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Chapter 6- Neurotransmitter Systems Introduction: • Three major classes of neurotransmitters: amino acids, amines, and peptides • First molecule identified as a neurotransmitter was acetylcholine, Ach • Cholinergic- cells that produce and release Ach • Noradrenergic- neurons that use the amine neurotransmitter norepinephrine (NE) • Glutamatergic- synapses that use glutamate • GABAergic- synapses that use GABA • Peptidergic- synapses that use peptides • Ach and all the molecular machinery associated with it are collectively called cholinergic system Studying Neurotransmitter Systems: • Certain criteria must be met to distinguish a molecule as a neurotransmitter: o The molecule must be synthesized and stored in the presynaptic neuron o The molecule must be released by the presynaptic axon terminal upon stimulation o The molecule must produce a response in the postsynaptic cell Localization of Transmitters and Transmitter-Synthesizing Enzymes: • Hints that a particular molecule may be a neurotransmitter: o Molecule is concentrated in the brain tissue o Application of the molecule to certain neurons alters their action potential firing rate • To confirm the molecule is a neurotransmitter, the molecule must be localized in and synthesized by particular neurons • Two techniques used are immunocytochemistry and in situ hybridization Immunocytochemistry: • Immunocytochemistry- a method used to anatomically localize particular molecules to particular cells o Once the neurotransmitter candidate has been chemically purified, it is injected into the bloodstream of an animal, where it stimulates an immune response o The response is the generation of large proteins called antibodies  Antibodies can bind tightly to specific sites on the foreign molecule such as the transmitter candidate  Best antibodies for this method bind very tightly to the transmitter of interest, and bind very little or not at all to other chemicals in the brain o This method can be used to localize any molecule for which a specific antibody can be generated In Situ Hybridization: • Is also useful for confirming that a cell synthesizes a particular protein or peptide • Recall: proteins are assembled by the ribosomes according to instructions from specific mRNA molecules • A unique mRNA molecule for every polypeptide is synthesized by a neuron • If the sequence of nucleic acids in a strand of mRNA is known, it is possible to construct in the lab a complementary strand that will stick to the mRNA molecule o Complementary strand is called a probe o Process by which the probe bonds to the mRNA molecule is called hybridization • In order to see if the mRNA for a particular peptide is localized in a neuron, we chemically label the appropriate probe so it can be detected, apply it to a section of brain tissue, allow time for the probes to stick to any complementary mRNA strands, then wash away all the extra probes that have not stuck; finally we search for neurons that contain the label • In situ hybridization, probes are usually labelled by making them radioactive o Since we cannot see radioactivity, hybridized probes are detected by laying the brain tissue on a sheet of special film that is sensitive to radioactive emissions o After exposure to the tissue, the film is developed like a photograph, and negative images of the radioactive cells are visible as clusters of small dots  This technique for viewing the distribution of radioactivity is called autoradiography • Immunocytochemistry is a method for viewing the location of specific molecules, including proteins, in sections of brain tissue • In situ hybridization is a method for localizing specific mRNA transcripts for proteins • Both methods put together, enable us to see whether a neuron contains and synthesizes a transmitter candidate Studying Transmitter Release: • Most regions of the outer central nervous system (CNS) contain a diverse mixture of intermingled synapses using different neurotransmitters • Read Pg. 137-138! Studying Synaptic Mimicry: • Knowing that a molecule is localized in, synthesized by, and released from a neuron is still not sufficient to qualify it as a neurotransmitter • A 3 criterion must be met: o The molecule must evoke the same response as that produced by the release of naturally occurring neurotransmitter from the presynaptic neuron • To asses the postsynaptic actions of a transmitter candidate a method called microionophoresis is used o Microionophoresis- a method of applying drugs and neurotransmitters in very small quantities to cells • Read this section on Pg. 138 Studying Receptors: • Each neurotransmitter exerts its postsynaptic effects by binding to specific receptors o As a rule no two neurotransmitters bind to the same receptor; but one neurotransmitter can bind to many different receptors • Each of the different receptors a neurotransmitter binds to is called a receptor subtype • Ach acts on two different cholinergic receptor subtypes: one type is present in skeletal muscle and the other is in heart muscle o Both subtypes are also present in many other organs and within the CNS • 3 Approaches to