Neurotransmitters

Defining a Neurotransmitter Secreted factor from neurons Limited to a specific population Regulated synthesis, enzyme Produce a measurable effect Bind a specific, saturable receptor Release in response to stimulus from axon terminal Storage in vesicles Degradation and/or re-uptake

TRANSPORT AND UPTAKE INTO VESICLES SYNTHESIS RELEASE Life cycle of neurotransmitters DEGRADATION OR RE-UPTAKE POST-SYNAPTIC RECEPTORS

Neurotransmitters and Neuromodulators Acetylcholine: Neuromuscular junction

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Functions of Ach in the CNS Basal Forebrain: arousal and attention Learning and memory Alzheimer Disease Parabrachial nucleus: REM sleep Continue to fire during REM # cells correlate with REM sleep Reward and Addiction (striatum?) Pain and other sensory input

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Neurotransmitters and Neuromodulators Acetylcholine Botulinum toxin: An acetylcholine antagonist; prevents release by terminal buttons. Black widow spider venom A poison produced by the black widow spider that triggers the release of acetylcholine. Neostigmine: A drug that inhibits the activity of acetylcholinesterase. Hemicholinium: A drug that inhibits the uptake of choline.

Neurotransmitters and Neuromodulators Monoamines Catecholamines Dopamine (DA) Norepinephrine (NE) Epinephrine Indolamines Serotonin (5-HT)

Neurotransmitters and Neuromodulators Monoamines Dopamine: Produces both excitatory and inhibitory postsynaptic potentials. Implicated in movement, attention, learning, reinforcing effects of abused drugs. Synthesized from tyrosine that we obtain from our diet.

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Neurotransmitters and Neuromodulators Monoamines Dopamine Nigrostriatal system: A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen of the basal ganglia); appears to play a role in the control of movement. Parkinson’s Disease: A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system; Parkinson’s disease has been treated with L-DOPA.

Neurotransmitters and Neuromodulators Monoamines Dopamine Mesolimbic system: A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus; appears to play a role in the reinforcing effects of drugs that are commonly abused. Drug abuse/addiction

Neurotransmitters and Neuromodulators Monoamines Dopamine Mesocortical system: A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex; appears to influence formation of short-term memories, planning, and preparing strategies for problem solving. Schizophrenia

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Neurotransmitters and Neuromodulators Monoamines: Dopamine a-MT: (synthesis blocker) A drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines. Reserpine: (Vesicle blocker) A drug that interferes with the storage of monoamines in synaptic vesicles by blocking the VMAT2 vesicle transporter for DA, NE, and 5-HT.

Neurotransmitters and Neuromodulators Monoamines: Dopamine Apomorphine: (acts as agonist) A drug that blocks dopamine autoreceptors at low doses; at high doses binds postsynaptic receptors as well. Methylphenidate: (acts as agonist) A drug that inhibits the reuptake of dopamine; also known as “Ritalin”; used to treat children with attention deficit disorder.

Neurotransmitters and Neuromodulators Monoamines: Dopamine Termination of Signaling: Monoamine oxidase (MAO) A class of enzymes that destroy the monoamines; dopamine, norepinephrine, and serotonin. Deprenyl A drug that blocks the activity of MAO-B; acts as a dopamine agonist. Also used to treat Parkinson’s disease. Dopamine Transporter (DAT) Reuptake of DA into pre-synaptic terminal DA may be oxidized and damage other proteins if not imported into vesicles by the VMAT

Neurotransmitters and Neuromodulators Monoamines Norepinephrine (NE) Norepinephrine is synonymous with noradrenaline. Found in neurons of the brain and the autonomic nervous system. Almost every region of the brain receives input from noradrenergic neurons. Implicated to play central role in vigilance or attentiveness to events in the environment.

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Neurotransmitters and Neuromodulators Monoamines Norepinephrine (NE) Locus coeruleus: A dark-colored group of noradreneric cell bodies located in the pons near the rostral end of the floor of the fourth ventricle. Many NE neurons release NE non-synaptically, from axonal varicosities Greater diffusion, reach more targets

Firing Rate of LC neurons

Fusaric acid: A drug that inhibits the activity of the enzyme dopamine-ß-hydroxylase and thus blocks the production of norepinephrine. Allyn & Bacon 2004 Copyright © 2004 Allyn and Bacon

Neurotransmitters and Neuromodulators Monoamines Serotonin (5-HT) Serotonin: Serotonin is an indolamine neurotransmitter; also called 5-hydroxytryptamine (5-HT); thought to play a role in the regulation of mood, the control of eating, sleep, dreaming, and arousal; also thought to be involved in the regulation of pain.

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PCPA: A drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT. Allyn & Bacon 2004 Copyright © 2004 Allyn and Bacon

Neurotransmitters and Neuromodulators Monoamines Serotonin (5-HT) M system: A system of serotonergic neurons that originates in the median raphe nucleus; is a axonal fibers are thick and rounded and appear to form conventional synapses with other neurons. D system: A system of serotonergic neurons that originates in the dorsal raphe nucleus; its axonal fibers are thin, with spindle-shaped varicosities that do not appear to form synapses with other neurons.

