Objectives
Chemical transmission overview Glutamate GABA Noradrenaline Dopamine Serotonin Acetylcholine
Categories of Neurotransmitters
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
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
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
Steroids
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 receptors
Four main subtypes of EAA receptors can be distinguished, NMDA - ionotropic AMPA - ionotropic Kainate - ionotropic Metabotropic - G-protein
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
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).
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
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
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).
Noradrenaline excess
NA Sympathetic nervous system of brain ADD, ADHD ADD with comorbid anxiety Anxiety PTSD Panic attacks Depression Sleep disturbances Mediating survival mechanisms
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 Significance
Dopamine Synthesis
Dopaminergic neurons lack dopamine hydroxylase, and thus do not produce noradrenaline. Tyrosine hydroxylase needs iron as cofactor
Dopamine Metabolism
Dopamine Distribution
Dopamine is most abundant in the corpus striatum, a part of the extrapyramidal motor system concerned with the coordination of movement
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 -
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 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.
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
Serotonin imbalance
Depression Anxiety Obsessions and Compulsions Pain Sensitivity Aggression Sleep Disorders
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
Acetylcholine pathways
Acetylcholine Receptors
Acetylcholine Function
Muscarinic receptors appear to mediate the main behavioural effects associated with ACh,
Arousal Learning Short-term memory.
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