REVISION Flashcards by Jeffery Ho

Cortisol is released in response to? Function?

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

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!GABA B agonist and antagonist

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

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

Metab, Gi, inhibits release of GABA and Glu

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GHB is a partial agonist at?

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

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GABA C antagonist aids in

Inhibiting myopia development and facilitates learning and memory

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Lead toxicity

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

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

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n-Hexane toxicity leads to?

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

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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/

Fe 3+ - Tyrosine -> L-DOPA

ROS - Byproduct of ATP synthesis in mitochondria

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

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

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

NO NO

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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?

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

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What does the MyD88 KO lack?

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

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

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

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Why is MAOB inhibitor preferred over MAOA inhibitor?

MAOA inhibitor may cause hypertension

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

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

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)

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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?

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

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Effects of Clozapine

Extended therapeutic reach

Anti-suicide effects

Cause AGRANULOCYTOSIS – POTENTIALLY LETHAL SIDE EFFECT

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

Xanomeline

What are the 4 types of seizures

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

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

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

Characteristics of antiepileptic drugs

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)

Why is vigabatrin used with caution?

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

Why is Valproate used commonly for epilepsy?

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

What inactivates sTNF and TM TNF?

Monoclonal antibodies

How is depression defined?

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

Scopolamine

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

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

Pleasure/limbic, DA, nucleus accumbens, hippocampus

What is the inverted U-shape curve hypothesis by Volkow

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

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

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

What drug increases attention in ADHD children?

Ritalin

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

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

Why should addiction be treated like a disease?

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

Difference between N-REM and REM sleep

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%

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

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

Date rape drug

Flurazepam

Which subunits do GABA bind to? What about BZ?

GABA - a1, b2 BZ - a1/2/3, g2

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

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

CB1R a) Dense in? Low density in? b) Where is it found in the periphery? c) Effects

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)

What is one feature all cannabinoid agonists have in common?

Highly fat soluble - slow residual elimination

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

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