Overview CNS Chemical Transmission

TCM INTI University Tay Ju Lee MD

Objectives
Chemical transmission overview Glutamate GABA Noradrenaline Dopamine Serotonin Acetylcholine

Categories of Neurotransmitters

Excitatatory Amino Acids

Glutamate

Inhibitory Amino Acids

GABA & Glycine

Monoamine Mediators & Pathways

Noradrenaline Dopamine 5 HT Acetylcholine Others

Question to keep in mind

Whats the transmitter? What & Where are the receptors?

How do they work?

What do they do in CNS? What are clinically important drugs associated with the receptor?

Chemical transmission
The basic processes of synaptic transmission in the CNS are essentially similar to those operating in the periphery Glial cells, particularly astrocytes, participate actively in chemical signalling, functioning essentially as 'inexcitable neurons'.

Definitions

Neurotransmission
neurotransmitters are released by presynaptic terminals and produce rapid excitatory or inhibitory responses in postsynaptic neurons

Neuromodulation
neuromodulators are released by neurons and by astrocytes, and produce slower pre- or postsynaptic responses

Neurotrophic factors
Neurotrophic factors are released mainly by nonneuronal cells and act on tyrosine kinase-linked receptors that regulate gene expression and control neuronal growth and phenotypic characteristics

Speed & receptors

Fast neurotransmitters (e.g. glutamate, GABA) operate through ligand-gated ion channels

Slow neurotransmitters and neuromodulators (e.g. dopamine, neuropeptides, prostanoids) operate mainly through G-protein-coupled receptors.

Mediator typea
Conventional smallmolecule mediators

Examples

Targets

Main functional role

Fast synaptic neurotransmission Neuromodulation

Glutamate, GABA, Ligand-gated ion acetylcholine,dopamine channels G-protein, 5-hydroxytryptamine, coupled receptors etc. Substance P, G-protein-coupled neuropeptide Y, receptors corticotrophin-releasing factor, etc.

Neuropeptides

Neuromodulation

Lipid mediators
Nitric oxide Neurotrophins, cytokines

Prostaglandins, endocannabinoids
Nerve growth factor, brain-derived neurotrophic factor, interleukin-1

G-protein-coupled receptors
Guanylate cyclase

Neuromodulation
Neuromodulation

Kinase-linked receptors Neuronal growth, survival and functional plasticity

Steroids

Androgens, oestrogens Nuclear receptors (also Functional plasticity membrane receptors)

GLUTAMATE

Glutamate Roles
Increasing glutamate increases the firing rate of a population of neurons Excitability Role in Cellular Memory Pain Perception Potentiation Amplification

Glutamate

Widely & fairly uniformly distributed Made from glucose via Kreb cycle

Interconnection between Excitatory & Inhibitory amino acids makes it difficult to study the functional role of individual ones.

Glutamate & GABA interlinked

Glutamate receptors
Four main subtypes of EAA receptors can be distinguished, NMDA - ionotropic AMPA - ionotropic Kainate - ionotropic Metabotropic - G-protein

Dual Role of NMDA

NMDA receptors mediate slower excitatory responses and, through their effect in controlling Ca2+ entry, play a more complex role in controlling synaptic plasticity (e.g. long-term potentiation).

NMDA receptors
Highly permeable to Ca2+, as well as to other cations Na+ Activation of NMDA receptors Ca2+ entry. Blocked by Mg2+ Activation requires glycine & glutamate Selective NMDA blocking agents

Ketamine & Phencyclidine (PCP-angel dust) both dissociative anaesthetic

Main sites of drug action on NMDA and GABAA receptor

NMDA & Calcium

Function of Glutamate receptors

NMDA Slow component to excitatory synaptic potential AMPA mediate fast excitatory synaptic transmission in CNS, occurs in astrocytes Kainate presynaptic role Metabotropic pre & post associated with modulation

Presynaptic inhibit calcium channels Postsynaptic inhibit potassium channels

Glutamate
Chronic Pain Mood Lability Bipolar disease Paroxysmal symptoms Neurodegeneration

Synaptic plasticity
Synaptic plasticity is a general term to describe long-term changes in synaptic connectivity and efficacy, either following physiological alterations in neuronal activity (as in learning and memory), or resulting from pathological disturbances (as in epilepsy, chronic pain or drug dependence).

