Neurochemistry and neuroendo

Question 1

G Protein receptors

Answer 1

► Class 2
► Trans-membrane protein: all span the cell membrane seven times (serpentine receptors).
► Cyclise mediated second messenger activation (GTP, ATP etc)
► Gs-proteins are stimulatory; Gi-proteins are inhibitory to the adenylate cyclase
► Third variant acts via phospholipase C
► e.g. DA receptors, most 5HT except 3, NEN and neuropeptides including opioid receptors are G coupled.

Question 2

Dopamine receptors D1-D5

Answer 2

D1 - 5 : All G protein coupled
D1-like  D1 & D 5; increase adenylate cyclase (stimulatory)

D1 exclusively postsynaptic; resistant to antagonism
D5 more limbic in distribution; 10times higher dopamine affinity

D2,3& 4 ; decrease adenylate cyclase (inhibitory)
D4 primarily - frontal cortex and clozapine high affinity.
D4-selective antagonists do NOantipsychotic efficacy.

Question 3

Kapur 2003 proposal about dopamine and mesolimbic function

Answer 3

Clinical relevance: Kapur proposed that in the normal individual, the role of mesolimbic dopamine is to attach significance or ‘salience’ to an external stimulus, or an internal thought,. This converts a neutral piece of information into an attention grabbing information (Kapur, 2003).

Question 4

Noradrenaline receptors alpha and beta:

Answer 4

α1 phospholipase C coupled; mostly postsynaptic
α2 Gi coupled ; mostly presynaptic autoreceptors

β-Gs coupled; predominate locus ceruleus – may regulate α

β1-receptors – high affinity to norepinephrine
β2-receptors – high affinity to epinephrine

Question 5

Locolisation of serotonin

Answer 5

Most serotonin is in periphery (gut, platelets) but cannot cross BBB.

Median and the dorsal raphe nuclei; widespread cortical projection; also spinal cord

Question 6

location/types of following receptors:

5HT1A

5HT1B

5HT1D

5HT2

Answer 6

5-HT1A receptors – Gi coupled postsynaptic; Antidepressant response; sexual behaviour

5-HT1B receptors – Gi coupled presynaptic;

5-HT1D receptors – Gi coupled -pre and postsynaptic.

5-HT2 receptors - phospholipase C coupled; postsynaptic; antagonism leads to antipsychotic response (atypicals) and sedation;
LSD causes 5-HT2 stimulation;
down regulation after AD/ ECT.

5-HT6 may be involved in antidepressant action

Question 7

DOPA decarboxylase (DDC) function

Answer 7

synthesizing 2 important neurotransmitters, dopamine and serotonin

Following the hydroxylation of tyrosine to form L-dihydroxyphenylalanine (L-DOPA), catalyzed by tyrosine hydroxylase,
DDC decarboxylates L-DOPA to form dopamine. This
neurotransmitter, particularly abundant in basal ganglia.

Dopamine is also produced by DDC in the sympathetic nervous system and is the precursor of the catecholaminergic hormones, noradrenaline and adrenaline in the adrenal medulla.

In the nervous system, tryptophan hydroxylase produces 5-OH tryptophan,
decarboxylated by DDC, giving rise to serotonin.

DDC is a homodimeric, pyridoxal phosphate-dependent enzyme.

Question 8

functions of ACH and

localisation

Answer 8

Modulate arousal, attention (muscarinic in CNS) 
learning, memory, 
REM sleep
pain perception
thirst and parasympathetic mediation. 

1. ascending system of cholinergic neurons originating in
   the reticular formation
2. cholinergic cells in the nucleus basalis of Meynert

Question 9

Reuptake of GABA

Answer 9

Source: glutamic acid (glutamate)
Synthetic enzymes:
glutamic acid decarboxylase (GAD)

Breakdown enzymes:
GABA transaminase

Breakdown product:
Broken down to glutamate, and then eventually to
succinic acid

Reuptake: reuptake into both presynaptic nerve terminals and surrounding glial cells; uptake system is bidirectional and both temperature- and ion-dependent process; (inhibited by tiagabine)

Function: Mediates anxiety, seizure cessation, and actions of benzodiazepines, barbiturates, and alcohol.

