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readerL8 - Neurotransmitters Page 8-1 The are three major...

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Unformatted text preview: Neurotransmitters Page 8-1 The are three major classes of neurotransmitters: (1) low molecular weight molecules (Classic neurotransmitters), including amino acids, biogenic amines, and acetylcholine (2) peptides (3) gases Amino acid The major excitatory and inhibitory transmitters in the vertebrate brain are both amino acids: GABA ( -aminobutyric acid) is the main inhibitory transmitter; Glutamate is the main excitatory transmitter. (1) GABA: Inhibition is a very important feature of neural circuits in the brain. In the cortex, as many as 1 of every 5 neurons is an inhibitory neuron releasing GABA as a neurotransmitter. (a) Application of drugs that block GABA's inhibitory influence in the cortex produces convulsions. (b) Three classes of GABA receptors: two are ionotropic receptor (GABAA and GABAC); the GABAB receptor is metabotropic. (c) In addition to having a binding site for GABA, the GABAA receptor also has binding sites for two different types of modulators: (i) benzodiazepines (such as Valium), which act as anti-anxiety drugs and muscle relaxants (ii) barbiturates, which act as anesthetics and anticonvulsants Page 8-2 (d) As you would expect from their actions, both classes of drugs increase inhibition in the brain by increasing the chloride current that can pass through an open GABA receptor pore: Benzodiazepines increase the frequency of channel openings Barbiturates increase the duration of channel openings. (2) Glutamate Glutamate is the most important excitatory neurotransmitter in the central nervous system, activating at least three different cation channel receptors: the NMDA receptor, the AMPA receptor, and the kainate receptor. The importance of glutamate revealed by the distribution of its receptors. Both NMDA and AMPA receptors are widely expressed in the brain. Marked differences in the relative levels of distribution are also found. NMDA receptors AMPA receptors NMDA: N-methyl-D-aspartate AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (3) Other amino acid transmitters include the excitatory aspartate and the inhibitory glycine. Biogenic amines Page 8-3 Unlike GABA and glutamate, the biogenic amines are found in very few cells-- in only a few thousands of the billions of neurons in the human brain contain biogenic amines. Many of the cells containing the biogenic amines are found in brain stem nuclei. Although few cells contain the biogenic amines, they have very widespread influences on the brain, because these few cells send axons to almost all regions of the brain and spinal cord. Generally the biogenic amines act through metabotropic receptors (that is receptors that do not contain an ion channel, but rather activate second messenger cascades which eventually open other ion channels) and they tend to have a modulatory effect in widespread areas of the brain. (1) Norepinephrine Most of the cells in the brain that contain norepinephrine are found in the locus coeruleus, which is part of the ascending reticular activating system. This pathway controls aspects of attention, arousal and circadian rhythms. The effect of norepinephrine in this system tends to be excitatory. For example, in the hippocampus, norepinephrine from neurons with cell bodies in the locus coeruleus blocks the slow calciumactivated potassium current that normally causes a hyperpolarization after a train of action potentials. Blocking this hyperpolarization allows the hippocampal neurons to fire more action potentials. Norepinephrine (2) Serotonin (5-HT, 5-hydroxytryptamine) Serotonin is found in neurons in the raphe nuclei. Serotonin from these cells plays a number of different roles: (i) In the spinal cord, serotonin modulates transmission in pain pathways. (ii) Serotonin projections to the brain are involved in the sleep/ wake cycle. (iii) Serotonin is also involved in aggressive behavior and the establishment of social hierarchies. Serotonin's role in perception is highlighted by the fact that the hallucinogenic drug LSD (lysergic acid diethylamide) acts primarily on serotonin receptors. Generally, the effect of serotonin is to reduce potassium conductances and increase sodium conductances. @ Is serotonin acting as an excitatory or an inhibitory neurotransmitter? (3) Dopamine (a) Many of the brain's dopamine-containing neurons are found in the substantia nigra in the midbrain. In the rat, there are only 7000 dopamine cells in the substantia nigra, but each cell makes 250,000 synapses in the basal ganglia, an area involved in the control of movement. Serotonin Page 8-4 Dopamine Page 8-5 (b) The action of dopamine in the nervous system is a "neuromodulation" effect, meaning it is activated by indirectly coupled receptors. The effects have an inherently slow time course and the specificity is determined by the distribution of the receptors. (c) Degeneration of these dopamine neurons causes Parkinson's disease, which has the symptoms of difficulty initiating movements, muscle rigidity, and tremor at rest. The modulatory nature of the dopamine projection is highlighted by the fact that the symptoms of Parkinson's disease can be treated by giving patients oral doses of a dopamine precursor, L-DOPA. If the precise connections from the substantia nigra to the basal ganglia were crucial for function, then dopamine would need to be applied to very specific synapses in order to have an effect on the patients' symptoms rather than just being up regulated in this very non-specific way. Acetylcholine (1) Acetylcholine is the first compound to be identified as a neurotransmitter in the