1
Q
What is a receptor?
A
- Protein
- Located in cell surface membrane
- Characteristic 3D structure
- target of specific drug/ligand
2
Q
What is the effect of an agonist binding to a receptor?
A
Activation, producing biochemical/cellular effects
3
Q
Which receptors are glutamate ionotropic receptors?
A
- AMPA
- NMDA
- Kainate (several types)
4
Q
Which receptor is a glutamate metabotropic receptor?
A
mGluR1-8
5
Q
Which receptor is a GABA ionotropic receptor?
A
GABA(A) receptor
6
Q
Which receptor is a GABA metabotropic receptor?
A
GABA(B) receptor
7
Q
Which receptors are acetylcholine ionotropic receptors?
A
nACh (several types)
8
Q
Which receptors are acetylcholine metabotropic receptors?
A
M1-5
9
Q
Which receptor is a serotonin ionotropic receptor?
A
5-HT_3
10
Q
Which receptors are serotonin metabotropic receptors?
A
13 different types
11
Q
Which receptors are dopamine ionotropic receptors?
A
None
- dopamine has no ionotropic receptors
12
Q
Which receptors are dopamine metabotropic receptors?
A
D1-5
13
Q
What are ionotropic receptors?
A
- Ligand-gated ion channels,
- comprised of several subunits,
- that mediate/modulate fast synaptic potentials
- immediate changes in milliseconds
14
Q
What are metabotropic receptors?
A
- G-protein-coupled receptors,
- that mediate/modulate slow synaptic transmission
- long-term changes in seconds, activating biochemical pathways
15
Q
What is the action time scale of kinase-linked receptors?
A
Hours
- e.g. cytokine receptors
16
Q
What is the action time scale of nuclear receptors?
A
Hours
- e.g. oestrogen receptors
17
Q
What are the key steps in synaptic transmission?
A
Pre-synaptic:
- Action potential arrives
- Depolarisation
- Opens voltage-gated Ca2+ channels
- Ca2+ flood in -> change in vesicular proteins (surrounding stored NTs)
- Diffusion in synaptic cleft
Post-synaptic:
- Activation of NT receptors
- Removal of NT
18
Q
How do drugs interfere at all stages of the synaptic transmission?
A
> Pre-synaptic:
- drugs interfere with synthesis, storage and release of NTs
> Post-synaptic:
- drugs interfere with receptors and removal mechanisms
19
Q
How do drugs interfere with the synthesis of neurotransmitters?
A
- Removal or enhanced synthesis of NTs
- Slow onset of action: need to remove NTs that have been synthesised and stored
20
Q
How does L-dopa interfere with the synthesis of neurotransmitters?
A
Enhances dopamine synthesis in Parkinson’s Disease
21
Q
How do drugs interfere with the storage of neurotransmitters?
A
- “Leakage” of NTs into nerve terminals
22
Q
How does amphetamine interfere with the storage of neurotransmitters?
A
Causes release of dopamine and noradrenaline
23
Q
What does the neurotransmitter release depend on?
A
Voltage and calcium:
- NT release requires depolarisation to activate voltage-gated calcium channels (VOCCs)
- > VOCCs play pivotal role in synaptic transmission
24
Q
Which drug blocks voltage-gated calcium channels?
A
Conotoxin
- toxins produced by marine snails
25
What is the effect of conotoxin on the synapse?
- Blocks voltage-gated calcium channels
- > preventing NT release
-> Paralyses synapses
26
What are the two types of post-synaptic receptors?
Ionotropic and metabotropic receptors
27
What is a homomer receptor?
Ionotropic receptor composed of similar subunits
28
What is a post-synaptic heteromer receptor?
Ionotropic receptor composed of different subunits
29
What are the two types of pre-synaptic receptors?
- Autoreceptors
| - Heteroreceptors
30
What are autoreceptors?
- Presynaptic receptors,
- that mediate the transmission of neurotransmission back to itself
- α_2-adrenoceptors
31
What are heteroreceptors?
- Presynaptic receptors,
- that mediate the inhibitory effects of one neurotransmitter on the release process of another
- opioid receptors (kappa, mu, delta)
32
What is the action of antagonists at pre-synaptic inhibitory receptors?
They will increase the release of NTs
33
What are pre-synaptic nicotinic acetylcholine receptors?
Excitatory pre-synaptic receptors
34
What is the action of co-agonists?