Neurotransmitters and Neuromodulators Monoamines Serotonin (5-HT) 5-HT Transporter: Energy dependent re-uptake of 5-HT back into the pre-synaptic terminal. Fluoxetine (Prozac): A drug that inhibits the reuptake of 5-HT. Used as an anti-depressant, also to treat OCD and anxiety.

Serotonin Transporters Fenfluramine disrupts the proton gradient, blocks uptake of serotonin into vesicles, and also inhibits SERT uptake of 5-HT. Also makes SERT run in reverse—build up of 5-HT inside the cell favors export of 5-HT via SERT into the synapse. MDMA (ecstasy) has the same effects. Unregulated release is not good. Chronic inhibition of SERT (cocaine) causes its downregulation. SERT activity regulated by activity in both directions

Neurotransmitters and Neuromodulators Monoamines Serotonin (5-HT) Fenfluramine: A drug that stimulates the release of 5-HT and prevents its uptake; used as an appetite suppressant. LSD: Lysergic acid diethylamide This drug produces distortions of visual perceptions (hallucinations). A drug that stimulates 5-HT2a receptors. MDMA (ecstasy): NE and 5-HT agonist: excitatory and hallucinogenic effects Causes transporters to run backward (extrude neurotransmitter that is not secluded in vesicles)

Neurotransmitters and Neuromodulators Amino Acids The most common amino acid transmitters are: Glutamate Gamma-amino-butyric acid (GABA) Glycine

Neurotransmitters and Neuromodulators Amino Acids Glutamate Glutamate: An amino acid; the most important excitatory neurotransmitter in the brain. Synthesis: a-ketoglutarate glutamate TCA cycle intermediate

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Glutamate Role in Learning Allyn & Bacon 2004

A balance of excitation and inhibition Allyn & Bacon 2004

Neurotransmitters and Neuromodulators Amino Acids GABA: An amino acid; the most important inhibitory neurotransmitter in the brain and spinal cord. Biosynthesis: Glutamate GABA Allylglycine: A drug that inhibits the activity of GAD and thus blocks the synthesis of GABA. Glutamic acid Decarboxylase (GAD)

Neurotransmitters and Neuromodulators Amino Acids GABA Benzodiazepines: A category of anxiolytic drugs; an indirect agonist for the GABAA receptor. A class of ligands in its own right: agonists, antagonists, and inverse agonists exist for this site Anxiolytics (valium) Muscle relaxers Sleep aids (ambien)

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Neurotransmitters and Neuromodulators Peptides Neurons of the central nervous system release a large variety of peptides. A neuron manufactures both the polypeptides and the enzymes that it needs to break them apart. Synthesis takes place in the soma and they are delivered to the terminal buttons by axoplasmic transport. Further processing occurs in vesicles. Most peptides appear to serve as neuromodulators, some act as neurotransmitter.

Neurotransmitters and Neuromodulators Peptides: Opioids Endogenous opioid: A class of peptides secreted by the brain that act as opiates; drugs that affect opioid receptors reduce pain. “runner’s high” Three types of opiate receptors:  Naloxone: A drug that blocks opioid receptors. Given to reverse overdose of heroin.

Neurotransmitters and Neuromodulators Peptides: Opioids Role of endogenous opioids Analgesia: Activation of opiate receptors by endogenous or synthetic opiates causes reduction in pain sensitivity. Inhibition of species typical behaviors such as fleeing and hiding. Reward and reinforcement, both of species specific behaviors (mating and maternal care) and of drugs of abuse.

Neurotransmitters and Neuromodulators Lipids Cannabinoid: A lipid; an endogneous ligand for receptors that bind with THC, the active ingredient in marijuana. Anandamide: Produced and released on demand, not stored in vesicles. Inhibit function of 5-HT3 receptors, prevent vomiting. THC can be used to control nausea and vomiting in patients receiving chemotherapy and radiation. Very effective in children.

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Anandamide may regulate both glutamate and GABA release Anandamide may regulate both glutamate and GABA release. Produced on demand, not stored. Typically act retrograde. Important for LTD at GABA synapses in HPC and amygdala, and at glutamate synapses in striatum and NAc. May underlie memory deficits associated with marijuana use. Extensive similarity and cross talk between opiate and CB receptors, important for addiction and cross priming.

Neurotransmitters and Neuromodulators Nucleosides Adenosine: A nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain. Released by neurons and glia in response to low oxygen or glucose, activity dependent release. Causes vasodilation, which helps restore nutrient balance. Generally inhibitory—build up of adenosine is a precursor to sleep.

Neurotransmitters and Neuromodulators Nucleosides Caffeine: Blocks adenosine receptors Dis-inhibition leads to excitement Repeated administration causes tolerance, but not addiction (not positively reinforced)

Neurotransmitters and Neuromodulators Soluble Gases Nitric oxide (NO): A gas produced by cells in the nervous system; used as a means of communication between cells. Especially important for blood vessel dilation and some aspects of learning and memory storage. Nitric oxide synthase: The enzyme responsible for production of nitric oxide. Occurs in several cell-specific isoforms. nNOS, iNOS, eNOS

Slide 13 “good” vs “bad” wrt agonists and antagonists Allyn & Bacon 2004