central nervous system (CNS). We have already seen that acetylcholine acts as an excitatory neurotransmitter by binding to the ionotropic nicotinic acetylcholine receptors at the neuromuscular junction. (2) In the CNS, acetylcholine tends to act as a modulator like the biogenic amines. For this function it acts through the metabotropic muscarinic acetylcholine receptor. The effects of this receptor on ion channels are quite varied. Acetylcholine acting through the muscarinic receptor can increase cation conductance, increase or decrease potassium conductance, or decrease calcium conductance. Therefore acetylcholine in the brain can be either excitatory or inhibitory. Page 8-6 (3) Acetylcholine is important for cortical functions including learning, memory, and cognition. Much of the cholinergic input to the hippocampus and cortex comes from nuclei in the basal forebrain. (a) Learning can be disrupted by blocking muscarinic acetylcholine receptors with drugs like atropine. (b) Learning can be enhanced by increasing acetylcholine concentrations by blocking acetylcholinesterase with physostigmine. (c) The decline in cognitive capacity seen in normal aging is paralleled by declines in the levels of choline acetyltransferase, an enzyme involved in acetylcholine synthesis and the loss of acetylcholine containing cells in the basal forebrain. (d) In Alzheimer's disease, which causes memory and cognitive losses, lesions occur in the cholinergic neurons of the basal forebrain (as well as in other types of neurons). Treatment of Alzheimer's disease with drugs enhancing the action of cholinergic neurons, however, has been only mildly useful. Peptides A large number of peptides act as neurotransmitters in the brain. Many of these peptides are the same peptides that are found in the gut and pancreas where they have important roles in digestion. Digestive peptides that also act as neurotransmitters include secretin, gastrin, bradykinin, somatostatin, and vasoactive intestinal polypeptide. (1) Substance P Peptides have many different functions in the brain. One is to control pain. Substance P is a peptide transmitter that is found in the nerve terminals of small diameter nociceptive sensory neurons that carry pain information from the periphery to the spinal cord. Mice that lack substance p receptors show decreased sensitivity to pain. (2) Opioid peptides Page 8-7 @ Enkephalins are involved in pain control in the brain by blocking the release of substance P. They do this by decreasing the duration of action potentials in the substance P-containing neurons by activating a calcium-dependent potassium channel. Why would this activation decrease action potential duration? Enkephalin-containing neurons are found in nuclei in the brainstem, and in cells in the dorsal horn of the spinal cord. Patients with debilitating chronic pain can be treated by implanting stimulating electrodes in these areas. The patient can send current through these electrodes by pushing a button, and can thus stimulate neurons causing them to release enkephalin which prevents substance P release and relieves the pain. Gases Nitric oxide (NO) is a gas neurotransmitter. Unlike other transmitters that are released from vesicles, nitric oxide can diffuse directly across the cell membrane of the axon terminal. Nitric oxide is involved in long term potentiation, a form of synaptic plasticity that we will discuss later in the course. Overproduction of nitric oxide is neurotoxic, and may be associated with neurological diseases. Identification of neurotransmitters Identifying that the neurotransmitter used at the neuromuscular junction is acetylcholine was relatively straightforward, given that the synapse is large and can be easily isolated. Identifying the transmitters at other synapses, for example synapse in the vertebrate brain is much more difficult because the synapses are very small and are often surrounded by a large number of different types of neurons. (1) In general, four criteria are used to determine whether a particular transmitter is used at a particular synapse: Page 8-8 (a) Is the neurotransmitter synthesized by the presynaptic cell? (b) Is the neurotransmitter stored in the presynaptic neuron? (c) Is the neurotransmitter released from the presynaptic terminal? (d) Does application of the neurotransmitter to the postsynaptic cell mimic the effects of stimulation of the presynaptic neuron? (2) One relatively easy way to see what brain regions contain which neurotransmitters is to use techniques that allow you to visualize the locations of cells containing various substances associated with the neurotransmitters. (a) Formaldehyde fixation Some neurotransmitters including dopamine, norepinephrine and serotonin can be directly visualized in fixed tissue, because when treated with formaldehyde each of these transmitters fluoresces at a different wavelength of light, so they can be visualized as different colors using a fluorescence microscope. (b) Immunohistochemistry Other neurotransmitters can be visualized using immunohistochemistry, a technique that uses antibodies labeled with markers to identify specific neurotransmitters. Instead of trying to directly label neurotransmitters, other molecules associated with specific neurotransmitters can be targeted. (c) In situ hybridization The messenger RNA coding for synthetic enzymes involved in the synthesis of a given neurotransmitter can be labeled using in situ hybridization with labeled probes. Page 8-9 Neurotransmitter synthesis (1) The methods of synthesis for different types of neurotransmitters are very different. Low molecular weight transmitters such as acetylcholine, amino acids and biogenic amines are synthesized in the nerve terminal from common