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Monday, February 1, 2010

‘Satiety’ and ‘feeding’ center in the hypothalamus

Satiety center is a group of cells in the ventromedial hypothalamus that when stimulated suppress a desire for food.


Feeding center is a group of cells in the lateral hypothalamus that when stimulated cause a sensation of hunger.

In the hypothalamus, there are two nerve centers whose actions have opposite effects. If one of these, the feeding center, is stimulated, an animal will eat whether he is hungry or not. If the feeding center is removed, the animal will not eat. The other hypothalamic center is called the satiety center. The satiety center tells the organism when he has had enough to eat. Removal of the satiety center causes an animal to eat continuously and he will grow far beyond his normal size.

When we are subjected to certain stimuli, the hunger-producing center initiates the eating response. When we have eaten enough, the satiety center tells us to stop.

Many of the stimuli that tell the hypothalamus that we are hungry originate in the organs of the body. If the nutrient level of the blood is too low, the hypothalamus is alerted and the feeding center, initiates eating behavior. External stimuli can also initiate eating behavior. The sight, sound, and even the thought of food initiate impulses that eventually reach the feeding center in the hypothalamus. Specific hungers are stimulated by specific deficiencies

Neurotransmitter

Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell.Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse. Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation.


Criteria to identify neurotransmitter
1. presence in presynaptic nerve terminal

2. synthesis by presynaptic neuron

3. releasing on stimulation (membrane depolarisation)

4. producing rapid-onset and rapidly reversible responses in the target cell

5. existence of specific receptor

5HT receptors in CNS

5 HT receptors in CNS are all G-protein coupled receptors except 5HT3 receptors (ligand gated cation channel).

14 identified sub types.

5HT1 : mainly inhibitory, 5HT1A : autoreceptors that limit rate of firing of cells, widely distributed in limbic system and main target to treat anxiety and depression (5HT1A antagonist, Buspirone used for anxiety).

5HT1B & 5HT1D receptors : in basal ganglia
5HT1D agonists (Sumatriptan): used to treat migraine.

5HT2 (mainly 5HT2A) : excitatory postsynaptic effect and abundant in cortex and limbic system, target of hallucinogenic drugs, 5HT2 antagonists (methysergic) are used for treatment of migraine.

5HT3 : area postrema (in medulla, involved in vomiting) and other parts of brainstem extending to dorsal horn of spinal cord, cortex and PNS. 5HT3 antagonists (Ondansetron) are used to treat nausea and vomiting.

5HT4 : important in GIT, also present in CNS especially in striatum enhancing cognitive performance.

5HT6 : occur only in CNS, in hippocampus, cortex and limbic system, potential target for treatment of cognition and schizophrenia.

5HT7: hippocampus, cortex, thalamus and hypothalamus, blood vessels and GIT. May have thermoregulatory and endocrine function, cognitive function and sleep.

Monday, January 18, 2010

Gamma aminobutyric acid (GABA)

Learning Outcomes

At the end of the lecture, the students should be able to;

Describe the GABAergic system in the brain. Structure, synthesis, metabolisms, factors that control the activity of the system, organizational and pathways in the brain and its functions.

Relate the functions and its organizational pathways of the neurotransmitter in the brain.


GABA

Gamma-aminobutyric acid is the non-protein amino acid. Found in nearly all pro- and eukaryotic organisms including plants.

Numerous study on the cloning of GABA receptors, GABA transporters and the enzymes responsible for GABA synthesis have confirmed the presence of GABAergic synapse throughout CNS.

It is most highly concentrated in the substantia nigra & globus pallidus nuclei of the basal ganglia, followed by the hypothalamus, the periaqueductal grey matter (“central grey”) and the hippocampus.

Occuring in 30-40% of all synapses (second only to glutamate as a major brain neurotransmitter).

The GABA concentration in the brain is 200-1000 times greater than that of the monoamines or acetylcholine.

GABA and glycine are the principles inhibitory neurotransmitter.


Synthesis

GABA is produced by the decarboxylation of glutamate

Catalysed by the enzyme glutamic acid decarboxylase (GAD).

GAD
Found in several non-neuronal tissue (including ovary and pancreas).