- They cannot activate a receptor alone
- Act at separate sites on receptor protein
- e.g. Activation of NMDA receptors requires binding of both glutamate and glycine
35
What is the action of competitive antagonists?
They compete for the same site on receptor protein
36
What is the action of non-competitive antagonists
They act by another mechanisms
- e.g. PCP "angel dust" blocks the channel of NMDA receptor
37
What is the composition of GABA A receptors?
- Have an allosteric modulatory site = benzodiazepine (BDZ) site
- Multiple subunits: GABA, BDZ, ethanol, neurosteriods, barbiturates
- > heteromer ionotropic opening chloride ion channel
- hyperpolarisation of neuron
38
What is the action of benzodiazepine agonists?
Potentiate GABA
- through GABA A receptor BDZ site
- e.g. Diazepame (Valium)
39
What is the action of benzodiazepine inverse agonists?
Inhibit GABA
- through GABA A receptor BDZ site
- e.g. experimentally used only
40
What is the action of benzodiazepine antagonists?
- Block effects of BDZ agonists or inverse agonists
- no effects on GABA
- e.g. Flumazenil used for BDZ overdose
41
What are the two removal mechanisms of neurotransmitters?
1. Enzymatic destruction
- ACh is broken down by Acetylcholinesterase
- Monoamine oxidase (MOA) breaks down dopamine (DA), serotonine (5-HT), norepinephrine (NE)
2. Active reuptake
- e.g. DA uptake via dopamine transporter (DAT)
42
What is the effect of blocking the removal mechanisms of neurotransmitters?
It will potentiate the life of the neurotransmitter in the synapse
-> increase of synaptic concentration of NTs
- e.g. cocaine, Prozac (fluoxetine), Rivastigmine work by blocking removal mechanism
43
How does Rivastigmine work?
Prevents breakdown of ACh
- via inhibition of Acetylcholinesterase
-> enhances ACh synaptic concentration
44
How does Prozac (fluoxetine) work?
Serotonin reuptake inhibitor
-> increased 5-HT synaptic concentration
45
How does cocaine work?
Binds to dopamine transporter (DAT)
- blocking DA reuptake
-> increased DA synaptic concentration
46
What do the effects of neurotransmitters on the central nervous system depend on?
On the role played by the target neuron
- e.g. inhibition of inhibitory nerve in a circuit
- > disinhibition and overall increase in excitability
47
What determines whether a neurotransmitter is excitatory or inhibitory?
Determined by the receptor it acts on at target cell
48
What is the action of dopamine D1-like receptors?
D1 and D5 receptors activate adenylyl cyclase (which synthesizes cAMP)
49
What is the action of dopamine D2-like receptors?
D2, D3 and D4 receptors inhibit adenylyl cyclase (synthesizer of cAMP)
50
What is the effect of an increase in adenylyl cyclase activity?
Can lead to changes in protein transcription
- i.e. synthesis of receptors or ion channels expressed by particular nerve cell
- slow changes (hours to days)
51
Why do changes in protein transcription in a cell are slow (i.e. hours to days)?
Cell has to synthesise these new proteins and then insert them correctly into cell surface membrane
52
What are the four characteristic behaviours on the spectrum of psychoactive substance use?
> Beneficial use
- positive health, spiritual or social impacts
> Casual non-problematic use
- negligible health or social effects
> Problematic use
- negative consequences for individual, others, society
> Chronic dependance
- habitual and compulsive
53
What are the common pharmacological processes of drugs of abuse?
> Rapid and effective delivery to the brain
- more likely to be dependent
> Release of DA in reward pathway
> Potential development of neuroadaptation or tolerance
-> withdrawal symptoms
54
What is the typical psychoactivity associated with drugs of abuse?
Release of dopamine in the reward pathway
55
Are all drugs of abuse associated with withdrawal symptoms?
No
| - e.g. LSD, cannabis
56
What are the two types of drug dependence?
1. Psychological
- long lasting compulsion driven by rewarding effects of the drug
2. Physical
- physical withdrawal symptoms
57
What are the two pillars of psychological drug dependence?
1. Compulsion
- long lasting
2. Withdrawal
- emotional
- important to prevent relapse
58
What is psychological drug dependence driven by?
- Effects in limbic system (reward pathway)
| - Cognitive and behavioural reinforcement
sense of relief after taking drug
59
What is the positive reinforcement in psychological drug dependence?