cellular metabolites. Gas neurotransmitters are also made in the terminal itself. Although the synthetic pathways for the different low molecular weight neurotransmitters are all of course different, all share some important features: (a) In all cases the concentration of transmitter in the terminal is tightly controlled. (b) After release of transmitter causes a drop in the concentration, more transmitter is rapidly synthesized. (c) If too much transmitter is present, it will be degraded or synthesis will be slowed by feedback inhibition of the synthetic pathway. Page 8-10 (d) There are uptake mechanisms which bring transmitter (or in the case of acetylcholine a component of the transmitter) back into the axon terminal to be re-used. (2) Peptide transmitters are not synthesized in the axon terminal, because there are no ribosomes present in the axons or terminals. Therefore the peptides must be synthesized in the cell body and then moved down to the axon terminal by axonal transport. Axonal transport can move organelles in either direction, from the cell body down to the terminal, or from the terminal back to the cell body. Peptide transmitters are packaged into vesicles in the cell body and transported down the axon. Axonal transport Proteins or other materials found in axon terminals are often shipped from the cell body. The rates of movement of these components being transported are different: (1) Slow transport (or axoplasmic flow): slow movement, usually 1-2 mm/day. Structural proteins, such as tubulins and neurofilament proteins, move at this rate. The mechanisms of slow transport are still not very clear, but it is known that diffusion cannot account for the movement; an active process is involved. 2hr Post-fixation 2hr Anti-neurofilament (2) Axonal transport: fast movement, up to 400 mm/day. Membrane enclosed organnelles, such as mitochondria and synaptic vesicles packed with neurotransmitters, move at this rate. Such movement can not be accounted for by the axoplasmic flow. It is therefore called axonal transport. (a) Some components are transported down to the axon terminals (anterograde transport) and others back to the cell body (retrograde transport). Neuroanatomists have developed tracers that are carried in antegrade or retrograde directions by axon transport to label the connections of axons. (b) Different molecular motors are involved in transport down to the terminal and in transport back to the cell body: Kinesin always moves toward the plus end of the microtubules, so kinesin molecules can carry organelles to the axon terminal. Dynein moves towards the minus end of the microtubule, so it is involved in bring organelles back to the cell body. Page 8-11 For a movie: http://www.scripps.edu/milligan/projects.html Removal of neurotransmitters After neurotransmitters are released from nerve terminals, they need to be removed from the synaptic cleft so that their action on the postsynaptic cell will not continue after the presynaptic cell is no longer active. Mechanism for removing neurotransmitter include diffusion, degradation, and uptake. (1) For acetylcholine, the main mechanism is degradation. Acetylcholinesterase in the synaptic cleft breaks acetylcholine down into choline and acetate. The choline is then transported back into the terminal and recycled into more acetylcholine. Page 8-12 (2) The amino acids and biogenic amines have their action terminated by uptake mechanisms. There are specific transmitter transporters for each of these transmitters. The transporters use the energy of sodium traveling down its electrochemical gradient. (3) Many psychoactive drugs target the transmitter transporters: Cocaine blocks the uptake of norepinephrine. Tricyclic antidepressants also block the norepinephrine transporter. Newer antidepressants like prozac block the uptake of serotonin. (4) Peptide neurotransmitters are not taken up back into the terminals. They rely on diffusion and degradation to terminate their synaptic effects. Page 8-13 Why there are so many neurotransmitters? There are about a dozen classical neurotransmitters and many more peptide neurotransmitters. If the role of the neurotransmitters is to serve as a bridge that convey information between two neurons, why have so many chemical messengers? There might be several reasons: (1) Afferent convergence on common neuron. Many afferents terminate on a single neuron. A neuron must be able to distinguish between multiple afferent inputs that bring information to the neuron. Distinct transmitters from different afferents can help the neuron to distinguish different inputs. (2) Co-localization of neurotransmitters. Most of neurons contain more than one neurotransmitters. This may enable the neuron to transmit different information for different functional states. (3) Transmitter release from different regions. Neurotransmitters are typically released from axon terminals. However, neurotransmitters can also be released from dendrites or even varicosities along the axon. Different neurotransmitters can be stored at different regions for specific release. (4) Synaptic specialization versus non-junctional appositions between neurons. Some non-classical neurotransmitters can be released at sites without specialized synaptic structures. Neurons can form non-junctional appositions which could be sites for information transmission. (5) Fast versus slow responses of receptive neurons to neurotransmitters. Neurons respond to neurotransmitters at different speed. The temporal response differences to different transmitters from a presynaptic neuron allow the receptive neuron to respond differently depending on the antecedent activity in the neuron. ...
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