Question 10

source of glutamate

functions of glutamate

Answer 10

1. from 2-oxoglutarate and aspartate by aspartate
   aminotransferase,
2. from glutamine by glutaminase, or
3. from 2-oxoglutarate by ornithine aminotransferase

Important metabolic role – intermediary in oxidation
pathway (malate shuttle),
immediate precursor of all GABA in CNS,
intermediary in ammonia cycle;
NMDA - memory acquisition, developmental plasticity, epilepsy, ischemic brain injury. NMDA mediates long term potentiation (LTP = a change in physical properties of neurones and synapeses.e.g. in memory)

excitotoxic glutamate toxicity in stroke/schizophrenia/seizures suspected.

NMDA antagonists can cause hallucinations – e.g. PCP,
ketamine

Question 11

glutamate receptors

Answer 11

metabotropic - 8 in total; 3 groups.

1. mGluR1& mGluR5 – linked to phospholipase C

Ionotropic: NMDA and non-NMDA

2.  NMDA - made up of subunits with distinct binding
   sites for glutamate, glycine, phencyclidine (PCP),
   magnesium, and zinc.
3.  Non NMDA – kainate binding or AMPA type.

Question 12

Glycine function

Answer 12

Synthesized from serine by serine trans-ydroxymethylase
and glycerate dehydrogenase

mandatory adjunctive neurotransmitter for glutamate activity and an independent inhibitory neurotransmitter at
its own receptors

NON strychnine-sensitive glycine receptor= excitatory glycine site on NMDA

strychnine-sensitive glycine receptor= inhibitory, seen in spinal cord. May reduce negative schizo symptoms

Question 13

Substance P

Answer 13

primary NT in afferent sensory pathways (think PAIN)
also seen in the striatonigral pathway.
reduced levels in huntingtons

Question 14

Neurotensin (peptide)

Answer 14

coexists with dopamine in some axon terminals.

may benefit psychotic symptoms.

have reward-enhancing effects through its
antidopaminergic actions in the prefrontal cortex

Question 15

 Cholecystokinin

Answer 15

pathophysiologies of
schizophrenia, eating disorders and movement disorders.

CCK infusion induces panic attacks in people with panic disorder. CCK antagonists may have anxiolytic effects.

Question 16

Somatostatin is

Answer 16

also known as growth hormone-inhibiting factor (released from intestine?)

Question 17

Neuropeptide Y

Answer 17

has been shown to stimulate the appetite.

It is a 36 aminoacid peptide found in hypothalamus.
?aetiology of obesity where in the loss of negative feedback of Corticotrophin releasing hormone on NP-Y may be a cause for increased cortisol levels

Leptin – it has a key role in regulating energy intake and expenditure: it is produced by adipose tissue in response to fat levels. On fat storage, leptin signals the brain to stop seeking food by inhibiting NPY and AgRP (Agouti-related peptide).

may have role in AP related weight gain

Ghrelin – produced in somach and pancreas: stimulates appeptite

Question 18

different opiod receptors

Answer 18

Opiate receptors

µ receptor = morphine, opiate alkaloids, β-endorphin, and enkephalins, supra spinal analgesia
δ receptor = enkephalins
κ receptor = dynorphin, spinal analgeisa
σ receptor - naloxone DOES NOT reverse agonist activity. Phencyclidine, haloperidol, and steroids are agonists:
indicate that σ receptors play a role in motor function and possibly drug abuse.

Question 19

functions of smooth ER

Answer 19

Smooth ER plays different functions depending on the specific cell type including lipid (incl.phospholipid) and steroid hormone synthesis,
breakdown of lipid-soluble toxins in liver cells,
control of calcium release in muscle cell contraction.

Question 20

Choline acetyl transferase (ChAT)

Answer 20

reduced to a greater extent (85%) in patients with hallucinations in Lewy body dementia than in those without hallucinations (50%).
This is more pronounced in parieto-temporal regions, hippocampus and entorhinal cortex.
As a consequence, brain ACH levels are reduced in DLB similar to Alzheimer’s. This may partially explain the altered sleep-wake patterns seen in DLB and also the response of hallucinations to acetylcholinesterase inhibitors.

