REVISION

Question 1

Cortisol is released in response to? Function?

Answer 1

• Released in response to stress and low blood-glucose concentration
• Increases blood sugar through gluconeogenesis
• Suppress the immune system (inflammation)
• Increases alertness and cognition

Question 2

!GABA B agonist and antagonist

Answer 2

Ag: Baclofen – acts in spinal cord to reduce muscle spasm and treats alcholics
Antag: Saclofen

Question 3

GHB (Gamma Hydroxy Butarate)receptors are ion/metab and has the effect of?

Answer 3

Metab, Gi, inhibits release of GABA and Glu

Question 4

GHB is a partial agonist at?

Answer 4

GABA B receptors (some receptors have low, some have high affinity)

• Effect of GHB likely due to GABA synthesis
• GHB: At increasing concentrations: euphoria, anxiolysis, disinhibition

Question 5

GABA C antagonist aids in

Answer 5

Inhibiting myopia development and facilitates learning and memory

Question 6

Lead toxicity

a) Symptoms
b) Pathology
c) Recovery is accompanied by
d) Affects ____ and ___ transmission

Answer 6

a) Symptoms -lethargy, vomiting, irritability, loss of appetite & dizziness
progress to ataxia, reduced consciousness, coma & death
- “Footdrop” or “wristdrop ” due to segmental demyelination & axonal degeneration with Schwann cell degeneration (adults).

b) Pathology - edema of brain due to extravasation of fluid from capillaries, loss of neuronal cells and gliosis
c) Recovery - accompanied by epilepsy, mental retardation optic neuropathy and blindness
d) Glutamergic and dopaminergic

Question 7

n-Hexane toxicity leads to?

Answer 7

Damages to neurofilaments and cross-linked cytoskeletal proteins, which aggregate in distal axon proximal to the nodes of Ranvier HENCE signal transmission disrupted

Question 8

ROS hypothesis = Production of DA generates Fe3+ which reacts with ROS to switch on pathway that activates apoptosis - where do you get the Fe3+ from? ROS/

Answer 8

Fe 3+ - Tyrosine -> L-DOPA

ROS - Byproduct of ATP synthesis in mitochondria

Question 9

!Inflammation is initiated by immune cells present in the tissue - mainly resident macrophages that express ___ that lead to inflammation. They also recognize ____ and ____

Answer 9

PRRs - pattern recognition receptors
PAMPs -pathogen-associated molecular patterns
DAMPS - danger-associated molecular patters released by injured cells

Question 10

Does MyD88 play a role in neuronal survival following ischemia? Glial survival?

Answer 10

NO NO

Question 11

A mouse lacking MyD88 is given a stroke and TLRs cannot work so we are not activating TLRs but why are we getting a bigger infarct?

Answer 11

The experiment is looking at neurons only but we need to look at BRAIN as a whole because there is BLOOD present - the vascular system changes during a stroke and influences the brain.

In vitro - it is detrimental
In vivo - it is protective following stroke

*Suggests that inhibiting TLR system in the blood, stops the beneficial response of these blood cells

Question 12

What does the MyD88 KO lack?

Answer 12

Ability to get infiltrating cells there - you need TLR to get them to infarct as they are beneficial

Question 13

What role does DJ-1 and PINK-1 play in PD?

Answer 13

Involved in mitochondria - mutations in these 2 genes lead to an increased amount of ROS = death

Question 14

Why is MAOB inhibitor preferred over MAOA inhibitor?

Answer 14

MAOA inhibitor may cause hypertension

*Early use may delay disease progression by reducing formation of free radicals

Question 15

2 suggestions to treat PD
5 years from now?
5-10 years from now?
10-20 years?

Answer 15

Adenosine A2a receptor antag make D2 more sensitive to Da and mGluR5 antag may allow higher dosages of L-DOPA

Deep brain stimulation (DBS) and optogentics

Genetics - find genes and target them, cell replacement therapy (induced pluripotent stem cells) - take a skin cell from patient and reprogram it then use another mix of genes to turn it into DA neuron (these cells avoid transplant rejection but also may be susceptible to the same disease process)

Question 16

Donepezil (Aricept is brand name)

a) What is it?
b) Features - comp/non-comp, reversible/irreversible, half life?
c) Dosage?
d) Metabolised by?
e) Delays AD by how long?
f) Adverse effects?

