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Glutamate

- most common NT in the brain


- always excitatory
- NMDA receptors - only receptors regulated by both ligand (glutamate) and voltage -
spread mainly in the cerebral cortex (hippocampus, amygdala, basal ganglia, mostly)
and particularly vulnerable to glutamate excitotoxicity.

They are Calcium channels
- Non-NMDA channels - sodium channels


- Disorders
1. Excitotoxicity


Pg: Excessive glutamate release - leads to damage of the brain seen in strokes
and other forms of brain ischemia - leads to excessive calcium intake which starts
an intracellular cascade of events that terminates with ROS formation.


Plays a role in Huntington’s, Alzheimer’s, Parkinsonism, ALS.


2. Imbalance between glutamate (exictatory) and GABA - in Epilepsy


3. High anxiety of alertness caused by caffeine 

Pg: Caffeine blocks adenosine receptors - no inhibitor of glutamate release - many
glutamate transmitters are released.
4. Inhibiton of NMDA receptors is an important part of how the ethanol affects our
body - this is how the memory, the movements and emotions are disturbed.

GABA
- Major inhibitory NT in the CNS - Chloride ions influx in post-synaptic membrane.
- Mostly in striatum, substantia nigra and globes palladium of basal ganglia.

- Pathologies:
1- Seizures due to Vit B6 deficiency - vit. B6 is a cofactor in the synthesis of
GABA from glutamate - no B6 - no GABA - seizures
2- Epilepsy - imbalance of GABA and glutamate
3- Basal ganglia disorders due to shortage of GABA
a) Chorea - damage to striatum
• Sydenham chorea - in children after streptococcal infection - AI disease -Abs
against cells from striatum
• Huntington’s - genetic mutation (AD) in the Huntingtin gene - triplet DNA
increase - abnormal accumulation ofhuntigtin proteins in striatum and cortical
cells - cell death
• Pathogenesis:
- No GABA production - loss of inhibitory effect - high muscle activity and less
muscle tone (Hyperkinetic-hypotonic syndrome) - rapid, irregular, aimless
involuntary movements of muscles of face, limbs and trunk.
- In Huntington’s disease, chorea is accompanied by progressive dementia
(cortical cells are also damaged)

Dopamine
Along with noradrenaline and adrenaline, is part of the catecholamine group.
Occurs mainly in:
A. Meso-limbic (Reward system) - modulation of signals from the limbic system
(ventral tegmental area) to the nucleus accumbens (Reward center - sends projections
to the prefrontal cortex).

This system can be activated by:

- Endogenous stimuli - serotonin, endogenous opiates, noradrenaline

- Exogenous stimuli - Alcohol, drugs and nicotine 

Activation of the system - increase of dopamine output from VTA and nc. accubens-
high feelings of pleasure
B. Meso cortical system - From VTA to the frontal cortex - important for normal cognitive
functions and emotional behavior

Deficiency of dopamine - Schizophrenia
C. Nigro-striate system- related to basal ganglia and motor functions - the dopamine
acts as the modulator for increasing the stimulation of basal ganglia direct pathway,
and inhibition of the indirect pathway


-Deficiency of dopamine - indirect pathway not inhibited and direct pathway less
stimulated - too little stimulatory impulses for movement - Parkinson disease

-Excess - Tourette sy. (indirect pathway extremely inhibited and direct pathway too
active
D. Tubero-infundibular system - influence of hypothalami-pituitary system - dopamine
decreases the secretion of prolactin

Diseases:
I. Drug addiction 

Dopamine is the NT responsible for the stimulation of the center of pleasure (nucleus
accumbent)

- Cocaine, e.g., prevents the dopamine reuptake by binding to the proteins that
normally transport dopamine - prolonged dopamine effect

- Amphetamine also acts to increase dopamine levels

Frequent and repeated over-stimulation decreases the number of receptors and the
remaining receptors become less sensitive - drug tolerance = Addiction
II. Schizophrenia

- Most common psychosis - 1% of the world’s population 

- Characterized by positive symptoms, i.e., symptoms that should be absent are
present = delusions, hallucinations, inappropriate emotion, bizarre behavior; and
negative symptoms (Behaviors that should be present are absent) =deficits of social
interaction and emotional expression, speech disorders


Pg: theory - complex dopamine deregulation:

- less dopamine in the mesa-cortical pathway - negative symptoms 

- less inhibition of nucleus accumbens - too much activity of the nucleus - positive
symptoms


III. Attention deficit hyperactivity disorder



- excess of dopamine causes restlessness and hyperactivity 

-improper balance between dopamine and serotonin
IV. Tourette’s syndrome

- disorder characterized by tics, yelps + utterances

- Genetic increase of dopamine receptors sensitivity in basal ganglia and prefrontal
cortex
V. Parkinson’s disease 

- substantia nigra + globes pallidus damage

- Due to selective degeneration of substantial nigra pars compacta - decreased output
of Dopamine

-Pg: low dopamine in substatntia nigra - excess Ach - high GABA in striatum -
increased effect of basal ganglia - less inhibitory effect of reticular formation - rigidity -
hypo kinetic-hypertonic disease.

- Syy: rigidity - increased elementary postural reflexes, hypo mimic face, less motor
activity - walking difficulties, problems in initiating movement + resting tremor

Acetylcholine
- Produced by brainstem nuclei and by nuclei of basal forebrain cholinergic system
- Brainstem cholinergic system projects to the forebrain cholinergic system - ventral
tegmental area and thalamus
- Forebrain cholinergic system - projects to the hippocampus and entorhinal cortex
(memory) to the prefrontal cortex responsible for cognitive processes.
- Pathologies
• Alzheimer’s disease - most common type of dementia in elderly

- Gradual, progressive decline ion memory language skills and activities of the daily life 

- Incidence increase with age

Serotonin (5-hydroxytryptamine)
- There is no equilibrium between body and brain serotonin - serotonin in the brain is
independently synthesized from tryptophan that is transported across the BBB.
- Insulin facilitates the transport of tryptophan across BBB - the resultant mood
improvement and drowsiness induced by serotonin is a common effect of a large
carbohydrate meal.
- Serotonin influences the reward system positively
- Deficiency of serotonin - associated with overeating and bulimia; anxiety and
endogenous depression ( inhibitors of serotonin reuptake (SSRI) are helpful in
depression and bulimia treatment)
- Estrogens - increase levels of serotonin (menopause - depression)
- Pathologies:
• Seasonal affective disorder (SAD) = “winter blues” - autumn or early winter
depression

- Tendency to sleep more, eat more, crave carbs and sweets, gain weight; decreased
libido and irritability.

- Pg: Serotonin is used in the pineal gland for the production of melatonin - regulates
the diurnal circadian rhythm and seasonal behavior in mammals - its activity is
controlled by light - noradrenergic neurons near the optic nerve are inhibited by light
but in darkness, noradrenaline stimulation of pineal cells causes change of serotonin to
melatonin 

Thus - decrease in sunlight (autumns) more melatonin is produced - less serotonin in
the brain - depression 

High melatonin has depressive/hypnotic effect - it is sometimes used as hypnotic or for
jet lag prevention


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