NMDA antagonists prevent LTP

GABA

GABA
GABA functions as an inhibitory transmitter in many different CNS pathways. About 20% of CNS neurons are GABAergic; most are short interneurons, but long GABAergic tracts run to the cerebellum and striatum. GABA serves as a transmitter at about 30% of all the synapses in the CNS.

GABA Receptors
GABA acts on two distinct types of receptor GABAA receptor - ligand-gated ion channel
located postsynaptically mediate fast postsynaptic inhibition - Chloride

GABAB - G-protein-coupled receptor

located pre- and postsynaptically

Main sites of drug action on NMDA and GABAA receptor

GABA receptors

GABAA receptors are the target for several important centrally acting drugs,
Benzodiazepines, Barbiturates Neurosteroids General anaesthetics

GABAB receptor
Baclofen selective agonist - used to treat spasticity and related motor disorders

GABAB receptor

GABA at the synapse

Monoamine Transmitters
Noradrenaline (Norepineprine) Dopamine

5 HT (Serotonin)
Acetylcholine

NORADRENALINE

Noradrenaline Synthesis
The basic processes responsible for the synthesis, storage, release and reuptake of noradrenaline are the same in the brain as in the periphery and the same types of adrenoceptor are also found in pre- and postsynaptic locations in the brain.

Noradrenaline Function

The actions of noradrenaline are mainly inhibitory (-receptors), but some are excitatory (- or -receptors). Noradrenergic transmission functions in
the 'arousal' system, controlling wakefulness and alertness blood pressure regulation control of mood (functional deficiency contributing to depression).

NA dampen extraneous information drive a single experience and to ignore distractions

Noradrenaline excess
NA Sympathetic nervous system of brain ADD, ADHD ADD with comorbid anxiety Anxiety PTSD Panic attacks Depression Sleep disturbances Mediating survival mechanisms

Copper & Ascorbic Acid

What cofactors that drive Dopamine to Noradrenaline ?

Noradrenaline Pathway
The cell bodies of noradrenergic neurons occur in small clusters in the pons and medulla, and they send extensively branching axons to many other parts of the brain and spinal cord The most prominent cluster is the locus coeruleus (LC), located in the pons.
descending control of pain pathways

Noradrenergic Drugs

Psychotropic drugs that act partly or mainly on noradrenergic transmission in the CNS include
Antidepressants Cocaine Amphetamine. Antihypertensive drugs clonidine & methyldopa

DOPAMINE

Dopamine & Brain Function

The brain is designed to orientate itself to experience of high emotional valence Meaning of event Relevance Emotional significance Pain and pleasure Motivation Cerebral microcirculation

Dopamine Significance

Dopamine is particularly important in relation to neuropharmacology;

Parkinson's disease Schizophrenia hyperdopaminergic state Attention deficit disorder Substance abuse Endocrine disorders Fatigue, concentration difficulty, low motivation (anhedonia)

Dopamine Synthesis
Dopaminergic neurons lack dopamine hydroxylase, and thus do not produce noradrenaline. Tyrosine hydroxylase needs iron as cofactor

Dopamine Metabolism

Dopamine Distribution

Distribution of dopamine in the brain is more restricted than that of noradrenaline

Dopamine is most abundant in the corpus striatum, a part of the extrapyramidal motor system concerned with the coordination of movement

Dopamine Pathways & Function

Nigrostriatal pathway - 75% of the dopamine in brain

Cell bodies in the substantia nigra whose axons terminate in the corpus striatum. Motor Control Parkinsons Disease dopamine deficiency here.

Dopamine Pathways & Function

Mesolimbic/mesocortical pathways
Cell bodies in midbrain and whose fibres project to parts of the limbic system, especially the nucleus accumbens and the amygdaloid nucleus and to the frontal cortex. Focus and orient frontal lobes to pay attention Emotion and drug-induced reward systems Mesocorticol dopamine deficiency - ADHD Mesolimbic dopamine deficiency -

Dopamine Pathways & Function

Tuberohypophyseal system
Group of short neurons running from the ventral hypothalamus to the median eminence and pituitary gland
Regulate secretions of pituitary gland Prolactin release (inhibited) Growth hormone release (stimulated)

Dopamine Pathway

Dopamine Receptors
There are five dopamine receptor subtypes. Dopamine receptors.pdf
D1 and D5 receptors are linked to stimulation of adenylyl cyclase excitatory frontal lobe D2, D3 and D4 receptors are linked to inhibition of adenylyl cyclase - inhibitory subcortical areas Most known functions of dopamine mediated mainly by receptors of the

Dopamine at the Synapse

Dopamine Drugs

Vomiting
Dopaminergic neurons have a role in the production of nausea and vomiting. Nearly all dopamine receptor agonists (e.g. bromocriptine) and other drugs that increase dopamine release in the brain (e.g. levodopa) cause nausea and vomiting as side effects, Dopamine antagonists (e.g. phenothiazines, metoclopramide) have antiemetic activity.
D2 receptors occur in the area of the medulla (chemoreceptor trigger zone) associated with the initiation of vomiting and are assumed to mediate this effect.

