How drugs control the brain - L13 Flashcards
(43 cards)
1
Q
What happens when there is too much GABA?
A
- Loss of consciousness and coma
2
Q
What happens when there is too little GABA?
A
- Leads to convulsions and seizures
3
Q
How do epilepsy treatments act on GABA
A
- Many epilepsy treatments act to enhance GABA transmission
4
Q
Main types of neurons
A
- Projection neurons - GLU(exception is purkinje cell in cerebellum which is GABAergic)
- Local interneurons - GABA
5
Q
Types of influential interneurons affecting cortical pyramidal neurons?
A
- Basket cells
- Axo-axonic acells
- Dendrite-targeting interneurons
6
Q
How do interneurons influence cortical pyramidal neurons?
A
- Information is transferred from excitatory glutamatergic synapses to the pyramidal neuron dendrite
- Excitation travels along the dendritic tree to the soma and axon initial segment, where it could generate an action potential
- Along this dendro-somatic-axonal axis, information can be differently filtered by GABAergic synapses possessing specific basic and plasticity properties
7
Q
What are the two main families of GABA receptor families
A
GABA(a) ionotropic receptors and GABA(b) metabotropic receptors
8
Q
Describe GABA(a) ionotropic receptors
A
- Ligand gated Cl- channel
- Fast IPSPs
- Mainly GABAergic interneurons
- Post synaptic
9
Q
Describe GABA(b) metabotropic receptors
A
- G protein coupled receptors
- Indirectly coupled to K+ or Ca2+ channel through 2nd messengers(opens K+ channel, closes Ca2+ channel_
- Slow IPSPs
- Both pre- and post- synaptic
10
Q
What is the more recently discovered GABA receptor?
A
GABAc is a more recently discovered third class which is similar to GABAa in structure and functions, but are made of different type
11
Q
What are the subunits that make up GABA(a) receptors
A
- Heteropentameric structure - 2 alpha + 3 more subunits
12
Q
What is picrotoxin?
A
- Is a non-competitive GABAa antagonist that can cause convulsions
13
Q
What is a direct agonist of GABA(a) receptor?
A
- Muscimol
14
Q
What is a direct antagonist of GABA(a) receptor(experimental tool)?
A
- Bicuculline
15
Q
What are indirect agonists of GABA(a) receptors
A
- Benzodiazepine - binding increases the receptor affinity for GABA
- Increase frequency of channel opening
- Anxiolytic(drugs used to reduce anxiety) and hypnotic drugs with rapid onset, but less satisfactory in the long term
- Barbiturates increase the duration of channel openings(anaesthesia, epilepsy treatment)
- Alcohol - agonist
16
Q
What is the action of benzodiazepine action eg diazepam(valium)
A
- Benzodiazepine binding site on the alpha subunit of GABA(a) receptor
- Indirect agonist - benzodiazpine binds to alpha subunit, changes conformation of the receptor so GABA activation of receptor is more effective
17
Q
What are the effects of benzodiazepine
A
- Reduce anxiety
- Cause sedation
- Reduce convulsions
- Relax muscles
- Cause amnesia
18
Q
What is the effect of inverse agonists?
A
- Inverse agonists bind to benzodiazepine site and have opposite effects
- Produce anxiety and predisposition to convulsions
19
Q
How do barbiturates and alcohol affect GABA(A)Rs
A
- Bind at different sites on the receptor
- Both have same effect, to enhance GABA(A) activity and effects are additive
- Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors
- Low doses of alcohol - mild euphoria and anxiolytic effects
- Higher doses - incoordination, amnesia
20
Q
What is baclofen?