Within CNS it is specific marker of GABAergic neurons.

Present in the cytoplasm as both soluble and membrane-bound forms, principally
in the axon terminals.

Normally saturated with glutamate.

Activity requires the co-factor pyridoxal-5-phosphate (PLP; a form of vit B6).

Exists in two states
+ An inactive apoenzyme (apoGAD) lacking the co-factor
+ An active holoenzyme (holoGAD) complexed with PLP

Two isoforms of GAD;
In addition to the inactive and active GAD.

GAD67 and GAD65 respective molecular massess (67 and 65kDa).

Encoded by separate independently regulated genes GAD1 and GAD2.

Differ subtantially in amino acid sequence, interaction with PLP, kinetic properties and their regulation.

GAD65
Located preferentially in nerve terminal.

Not saturated with PLP.

Forms the majority of apoenzyme present in the brain.

The control of GAD activity
Feedback inhibition of GABA synthesis via promotion of conversion of GAD from
active to inactive states.

ATP appears inhibit.

Inorganic phosphate promote the reactivation of GAD by PLP.

Inhibitors of GAD
The hydrazides group such as isoniazid, semicarbazide etc.

Either directly or through interaction with the co-factor PLP.

Produces seizures in animal, reversed by Vit B6, precursor of PLP.

Intrauterine or neonatal seizures due to inherited defect in pyridoxine metabolism characterized by low GABA CSF can be treated with Vit B6.

Storage of GABA
Storage in vesicles and transported into by active transport.

The transport is dependent on a vesicular protein that transport GABA in exchange for luminal protons.

The proton electrochemical gradient is generated by H+-ATPase located in the vesicle membrane.

GABA transport is not specific; also transporting glycine.

Uptake of GABA
After release it is rapidly diffusing out of the synaptic cleft.

The ultimate removal of GABA is achieved by high affinity NA+ and Cl- dependent uptake GABA into both GABAergic neuron and glial cells.

GABA uptake coupled to the movement of Na+ down its electrochemical gradient into the cell.


Metabolism

A transamination reaction is catalysed by the mitochondrial enzyme 4-aminobutyrate aminotransferase (GABA transaminase; GABA-T).

The amino group is transferred onto the TCA cycle intermediate α–ketoglutarate, producing glutamate and succinic semialdehyde.

This synthesis and metabolism is often referred as the ‘GABA shunt’, as it acts as a shunt from α–ketoglutarate to succinate.

Majority of it is generated by means of GABA-shunt.


Pathways

GABA is found in a number or neurons
The majority are associated with the basal ganglia i.e. projections from striatum to globus pallidus and substantia nigra.

Projections from the globus pallidus and substantia nigra to several brains areas.

Outside the basal ganglia is projections is the Purkinje cell of the cerebellar cortex.

GABA is an inhibitory neurotransmitter as its principal action is to cause membrane hyperpolarization, thus reducing neuronal activity

The large number and widespread of distribution of GABAergic synapse has led to the idea that nervous system is highly restrained


GABA Receptors

Three distinct classess: GABA (B) and GABA (C)

GABA (A) and GABA (C) receptors from membrane channels (ionotropic receptors) and their activation leads to an increased permeability to chloride (Cl-) and bicarbonate (HCO3-) ions

GABA (B) receptors belong to the family of G-protein-coupled receptors (metabotropic receptors) and modify the activity the enzyme adenylate cyclase, suppress transmitter release by directly inhibiting calcium channels or hyperpolarise postsynaptic cells by activating potassium channels.


GABA (A)

The most GABA receptors in the CNS.

Binding of two molecules of GABA to the receptor causes the opening of an integral transmembrane anion channel.

Defined by their sensitivity to the antagonist bicuculline (competitive). Pirotoxin is non-competitive antagonist.

Many compounds can affect GABA (A) receptors the most important are benzodiazepines, barbiturates, neuroactive steroids and general anesthetics.

Muscimol activates GABA (A).


GABA (B)

Found in both peripheral and central.

Its action reduce the evoked release of transmitter.

The actions cannot be blocked by bicuculline and picrotoxin.

