapeutic use of amphetamines?

A

For ADHD

  • methylphenidate used
  • increases concentration

For appetite superessing

For narcolepsy

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14
Q

What type of drug is amphetamine?

A

Psychostimulant

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15
Q

What type of drug is cocaine?

A

Psychostimulant

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16
Q

What is the mechanism of action of cocaine?

A

Blocks catecholamine reuptake - it blocks DA from being released

increased DA, stimulant effect

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17
Q

What are the pharmacological effects of cocaine?

A

Pharmacological effects:
• Euphoria
• Locomotor stimulation
• Fewer stereotyped behaviours than amphetamine
• Heightened pleasure
• Lower tendency for delusions, hallucinations and paranoia

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18
Q

How is cocaine administered?

A

• HCl salt, inhaled and i.v. administration
o Nasal inhalation less intense, leads to necrosis of nasal mucosa

• Freebase form (‘crack’), smoked, as intense as i.v route

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19
Q

What are psychotomimetic drugs? give examples

A

drugs which are capable of producing an effect on the mind similar to a psychotic state.

ie MDMA (ecstasy)

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20
Q

What is the mechanism of ecstasy

A
  • Inhibits monoamine transporters (mainly 5-HT)
  • Also releases 5-HT
  • Large increase in 5-HT (followed by depletion)
  • increased 5-HT linked to psychotomimetic effects
  • increased DA linked to euphoria (followed by rebound dysphoria)
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21
Q

What type of drug is heroin?

A

Opioid

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22
Q

What is the effect of opioids and how does it happen?

A

• Opioids produce intense euphoria via acting on MOP (mu opioid receptor)

o Diamorphine (heroin) high abuse potential

23
Q

When is tolerance first seen for opioids?

A

Seen within 12 – 24 hours

24
Q

What is the mechanism behind opioids disinhibition effect?

A
  • Acts on mu opioid receptors
  • In the VTA there’s also GABAergic interneurons that release GABA which act on GABAr in the reward pathway (GABA is inhibitory)
  • It will inhibit the release of dopamine
  • Opioid receptors on the GABA interneurons – opioid receptors are inhibitory
  • Decrease in GABA release
  • So increase in DA release
25
Q

What type of drug is alcohol?

A

A general depressant

26
Q

What is the mechanism of action of alcohol?

A

• Potentiates GABA-mediated inhibition

• Inhibits presynaptic Ca2+ entry through voltage-gated Ca2+ channels
o Inhibits transmitter release

• Disinhibits mesolimbic DAergic neurons (increased reward)

• Induces the release of endogenous opioid peptides
o Reward effect decreased by naltrexone (endogenous opioid involvement)

27
Q

What are the pharmacological effects of alcohol?

A
  • Slurred speech, motor in-coordination, increased self confidence, euphoria
  • Impaired cognitive and motor performance
  • Higher levels linked to labile mood: euphoria and melancholy, aggression and submission
28
Q

What are the pharmacological effects of nicotine?

A
  • nACh (nicotine) receptors, a4β2 subtype
  • Receptors are ligand-gated cation channels (pre- and post-synaptic)
  • Receptors found pre-synaptically and in the cortisol of the neurones in NA
  • Enhance transmitter release and neuronal excitability including opioid peptides
  • Cortex & hippocampus (cognitive function) and ventral tegmental area (DA release and reward)
  • increased alertness, decreased irritability (dependent on dose and situation)
29
Q

What is the acute effect of drugs of abuse on the HPA axis?

A
  • HPA axis is usually activated due to stress – GLUT supresses the axis when stress is over
  • Hyper/Hypo activation causes dysregulation – you can not cope with stress thus makes it harder for drug users to quit
  • Opioids inhibit HPA axis in humans
  • Cocaine activates HPA axis
30
Q

What are the different types of withdrawal symptoms?

A
  • Physical, characterised by abstinence syndrome (LC): Sweating, gooseflesh (cold turkey), irritability, aggression
  • Psychological, craving to avoid withdrawal effects

Withdrawal symptoms are often opposite effects of the drugs – neuroadaptations are trying to oppose the drug abuse

31
Q

What are the withdrawal symptoms for psychostimulants?

A

deep sleep, lethargy, depression, anxiety & hunger

32
Q

What are the withdrawal symptoms for MDMA/ecstasy?

A

Depression, anxiety, irritability, increased aggression

33
Q

What are the withdrawal symptoms for heroin?

A

Sweating, gooseflesh (cold turkey), irritability, aggression, insomnia

34
Q

What are the withdrawal symptoms for nicotine?

A

Irritability, hunger, weight gain, impaired cognitive and motor performance, craving (persisting many years)

35
Q

What are the withdrawal symptoms for alcohol?

A

Tremor, nausea, sweating, fever, hallucinations, Seizures, confusion, agitation, aggression – acute withdrawal can be lethal

36
Q

What is the mechanism of Dependence & Tolerance for heroin?

A
  • Heroin binds to opioid receptor – It’s Gi coupled, and it will inhibit adenylyl cyclase and reduce cAMP
  • Eventually this will cause stress to the system – disrupts homeostasis
  • Body will try to desensitise itself to drug – opioid receptor won’t be as sensitive to the drug/wont react
  • Will cause cAMP to increase dramatically in numbers and activity, especially in noradrenergic neurones – increase in noradrenaline in the brain and that will cause the withdrawal symptoms
  • This shows neuroadaptation – how body copes with repeated drug use
37
Q

What happens to the reward system in the dependent stage of addiction?

