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

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

Acetylcholine (ACh)

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 ) .

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

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

Norepinephrine & Epinephrine (Noradrenaline & Adrenaline)

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 .

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 .

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 .

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

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

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

Dopamine (DA)

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)

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 ).

Glutamate

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 .

GABA

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 .

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

Serotonin

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 .

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

Opioid Peptides

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