A.k.a a bicuculline-insensitive receptors.

GABA effect mimicked by butanoic acid (baclofen); muscimol does not activate and not link to Cl- channel.


GABA (C)

Was not blocked by bicuculline.

Mimicked by cis-4-aminocrotonic acid (CACA).

Shared the same properties among the GABA analogues but not interact with GABAB receptors.

Activate anions channels permeable to Cl- (and HCO3-).

Not affected by benzodiazepine, barbiturates or any anaesthetics.


Function of GABA in the Brain

Inhibitory effect in the brain.

GABA-mediated inhibition does not act solely as simple suppression of excitability
Tonic inhibitory input can transform firing pattern.

Inhibitory connections may be organised to provide negative feedback (recurrent inhibition) via networks of neurons.

By controlling precise timing of firing in multiple tragets cells inhibitory interneurons may synchronize activity and even enhance the excitatory effect

Pathophysiologically its involved in epilepsy, anxiety, sleep disorder and other mood disorders as well as altering conscious level.

Friday, December 18, 2009

Clinical note

In vasogenic edema,(typically secondary to a brain tumor), the blood vessel are poorly developed, are leaky, and lack the transport properties of a normal BBB. This abnormal vessel permeability results in accumulation of interstitial fluid in the brain. Permeablity of the BBB can also be altered in infections such as bacterial meningitis; although this accounts for some of the adverse neurologic effects of infection, it also permits improved delivery antibiotics to the CNS.

Prof. Noriah's note (4)


Picture's source: http://www.stanford.edu/

Characteristic of CNS
Protected by cranium, meningis + csf

CSF
-secreted by choroid plexuses (special capillaries in ventricles of the brain → form BBB)
-act as shock absorbing medium

Brain stem
-midbrain
-pons → resp. center
-medulla → resp. center, cardiac center (coordinating reflex for vomiting, swallowing, coughing, sneezing)
-cerebellum → required for smooth coordinated movement + equilibrium

Blood brain barrier (BBB)
-Composed of endothelial cells packed tightly together to form tight junction that prevent passage of most molecules.
-An underlying basement membrane and specialized glial cells (astrocyte), which projects processes (pedicles) that attach to the walls of the capillary, reinforce this barrier.
-Very few substances can cross the BBB into brain tissue:
(1)Water is able to freely diffuse
(2)Glucose (the primary energy source of the brain) and amino acid require carrier-mediated transport
(3)Nonpolar lipid soluble substances can cross more readily than polar water-soluble ones
(4)Other active transport systems are present to pump weak organic acids, halides and extracellular K+ across the BBB

The blood – CSF barrier
-Cerebrospinal fluid (CSF) is clear, colorless fluid that normally contains none or few cells, a small amount of protein, and a moderate amount of glucose
-The blood – CSF barrier is composed of epithelial cells of the choroid plexus – a highly vascular structure, located within the ventricles .

Function of NS
Detect changes in internal and external environmental (in + outside the body)
via sense organs (receptors)

↓ (information sent to CNS by sensory nerve/afferent nerve)

CNS (brain/spinal cord) – intergrating center

↓ (analyse the sensory information via motor nerve/efferent nerve – send instruction to)

Muscle/gland

*Receptor
(a) special receptor
- hearing
- smell
- taste
- chemoreceptor
- osmoreceptor

(b) general receptor
- pain
- temperature
- proprioreceptor

Thursday, December 17, 2009

Prof. Noriah's note (3)

C) CNS
Consist of brain + spinal cord
Protected by cranium + vertebral column
Meninges + cerebrospinal fluid (csf)

Meninges:
3 layers
-dura mater
-arachroid + pia mater (form subarachroid space filled with CSF)

CSF
-secreted by choroid plexuses (CP)
-CP is a specialized capillaries located on the root of each ventricles
-CP produces CSF, secretes + filter harmful material, → form BBB (blood brain barrier)
-CSF circulate round the brain + spinal cord → enters superior sagittal sinus (venous sinuses) → jugular vein → superior vena cava

Function of CSF
-Protect the brain + spinal cord from banging / contact injury against the inner wall of cranium + wall of vertebral canal (shock absorbing medium)