Question 21

Question 9.
Which of the following receptors increase adenylate cyclase to stimulate cell machinery?
Alpha 1
Beta adrenergic
Dopamine D2
Dopamine D3
Dopamine D4

Answer 21

Alpha1 receptors are phospholipase C coupled;
Alpha 2 are Gi coupled(inhibitory).
Beta receptors Gs coupled - so they increase adenylate cyclase.
D2 receptors are also G protein coupled; but unlike the G-coupled D1 family of receptors, the
D2 family inhibits (decreases) adenylate cyclase activity.

Question 22

distribution of DA receptors

Answer 22

D1 and D2 are predominant in the caudate & putamen, and have wide distribution 1.e. striatum, hypothalmic, mesolimbic

D3-nucleus accumbens,
D4– prefrontal cortex,

D3 +D4: more localised: mesolimbic, cortical and hippocampal).

D5-Hippocampus.

Question 23

Question 22.
Which one among the following is a 5-HT 2a and 5-HT 2b agonist?
Bromocriptine
Bupropion
Clonidine
LSD
Riluzole

Answer 23

Bromocriptine is a dopamine receptor agonist, which is used to suppress galactorrhoea and postpartum lactation.

Clonidine is a noradrenergic agonist. LSD is a 5-HT 2a and 2b agonist and produces a hallucinogenic effect.

Question 24

exitatory AAs and receptors

Answer 24

Excitatory amino acids are glutamic acid, asparate and homocysteine.

excitatory amino acid receptors;
N-methyl D aspartate (NMDA),
amino-3 hydroxy 5-methyl 4-isoxazole propionate (AMPA), kainate
Metabotropic (G-protein coupled receptors).

Question 25

what is ketamine

Answer 25

Ketamine is a non-competitive antagonist at NMDA receptors

Question 26

4 neurochemical changes reported in Alzheimer’s disease

Answer 26

decreased levels of acetyl cholinesterase,
decreased levels of choline acetyl transferase (CHAT)
decreased GABA levels
decreased noradrenalin.

Question 27

neurochemical changes that have been reported with Huntington’s disease

Answer 27

Reduced GABA, 
Reduced glutamic acid decarboxylase
reduced acetyl choline, 
reduced substance P, 
reduced corticotrophin releasing factor are seen in 

Raised somatostatin

Question 28

Which of the following enzymes is involved in several catalytic reactions involving aminoacids leading to synthesis of substances such as dopamine, serotonin and tryptamine?

Decarboxylase
Hydrolase
Hydroxylase
Oxidase
Reductase

Answer 28

Monoamine Oxidases are a family of enzymes that catalyze the oxidation of monoamines.

They are present on the outer membrane of mitochondria.

Question 29

Question 35.

The enzyme involved in catabolism of GABA is

Answer 29

GABA transaminase.

Question 30

Question 36.
Which of the following are carrot-shaped eosinophilic inclusions seen in hematoxylin and eosinophilic stains?
Hirano bodies
Lewy bodies
Pick cells
Rosenthal fibres
Tau proteins

Answer 30

Rosenthal fibers appear on H&E stained sections as brightly eosinophilic carrot-shaped or corkscrew-like structures.

are alterations in astrocytic processes, which are diagnostic landmark of Alexander’s leukodystrophy.

present in association with longstanding gliosis as is seen around cavities in the CNS, in low grade, discrete astrocytomas such as pilocytic astrocytomas, and in patients suffering from Alexander’s disease.

Hirano bodies are oval to elongated rod-shaped, eosinophilic inclusions, which are few in normal elderly and high in people with Alzheimer’s disease.

Question 31

nicotine binding

Answer 31

Nicotine is highly lipid soluble and rapidly enters the brain after inhalation (smoking).
receptors are found on dopaminergic cell bodies and stimulation of nicotine receptors leads to release of dopamine.

Question 32

Dex supression test false +ves and -ves

Answer 32

false positive:
preganancy, cushings
weight loss
alcohol/enzyme inducers
barbiturates
anticonvulsants

negatives:
addisons, steroid
hypopituatarism
high dose BZs, indomethacin