1. Brain Neurotransmitters
Dr. Taha Sadig Ahmed,
Physiology Department , College of Medicine , King Saud University , Riyadh

2. Dr Taha Sadig Ahmed
Mediicine Bachelor and Bachelor of Surgery ( University of Khartoum )
PhD Clinical Neurophysiology . University of Bristol, England
MAANEM ( USA)
Consultnat , Clinical Neurophysiology,
Saudi Council of Health Specialities

3. Acetylcholine (ACh)

4. In the brain , cholinergic ( ACh producing ) neurons are present mainly in 2 areas 
(1) Nucleus Basalis projects to the neocortex ; (2) Pedunculopontine Nucleus (PPN . Ponto-Mesencephalic Cholinergic
Complex ) projects to the Thalamus
(1) Basal Forebrain ( namely
Nucleus Basalis of Myenert )
(2) Ponto-Mesencephalic
Cholinergic Complex
( see Brainstem Bulboreticular Facilitatory Area in Consciousness & Sleep lectures ) .

5. Functions :The brain Cholinergic system
is concerned with 
(1) Consciousness/wakefulness
alertness (see Brainstem Bulboreticular Facilitatory Area
in Consciousness & Sleep lectures ) .
(2) Memory & learning .
Defects in the brain cholinergic system interfere with learning and memory , such as in Alzheimer’s disease

6. ACh is synthesized at the nerve-ending & synthesis involves the reaction of Choline & Active acetate (Acetyl-CoA , Acetylcoenzyme A)
Cholinergic neurons actively take up choline via a transporter
The acetate is activated to become Acetyl-coenzyme A ( Acetyl-CoA), & then Acetyl-CoA reacts with choline to form ACh
This reaction is catalyzed by the enzyme Choline Acetyltransferase .
After being released into the
synaptic cleft , ACh ibinds to its
receptor & opens sodium channels
 depolariztion
It is then rapidly hydrolyzed by the
enzyme Actylcholinesterase
into Choline and Acetate

7. Norepinephrine & Epinephrine (Noradrenaline & Adrenaline)

8. The cell-bodies of Norepinephrine neurons are located in mainly Locus Cereulus
From Locus Cereulus the axons of noradrenergic neurons arborize widely in the brain , constituting the Locus Cereulus System .

9. The three Catecholamines ( dopamine , NE and epinephrine ) are formed by hydroxylation and decarboxylation of the amino acid Tyrosine .
Tyrosine is converted to Dopa and then Dopamine in the cytoplasm of cells by Tyrosine Hydroxylase and Dopa Decarboxylase
The Dopamine then enters the granulated vesicles , and inside them it is converted to Norepinephrine by the enzyme Dopamine Hydroxylase ( Dopamine beta-Hydroxylase , DBH)
L-Dopa is the isomer of Dopamine .
Tyrosine Hydroxylase is the rate-limiting enzyme of synthesis , & it is subject to feed-back inhibition by dopamine and norepinephrine , thus prividing internal control of the synthesis process .

10. Some brain neurons and adrenal medullary cells ( but not postgqanglionic sympathetic nerves ) contain the their cytoplasm the enzyme PNMT ( Phenylthanolamine-N-Methyl Transferase ) , which converts norepinephrine into epinephrine .
In these epinephrine-secreting neurons , norepinephrine leaves the vesicles to the cytoplasm , where it is converted by PNMT into epinephrine , and then enters other storage vesicles .

11. Raete-limiting enzyme
Tyrosine
Tyrosine Hydroxylase
Raete-limiting enzyme
DOPA
Dopa Decarboxylase
Dopamine (DA)
Dopamine Hydroxylase
Norepinephrine (NE)
PNMT
Epinephrine

12. Catecholamine Catabolism/Inactivation
(1) Re-uptake into the
presynaptic neuron
where it is degraded
intracellularly MonoamineOxidase
(MAO) enzyme;
(2) Extracellular inactivation by
Catechol-O-Methyl Transferase
(COMT)
NB : (1) COMT is NOT present in the presynaptic neuron
(2)COMT is present in larger amounts in Glial cells  that is why Glia play important role in removal /inactivation of catecholamines in brain synapses . .
COMTis actually attached extracellularly to the postsynaptic membrane  therefore it is also correct to say that Catecholamines are degraded on the Postsynaptic membrane .
Reuptake & degradation by MAO ( mechanism 1 ) is more impotrant for removal of catecholamines than mechanism 2