A

the reward system becomes suppressed because the drugs continuously stimulate it
• Will cause the user to take even more drugs to get the same feelings as before

38
Q

What can suppression of the rewards system cause?

A

Suppression causes depression, hedonia, social withdrawal and is a motivational trigger to consume the drug (negative reinforcement)

39
Q

How is the stress pathway affected in the dependent stage of addiction?

A

There’s also a recruitment of the stress pathway – big increase of CRH, stimulation of the hypothalamus and amygdala

40
Q

How is the frontal cortex affected in the dependent stage of addiction?

A

Hypofunction of the frontal cortex – inability to make decisions

41
Q

what do heroin and cocaine do to the HPA axis in the addiction phase and what is the general affect in the HPA axis during addiction?

A
  • Heroin addicts have: Hyporesponsivity HPA axis
  • Cocaine addicts have: Hyperesponsivity HPA
  • CRF in extended Amygdala increased in withdrawal
  • CRF antagonist block withdrawal in animal models
  • CRF desregulation long lasting (tolerance kicks in)
42
Q

How is dopamine/dopamine receptors affected in dependence?

A
  • Decreased frontal cortex activity
  • Decreased striatal D2 (dopamine receptor) binding – PET imaging shows drugs users (dependant users) have less D2 than non-users, this also increases craving for the drug (this shows how drug use supresses the reward system)
  • fMRI studies show non-users have higher overall activity in the brain and the frontal cortex compared to drug users – this is also seen in mental health disorders like depression
43
Q

How are the nicotinic receptors (a4b2) affected in dependence?

A
  • Up-regulation of α4β2*
  • Rapid development of tolerance (desensitization of nACh receptors)
  • Radiographic evidence shows that in rats and humans that were given nicotine had an increase in nicotinic (a4b2) receptors
  • A4b2 associated with cravings
44
Q

What may cause relapse?

A
  • relapse can be triggered by certain cues related to the drug: the location where they took the drug, certain people
  • Stress can also cause relapse
45
Q

What brain regions are important in relapse?

A
  • Hippocampus (memory)
  • Amygdala (emotional memory)
  • prefrontal cortex (involved in stress modulation)

fMRI studies show drug dependant users have high activity in the frontal cortex and hippocampus after seeing cocaine related images compared to non-users

46
Q

How is the pre-frontal cortex connected to the orbital frontal cortex?

A

Pre-frontal cortex (decision-making centre) has inhibitory connections to the orbital frontal cortex (which gives reward the saliency) and it usually tells the OFC not to make certain decisions in a normal brain

47
Q

What happens to the brain connections in addiction?

A
  • the connection of the emotional centres to the rewards centre becomes stronger
  • connections between reward centres and the front cortex and OFC also become stronger.
  • Striatum also becomes much more active.
  • The inhibitory connection between the executive decision-making centre and OFC becomes weaker
  • OFC it’s not under the executive decision-making centre anymore and this will drive the consumption of the drug based on impulses.
48
Q

What substances are increased/decreased in positive reinforcement?

A

Increased:

  • Dopamine
  • Serotonin
  • Natural opioids

Decreased:

  • GABA
  • cAMP
49
Q

What substances are increased/decreased in negative reinforcement?

A

Increased:

  • NA
  • CRF/CRH
  • GLUT
  • cAMP
  • nicotinic receptors (a4b2)

Decreased:

  • dopamine
  • serotonin
50
Q

What is the role of dopamine in addiction?

A
  1. Intake of drugs of abuse leads to increase in dopamine in nucleus accumbens and other limbic regions
  2. Psychostimulants induce reward via a DA dependent mechanism
  3. D2 knockout mice show no effect on withdrawal symptoms of morphine after chronic administration
  4. Opiate and alocohol SA persists when DA projections are destroyed (DA independent mechanism)
  5. Nicotine activates dopaminergic system via nicotinic receptors VTA and Nacb

D2 antagonists are largely ineffective in drug addiction treatment

51
Q

What is the role of endogenous opioids in addiction?

A
  1. Mu agonists are reinforcing and cocaine reinforcement is modulated by opioid antagonists
  2. Mu antagonists are effective in limiting craving and relapse
  3. Injections of opioids into the VTA generate self-administration
  4. Mu opioids facilitate intracranial self stimulation
  5. Mu opioid receptor knockout mice show loss of addictive responses to opioids, alcohol, cannabinoids and nicotine
  6. Proenkephalin knockout mice show loss of addictive response to cannabinoids and nicotine
  7. Alcohol and nicotine induce the release of endogenous opioids
  8. Cocaine induces MOP and KOP upregulation which is persistent
52
Q

What is the role of GABA in addiction?

A
  1. Firing of dopaminergic neurones in VTA is inhibited by GABA interneurones
  2. Opioids indirectly remove this inhibition by presynaptic inhibition of GABA interneurones and is responsible for the rewarding effects of opioids
  3. GABA-B agonist (baclofen) reduces nicotine reward in humans
  4. Cannabinoids inhibit GABA release. Effects of cannabinoids mediated indirectly via opioid receptors
  5. GABA agonist in Amygdala decrease alcohol substance abuse
  6. Chronic alcohol decreased GABA and increased NMDA
53
Q

How can the link between genetics and addiction be explored?

A
  • Human approaches to identify “addiction genes”
  • Twin studies
  • Identification of SNPs in addicted individuals
  • Searching for abnormal mRNAs at autopsy
  • Genome-wide scans of addicted vs normal individuals
  • Genealogical approach and linkage analysis from genome-wide scan of families (in populations that are genetically homogeneous)

pharmacology (21 decks)

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