Analogy
Dopamine is caveman hanging out at his woods, he has to sit quietly, pay attention to where the prey is, at the right moment kill it activating arousal neurotransmitter Serotonin is dragging the meat back to cave, chewing on it by the fire, eating, then go to sleep homeostasis neurotransmitter

SEROTONIN

Serotonin (5-HT)
Lysergic acid diethylamide (LSD), a drug known to be a powerful hallucinogen acted as a 5-HT antagonist on peripheral tissues, and suggested that its central effects might also be related to this action. 5HT2A 5-HT is mainly found in 99% in gut, but1% in brain important. Selective serotonin reuptake inhibitors constitute an important group of antidepressant drugs.

5-HT Synthesis
5-HT synthesis resembles noradrenaline.
Except precursor is Tryptophan not Tyrosine Availability of tryptophan is the main factor regulating synthesis

5-Hydroxytryptamine pathways

Serotonin Pathways

5-HT neurons are concentrated in the midline raphe nuclei in the pons and medulla, Projecting diffusely to the cortex Limbic system Hypothalamus Spinal cord Similar to the noradrenergic projections.

Serotonin at the receptor

5-HT Receptors
9 main receptors 5-HT1A 5-HT1B 5-HT1D 5-HT2 5-HT3 5-HT4 5-HT6 5-HT7 5-HT Receptors.pdf

5-HT Functions

Functions associated with 5-HT pathways mainly vegetative functions

Social engagement Mood and emotion Appetite Sleep/wakefulness Control of sensory pathways, including nociception Body temperature control Vomiting

Serotonin imbalance
Depression Anxiety Obsessions and Compulsions Pain Sensitivity Aggression Sleep Disorders

Tryptophan Hydroxylase Modulation

Inhibited By Nitric oxide L Dopa Polychlorinated biphenyls Nicotine

Activated By Oxygen Folic acid Sulfhydryl groups SSRIs

Natural Serotonin Agonists

5 HTP Folic acid( MTHF crosses BBB) DHEA Vitamin D St Johns Wort (Hypericum chinense) Physical activity

5-HT receptor selective drugs

Serotonin reuptake inhibitors (SSRIs)fluoxetine, used as antidepressants 5-HT1D receptor agonists, sumatriptan - treat migraine 5-HT1A receptor agonist used in treating anxiety - buspirone & vitamin D 5-HT3 receptor antagonists, ondansetron - antiemetic agents Antipsychotic drugs - clozapine

ACETYLCHOLINE

Acetylcholine Synthesis
Synthesis, storage and release of acetylcholine (ACh) in the central nervous system (CNS) are essentially the same as in the periphery

Acetylcholine pathways

ACh is widely distributed in the CNS, important pathways being:

Magnocellular forebrain nuclei which send a diffuse projection
Degeneration Alzheimers Dementia

Septohippocampal projection Short interneurons in the striatum and nucleus accumbens.

Acetylcholine pathways

Acetylcholine Receptors

Acetylcholine has mainly excitatory effects

Nicotinic (ionotropic) Muscarinic (G-protein-coupled some muscarinic ACh receptors (mAChRs) are inhibitory.

The mAChRs in the brain are predominantly of the M1 class

Acetylcholine at the Synapse

Acetylcholine Function

Muscarinic receptors appear to mediate the main behavioural effects associated with ACh,
Arousal Learning Short-term memory.

Muscarinic antagonists (e.g. scopolamine) cause amnesia.

Acetylcholine Drugs

Acetylcholinesterase Inhibitor
Tacrine Donepezil Galantamine Rivastigmine

Memantine, an NMDA receptor antagonist. Huperzine(Huperzia serrata) chinese club moss - Reversible and selective ACHe
inhibitor.

References
Rang et al (2007) Rang & Dales Pharmacology 6th Ed. Jay Lombard DO Neurotransmitters & Behaviour