A
- GABA(b) receptor agonist
- Used as a muscle relaxant to reduce spasticity eg in huntington’s disease
21
Q
What is the effect of Gi coupled receptor
A
- Inhibits adenylyl cyclase
- Gby gated k+ channels
- Increases K+ conductance
- Decreases Ca2+ conductance(presynaptically)
- Slow hyperpolarizing current(late inhibitory postsynaptic potential)
22
Q
Does inhibition of GABA(b) transmission have the same effect as inhibiting GABA(a) receptors
A
No. eg seizure
23
Q
What are diffuse modulatory systems
A
- Specific populations of neurons that project diffusely and modulate the activity of glutamate and GABA neurons in their areas
24
Q
What are patterns of communication in the neurotransmitter systems -
A
- Point-point-point systems
- Hormones released by the hypothalamus
- ANS neurons activating body tissues
- Diffuse modulatory system with divergent axonal projections(not classical synapse)
25
What are the systems that are part of the dopaminergic system
- Nigrostriatal system(75% of brain DA) - motor control
- Mesolimbic system
- Mesocortical system(behavioural effects)
- Tuberohypophyseal system(endocrine control)
Cell bodies in the midbrain that project into the forebrain
26
Is dopamine excitatory or inhibitory
- Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
27
What are the metabotropic dopamine receptors?
- D1-5
28
How do D1-like receptors function?
- D1-like(1 and 5)
- Gs stimulates adenylyl cyclase
- Stimulates phospholipase C
- Postsynaptic
29
How do D2-like receptors function?
- D2-like(2,3 and 4)
- Gi - inhibit adenylyl cyclase
- open K+ channels
- Close Ca2+ channels
- Postsynaptic
- presynaptic autoreceptors(D3)
30
What is the nigrostriatal system?
- Cell bodies in the substantia nigra project to the striatum(caudate nucleus and putamen)
- Important part of the basal ganglia involved in movement
31
What can dysfunction of the nigrostriatal system cause?
- Parkinson's disease - destruction of DA projections from SN to basal ganglia
- Huntington's disease - destruction of DA target neurons in striatum
32
What drugs are used to treat parkinson's
- L-DOPA, monoamine oxidase inhibitors, dopamine receptor agonists-treatments for parkinson's disease
33
Why is substantia nigra a 'black substance'
- Due to high levels of melanin in dopaminergic neurons
34
What is the mesolimbic system
- Cell bodies in ventral tegmental area(VTA) project to the limbic system, nucleus accumbens(Nacc)
- Role in reinforcement(reward) of several categories of stimuli, including drugs of abuse
35
What happens when there is dysfunction of the mesolimbic system
- Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
- eg. cocaine and amphetamine - psychomotor stimulants
36
What are the immediate effects of psychomotor stimulants when there is dysfunction of the mesolimbic system
- Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
- Large doses can cause stereotypy(persistent repetition of an act) and psychosis
- Cause peripheral effects, that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc
37
What are the long-term effects of psychomotor stimulants where there is dysfunction of the mesolimbic system
- Natural rwards, eg water, food, sex increase DA transmission and leads to reinforcement of associated behaviours
- Increased DA by cocaine etc short, circuits pathway, drug taking behaviours become reinforced
- Downregulation of endogenous DA system - craving
38
What is the mesocortical system?
- VTA projections to prefrontal cortex
| - Role in functions such as working memory and planning
39
What drugs are typical antipsychotics that have an effect on the mesocortical system
- Chlorpromazine and haloperidol
40
Effect of chlorpromazine and haloperidol on the mesocortical system
- DA receptors anatagonists(pre and postsynaptic)
- Increase DA turnover - lose autoreceptor inhibition
- Blockade of postsynaptic receptors - upregulation
41
What are the side effects of antipsychotics on other dopaminergic systems?
- Action on other dopaminergic systems
| - Extrapyramidal side effects - tardive dyskinesia etc (chronic blockade causes system to become supersensitive)
42
What is an atypical antipsychotic
- Specific to receptor subtype
| - eg clozapine - antagonist of D4 receptors(cortex only)
43
Effects of clozapine
- Reduce psychosis associated with schizophrenia
| - Antipsychotic effects without EPS
