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

2. Acetylcholine (ACh) 2

3. 3 In the brain, cholinergic ( ACh producing ) neurons are present mainly in 2 areas  (1) Basal Forebrain ( namely Nucleus Basalis of Myenert ) (2)Ponto-Mesencephalic Cholinergic Complex ( see Brainstem Bulboreticular Facilitatory Area in Consciousness & Sleep lectures ).

4. 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 4

5. 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 5

6. Norepinephrine & Epinephrine (Noradrenaline & Adrenaline) 6

7. 7 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.

8. 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. 8

9. Some brain neurons and adrenal medullary cells ( but not postganglionic 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. 9

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

11. 11 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 (1) Re-uptake into the presynaptic neuron where it is degraded intracellularly MonoamineOxidase (MAO) enzyme; (2) Extracellular inactivation by Catechol-O-Methyl Transferase (COMT) Catecholamine Catabolism/Inactivation

12. 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 & (3) aggressive behavior. Deficiency of Norepinephrine or Serotonin  Depression

13. Dopamine (DA) 13

14. Tyrosine Dopa Dopamine (DA) Tyrosine Hydroxylase Dopa Decarboxylase 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.

15. 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  (1) Schizophrenia-like symptomsor & to (2) Addiction ( if stimulated by a narcotic drug ).

16. Glutamate 16

17. I n 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. 17

18. GABA 18

19. 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. 19

20. 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 20

21. Serotonin 21

22. 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 Drugs that inhibit serotonin uptake such as Prozac (Fluoxetine ) are also effective antidepressants These are called SSRIs (serotonin-specific reuptake inhibitors) which inhibit reuptake and destruction of serotonin  & thereby prolong its action.. SSRI also improve mood ( reduce anxiety ) and decrease appetite. Too much serotonin activity  can lead to Hallucinations ( e.g., hallucinogenic drugs)

23. Glycine 23 In the CNS, especially spinal cord, glycine is Inhibitory neurotransmitter  by opening Chloride channels  IPSP (hyperpolarization)

24. Opioid Peptides 24

25. 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