Answer 16

a) Anticholinesterase used to treat AD
b) Non-comp and irreversible in terms of binding and have similar efficacy, with half life of 70 hours
c) Once a day 5 to 10 mg
d) Metab by cytochrome P450 isoenzymes CYP3A and CYP2D6
e) Delays deterioration by 6- 12 months
f) SE: Nausea, diarrhoea, anorexia, headache, insomnia, depression, drowsiness, dizziness, fatigue, sweating, tremor, muscle cramps

Question 17

Effects of Clozapine

Answer 17

Extended therapeutic reach

Anti-suicide effects

Cause AGRANULOCYTOSIS – POTENTIALLY LETHAL SIDE EFFECT

Question 18

List one selective MuscR agonist that is a novel treatment approach for schiz

Answer 18

Xanomeline

Question 19

What are the 4 types of seizures

Answer 19

1) Focal (partial) seizures - abnormal activity in a certain area in the brain
a) Simple (no loss of consciousness)
-Motor, sensory (unusually intense smell), autonomic (sweating, palpations), psychic (hallucinations)
*These seizures also come with auras (déjà vu)
b) Complex (loss of consciousness)
Most arise from the temporal lobe (encompasses limbic system - involved in motion, memory, behaviour)
*Also accompanied by auras (perceptual disturbance) and repetitive behaviours

2) Generalized seizures - involves entire hemisphere
a) Tonic-clonic aka grand mal:
Tonic - Patient loses consciousness without warning, tonic contraction, loud moan from constriction of layrnx

Clonic - superimposed relaxation and constriction of muscles. Next is hyperinhibitory phase where muscles are flaccid and bowel and bladder incontinence

b) Absence aka petit mal
Patient stops abruptly, staring off into space and lasts for 10-45 seconds. Occurs multiple times a day

Question 20

Describe what is meant by ‘use-dependent’ in the context of the Na+ channel and why this is important

Answer 20

Carbamazepine, Lamotrigine and Phenytoin block the voltage-dependent channel in the INACTIVE state ONLY during HIGH FREQ FIRING so normal transmission is not affected- channels needs to be activated before it will bind so it can go from active to inactive state

Question 21

Characteristics of antiepileptic drugs

Answer 21

• All available orally so can cross BBB
• Most metabolised hepatically by cytochrome p450 family
• Narrow therapeutic index (the drugs can get saturated, so increasing dose will increase the conc A LOT and if dosage is too high, it will be toxic)

Question 22

Why is vigabatrin used with caution?

Answer 22

Causes irreversible visual field constriction in 20 - 40% of patients

Question 23

Why is Valproate used commonly for epilepsy?

Answer 23

Multiple actions - Enhances GABA action, inhibits Na+ and Ca2+ channels

Question 24

What inactivates sTNF and TM TNF?

Answer 24

Monoclonal antibodies

Question 25

How is depression defined?

Answer 25

1) Minimum of 5 symptoms on a sustained level:
1) Depressed mood
2) Diminished pleasure/interest in activities
3) Weight gain
4) Sleep disturbances
5) Psychomotor agitation or retardation
6) Fatigue
7) Feelings of worthlessness
8) Diminished concentration
9) Suicidality

2) Symptoms causes clinically significant distress in social, occupational, or other important areass of functioning
3) Symptoms not due to substance abuse or a general medical condition
4) Symptoms are not better accounted for by bereavement
5) Symptoms do not meet criteria for a mixed episode

Question 26

Scopolamine

Answer 26

MuscR antagonist – used at the right dose, it can have long lasting rapid onset antidepressant effects, only works in a proportion of people resistant to classic anti-depressant treatments that don’t target Ach system in general