study the different receptor subtypes have been useful: o Neuropharmacological analysis of synaptic transmission o Ligand-binding methods o Molecular analysis of receptor proteins Neuropharmacological Analysis: • Skeletal muscle and heart muscle respond differently to various cholinergic drugs • Nicotine (derived from tobacco plant), is a receptor agonist in skeletal muscle but has no effect in the heart o The receptor is called nicotinic ACh receptors in skeletal muscle • Muscarine (derived from poisonous species of mushroom), has little or no effect on skeletal muscle but is an agonist at the cholinergic receptor subtype in the heart o The receptor is called muscarine ACh receptors in the heart • ACh slows the heart rate • Muscarine is poisonous because it causes a precipitous drop in heart rate and blood pressure • Nicotinic and muscarinic receptors also exist in the brain • Glutamate receptors mediate much of the synaptic excitation in the CNS o 3 subtypes of glutamate receptors are:  AMPA receptors  NMDA receptors  Kainite receptors • Each named for a diff. chemical agonist o The neurotransmitter glutamate activates all 3 receptor subtypes  But AMPA acts only at the AMPA receptor, NMDA acts only at the NMDA receptor and so on • Pharmacological analyses were used to split the receptors into two subtypes: o NE receptors into alpha and beta o GABA receptors into GABA anA GABA B Ligand-Binding Methods: • Any chemical compound that binds to a specific site on a receptor is called a ligand for that receptor • Ligand-binding method- technique of studying receptors using radioactively labelled ligands o A ligand for a receptor can be an agonist, an antagonist, or the chemical neurotransmitter itself Molecular Analysis: • Read Pg. 141 Neurotransmitter Chemistry • Most of the known neurotransmitter molecules are either: o Amino acids o Amines derived from amino acids o Peptides constructed from amino acids • ACh is an exception; but it is derived from acetyl CoA, • Choline which is important for fat metabolism throughout the body • Amino acid and amine transmitters are generally each stored in and released by separate sets of neurons • Dale’s principle- idea that a neuron has only one neurotransmitter • Many peptide containing neurons violate Dale’s principle because these cells usually release more than one neurotransmitter: an amino acid or amine and a peptide • Co-transmitters- two or more transmitters released from one nerve terminal • But still most neurons release only a single amino acid or amine neurotransmitters Cholinergic Neurons: • Acetylcholine (ACh)- is the neurotransmitter at the neuromuscular junction and therefore is synthesized by all the motor neurons in the spinal cord and brain stem • ACh synthesis requires a specific enzyme, choline acetyltransferase (ChAT) • ChAT is manufactured in the soma and transported to the axon terminal like all presynaptic proteins • Only cholinergic neurons contain ChAT, therefore this enzyme is a good marker to identify cells that use ACh as it’s neurotransmitter • ChAT synthesizes ACh in the cytosol of the axon terminal, and the neurotransmitter is concentrated in synaptic vesicles by the actions of an ACh transporter o ChAT transfers an acetyl group from acetyl CoA to choline o Source of choline is the extracellular fluid, where it exists in low micromolar concentrations o Choline is taken up by the cholinergic axon terminals via specific transporter o Because the availability of choline limits how much ACh can be synthesized in the axon terminal, transport of choline into the neuron is said to be the rate-limiting step in ACh synthesis • Rate-limiting Step- in a biochemical reaction that leads to the production of a chemical, the one step that limits the rate of synthesis. • Cholinergic neurons also manufacture the ACh degradative enzyme acetylcholinesterase (AChE) o AChE is secreted into the synaptic cleft and is associated with cholinergic axon terminal membranes o AChE is also manufactured by some noncholinergic neurons, so this enzyme is not as useful a marker for cholinergic synapses as ChAT • AChE degrades ACh into choline and acetic acid o This happens very quickly because AChE has one of the fastest catalytic rates among all known enzymes • Inhibition of AChE prevents the breakdown of ACh, disrupting transmission at cholinergic synapses on skeletal muscle and heart muscle o Deaths from the irreversible inhibition of AChE is typically a result of respiratory paralysis Catecholaminergic Neurons • Amino acid tyrosine is the precursor for three different amine neurotransmitters that contain a chemical structure called a catechol • These neurotransmitters are called catecholamines o Catecholamine neurotransmitters are:  Dopamine (DA)  Norepinephrine (NE)  Epinephrine (Adrenaline) • Catecholaminergic neurons are found in regions of the nervous system involved in the regulation of movement, mood, attention, and visceral function • All catecholaminergic neurons contain the enzyme tyrosine hydroxylase (TH), which catalyzes the first step in catecholamine synthesis, the conversion of tyrosine to a comp
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