Pleasure from compound (drug), through the reward pathway
60
What is the negative reinforcement in psychological drug dependence?
Relief from withdrawal symptoms
61
What are the two types of drug tolerance?
1. Acute
- short lasting
2. Chronic
- following prolonged exposure
- pharmacodynamic (cellular) tolerance
- pharmacokinetic (metabolic) tolerance
-> tolerance once developed, may not last indefinitely
62
What is cross-tolerance?
Tolerance developed between members of the same class of drug
63
When does acute tolerance occur?
When a drug acts at a receptor which becomes desensitised by the first dose
- e.g. alcohol
64
What is the 'Mellanby effect'?
George Mellanby, study in early 1900s:
| - effects of alcohol are more pronounced when blood alcohol level (BAL) is rising
65
What is pharmacokinetic tolerance?
Chronic tolerance due to an increase in the metabolism of the drug
- e.g. drugs causing induction of CYP450
- e.g. amphetamine
66
How do drugs causing an induction of the CYP450 enzymes generate a pharmacokinetic tolerance?
More CYP450 = more drug molecules being broken down = drug around for less time
-> diminished response per dose of the drug
67
How can amphetamine generate a pharmacokinetic tolerance?
Tolerance = increased urine pH
| -> increases excretion of amphetamines
68
What is the process of G-protein-coupled receptor desensitisation?
1. Binding of drug to GPCR produces beta-gamma subunit, which dissociates together with alpha subunit
2. Phosphorilation of GPCR by enzymes:
- G-protein-coupled kinases (GRKs) which bind to GPCR
3. Dynamin binds to phosphorylated GPCR
- > causes internalisation of the receptor in clathrin-coated tips
- once phosphorylated GPCR is internalised, it's de-phosphorylated
Either:
4. GPCR is put into recycling vesicle and re-inserted back into cell surface membrane
or
5. GPCR is sent to lysosome for degradation
69
What does the internalisation of a G-protein-coupled receptor via binding of dynamin consist of?
Removing GPCR away from cell surface membrane and internalising it
70
What are lysosomes?
Subcellular organelles
- surrounded by a semipermeable membrane,
- contains numerous hydrolytic enzymes,
- involved in digestion, defense, and reproduction
71
How does cross-tolerance develop in individuals?
Individuals who are already tolerant to one drug can develop tolerance to other drug from the same class
e. g. Heroin -> cross-tolerance to opioid painkillers
e. g. Alcohol -> cross-tolerance to benzodiazepines
72
What is the lifespan of physical drug dependence?
Relatively short
| - approx. 2 weeks
73
How is the duration of the physical drug dependence related to the half-life of the drug?
Longer half-life of drug = longer syndrome duration
74
How is the magnitude of the physical drug dependence related to the half-life of the drug?
Negative correlation:
| shorter half-life = more intense syndrome
75
How can the syndrome of physical drug dependence be reversed?
By administration of an agonist
76
What is the cycle of physical drug dependence?
> Chronic drug administration
- adaptions occur at various levels (genetic, cellular)
- > Drug use stops
- adaptations persist and act unopposed -> withdrawal
- > Withdrawal syndrome
- depends on drug characteristics
- generally short term
- can be medicated
- > Negative reinforcement
- can be uncomfortable and can motivate avoidance of withdrawal symptoms by continued drug use
-> Chronic drug administration
77
What are the six factors that need to be taken into account to understand the effects of drugs on the central nervous system?
1. Pharmacodynamics
- affinity for and intrinsic activity at site of action
2. Pharmacokinetics
- drug concentration - metabolism
3. Biology of the patient (genetics, age, disease)
4. Neuroadaptive processes to primary interaction of drug and target
5. Blood-brain barrier
6. Drug's site of action in the brain
Decks in class (14)
# Cards
-
Historical perspectives on drug use and addiction; diagnosing addiction44
-
Risk factors for drug use41
-
Theories of addiction41
-
Introduction to Behavioural Addictions24
-
Biological basis of addiction48
-
Introduction to pharmacokinetics and pharmacodynamics66
-
How the brain adapts77
-
Addiction: genes and environment45
-
Differences in vulnerability13
-
Key ideas in treatment103
-
Nicotine addiction and treatment58
-
Drug policy36
-
Use prevention29
-
Focus on Cannabis policy41