Question 27

Stated below is how drug-related stimuli attain salience:

Drugs produce euphoria by activating _____ centres in the brain via release of __ in the _____ _______. The limbic system is closely tied to learning centres such as the _________, and repeatedly pairing drug-induced euphoria with drug-related stimuli creates an association

Answer 27

Pleasure/limbic, DA, nucleus accumbens, hippocampus

Question 28

What is the inverted U-shape curve hypothesis by Volkow

Answer 28

There is an optimal level of DA stimulation for the drug to be perceived as pleasant. Those with low D2 receptors will fill euphoria when drugs increase DA as in pushes it to the peak of the curve.

Those with high D2 receptors will fill unpleasant as the drug pushes them into the lower range of the curve

Question 29

What gene influences the expression of DA D2 R density in the brain?

Answer 29

Taq1A allele - having 2 copies of the allele is associated with reduced density of D2 R in the striatum (midbrain), also predicts risk of drug dependence and may have resistance to drug treatment and learn following reward rather than from punishment

Question 30

What drug increases attention in ADHD children?

Answer 30

Ritalin

Question 31

Ritalin is able to increase cognitive abilities in drug users - why don’t they all take it?

Answer 31

It depletes D2 receptors further - to the point that the drug users will develop PD symptoms and lead to relapse and greater impulsivity for reward

Question 32

Why should addiction be treated like a disease?

Answer 32

1) Genetic disposition - taq1 allele
2) Neuroanatomical r/ship b/w sensitivity to drug euphoria and the transition to dependence
3) Alterations in neural mechanisms underlying rewards and control - that sensitises the individual to seek the drug in their environment, limit their ability to control their response once encountered

Question 33

Difference between N-REM and REM sleep

Answer 33

N-REM/REM (Paradoxical sleep)

• Slow EEG/EEG similar to awake person
• High amplitude/Low
• Muscular activity/No
• Dreaming rare/common
• Easily awakened/Hard to arouse
• 80& of sleep time/20%

Question 34

List one non-BZ – what is it used for? Mechanism of action? How are effects reversed?

Answer 34

Zolpidem (Stillnox) is used in short treatment of insomnia, binding to a1 subunit of GABA A R. Has little anticonvulsant or muscle relaxant activity

All identified effects of Zolpidem are reversed by the benzodiazepine antagonist Flumazenil

Question 35

Date rape drug

Answer 35

Flurazepam

Question 36

Which subunits do GABA bind to? What about BZ?

Answer 36

GABA - a1, b2

BZ - a1/2/3, g2

Question 37

Mechanism of action of ziconotide

a) Where does it act?
b) What does it do?
c) Route of admin and why?

Answer 37

a) Dorsal horn
b) N-type Ca2+ channel antagonist - inhibiting Ca2+ influx and hence decreased release of NT
c) Intrathecal pump- for severe and neuropathic pain, this is because N-type Ca2+ channels are everywhere in the periphery so could have severe depressing CV effects if given i.v as if affects symp and vagal components of the barareflex. If given i.t - has no effect on CV system

Question 38

CB1R

a) Dense in? Low density in?
b) Where is it found in the periphery?
c) Effects

Answer 38

a) Dense in hypothalamus, cortex, hippocampus, cerebellum and pain pathways in brain and spinal cord. Low density in brainstem (where else miu opioid R has high density)- lack of serious respiratory depression or cardiotoxicity
b) Sensory neurons (primary sensory afferents), vasculature, urogenital tissues, gut, skin
c) Analgesia, motor coordination, CV, memory disruption, anti-emesis, appetite stimulation (munchies after doing weed)

Question 39

What is one feature all cannabinoid agonists have in common?

Answer 39

Highly fat soluble - slow residual elimination

Question 40

Why would development of sel. CB2R ligands have therapeutic potential in treatment of neuropathic pain?

Answer 40

Mainly on Glia, up-regulated in microglia in response to inflammation and reduces inflammation

• MS related pain, neuropathic pain
• Increases efficacy of opioids
• Lack of CNS SE