13. Functions : of the Brain NE System
(1) It constitutes part of the RAS ( Reticualr Activating System alertness ) + plays role in 
(2) fight-flight situations , including competitive athletic behavior & aggressive behavior .
Deficiency of Norepinephrine or Serotonin  Depression

14. Dopamine (DA)

15. Tyrosine
In certain parts of the brain , catecholamine synthesis stops at dopamine ( DA) .
Like other catecholamines , after being secreted into the synaptic cleft , DA is either reuptaken into the presynaptic membrane & inactivated intracellularly by MAO ( main way of removal from synaptic cleft) , or removed from the cleft by the action of COMT on it .
Tyrosine Hydroxylase
Dopa
Dopa Decarboxylase
Dopamine (DA)

16. In the brain , dopaminergic neurons comprise 
(A) Nigrostriatal System :
Dopaminergic fibers originate in Substantia Nigra and project to the Striatum .
This system is involved in motor control , & DA deficiency in Basal Ganglia  Parkinsonism
(B) Mesocortical System :
Arises from the Ventral Tegmental Area ( VTA) , and projects to Nucleus Accumbens and Limbic System .
The Mesocortical System is involved in behaviors of Pleasure , Reward , and Addiction
Mesocortical System overstimulation can lead to Schizophrenia-like symptomsor & to Addiction ( if stimulated by a narcotic drug ).

17. Glutamate

18. In Health :
(1) Glutamic acid (and aspartic acid) : are major excitatory NTs in CNS.
(2) Glutamate NMDA receptor involved in Long-Term Potentiation & memory storage.
In Disease :
(1) Excess Glutamate activity is implicated in some types of epileptic seizures
(2) Under some pathological conditions , such Stroke , ALS (Amyotrophic Lateral Sclerosis) , and Alzheimer's diseases, it acts as an excitotoxin  producing exceesive influx of calcium into the neurons  causing neuronal death .

19. GABA

20. GABA is an important inhibitory transmitter in the brain (including being responsible for presynaptic inhibition ).
Formation : GABA is formed by decarboxylation of Glutamate . The enzyme which catalyzes this reaction is Glutamic Acid Decarboxylase (GAD , Glutamate Decarboxylase ).
Inactivation : by 2 ways 
(1) GABA is metabolized by the enzyme GABA transaminase .
(2) In addition , there is active reuptake of GABA via a GABA transporter . This vesicular GABA transporter transports GABA and Glycine into secretory vesicles .

21. Activation of GABA receptors can lead to 
(1) increased potassium channel conductance  potassium outflux ( efflux)  hyperpolarization
(2) increased chloride channel conductance  chloride influx  hyperpolarization
(3) decreased calcium channel conductance  inhibited calcium influx hyperpolarization
The increase in chloride conductance produced by GABA receptors is potentiated by the Diazepam ( Valium ) and other Benzodiazepines .
The Benzodiazepines have (1) marked anti-anxiety effect ; and are effective (2) muscle relaxants , (3) anticonvulsants , and (4) sedatives

22. Serotonin

23. Function : improved mood & decrease appetite .
Serotonin is formed by the hydroxylation & decarboxylation of tryptophan , whose neuronal cell bodies are present in Raphe Nuclei ( that is why serotonin is present in brain Raphe Nuclei )
After release , it is removed from the synaptic space by an active reuptake mechanism . Thereafter , inside the nerve-ending it is inactivated by the enzyme Monoamino Oxidase (MAO)
Function : improved mood & decrease appetite .
Deficiency of serotonin  depression
Antidepressant drugs include 
(1) Drugs that inhibit MAO ( Monamine Oxidase Inhibitors ) ,and
(2) SSRIs (serotonin-specific reuptake inhibitors) which inhibit reuptake and destruction of serotonin  prolong action of serotonin .
Too much serotonin activity  can lead to Hallucinations ( e.g., hallucinogenic drugs)
SSRI also improve mood
( reduce anxiety ) and decrease appetite .

24. Glycine
In the CNS , especially spinal cord , glycine is Inhibitory neurotransmitter  by opening Chloride channels  IPSP (hyperpolarization)

25. Opioid Peptides

26. Opium ألأفيون is a plant that was known from the dawn of history ,
Morphine is a drug derived from
opium .
It is a powerful analgesic & euphoric
drug .
However , if not used wisely , it can be highly addictive
Morphine & realted derivatives of opium are called opiate drugs ( they are called external opiates ) .
Their analgesic/euphoric actions are
medaited by opioid receptors within the
body
Opium Puppy