Chapter 4: Psychopharmacology and Neurotransmitters PDF

Chapter 4 Psychopharmacology and Neurotransmitters Principles of Psychopharmacology An Overview of Psychopharmacology Pharmacokinetics Drug Effectiveness Effects of Repeated Administration Placebo Effects Copyright © 2021, 2017, 2013 Pearson Education, Inc. All...

Chapter 4 Psychopharmacology and Neurotransmitters Principles of Psychopharmacology An Overview of Psychopharmacology Pharmacokinetics Drug Effectiveness Effects of Repeated Administration Placebo Effects Copyright © 2021, 2017, 2013 Pearson Education, Inc. All Rights Reserved Psychopharmacology is a subdiscipline in the field of pharmacology. Psychopharmacologists study drugs that affect the nervous system and behavior in two broad classes: therapeutic drugs and drugs of abuse. An Overview of Psychopharmacology Psychopharmacology Two major aspects of The study of the effects of drug influence: drugs on the nervous system Drug Effects and behavior Sites of Action Drug An exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses Psychoactive Drug chemicals that alter the functions of cells in the nervous system 1. Drug Effects the changes we can observe in an individual’s physiological processes and behavior Opiates decreased sensitivity to pain slowed digestion sedation muscular relaxation pupil constriction euphoria (at high doses) 2. Sites of Action the locations where drug molecules bind with molecules located on or in cells of the body, to affect some biochemical processes of these cells Opiates’ SoA Specialized receptors in the membrane of some neurons attach ➔ activate ➔ alter the activity of these neurons and produce their effects Pharmacokinetics (PK) Life Cycle of a Drug Molecule The steps by which drugs are… (1) absorbed (2) distributed within the body (3) metabolized (4) excreted  What are the ways we can take Cocaine? (and other drugs) Part 1: Sharp Syringe directly into a large muscle, such as those found in the upper arm, thigh, or buttocks. The drug is absorbed into the bloodstream through the capillaries that supply the muscle Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe inject a very small amount directly into the brain Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe injected beneath the skin (in the fatty tissue past the dermis) Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe get past the blood–brain barrier by injecting the drug into a cerebral ventricle Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe most commonly used in administering drugs to small laboratory animals (rats and mice) Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe Insulin & MMR Vaccine are administered this way Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe used very rarely in humans—primarily to deliver antibiotics directly to the brain to treat certain types of infections. Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe drug is dissolved or suspended in a liquid and injected through a hypodermic needle into a vein Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe drug is injected through the abdominal wall into the space that surrounds the stomach, intestines, liver, and other abdominal organs Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration Part 1: Sharp Syringe fastest route: absorbed and widely distributed immediately. can reach the brain within a few seconds Intravenous (IV) injection Intraperitoneal (IP) injection Intramuscular (IM) injection Subcutaneous (SC) injection Intracerebral (IC) administration Intracerebroventricular (ICV) administration  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration general anesthetics Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration will reach reach SoA slowly: absorbed into the blood through the digestive tract Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration placing a drug beneath the tongue Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration drug’s route is through touching the mucous membrane lining the passages of your nose Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration nicotine patches Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration cannot be used for drugs that are easily destroyed by digestive enzymes Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration nicotine, freebase cocaine, and psychoactive compounds in marijuana Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration faster onset of therapeutic effects (compared to oral administration) and less risk of irritating the stomach Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration “insufflation” Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration undergoes first-pass metabolism in the liver, reducing the number of active drug molecules available to produce an effect in the rest of the body Part 2: Other Body Parts  👄 Oral administration 👅 Sublingual administration 🫁 Inhalation 💪 Topical administration 👃 Intranasal administration absorbed into the bloodstream through the capillaries that supply the mucous membrane that lines the mouth Part 2: Other Body Parts  Cocaine in Blood Plasma The graph shows the concentration of cocaine in blood plasma after intravenous injection, inhalation, oral administration, and sniffing. Source: Adapted from Feldman, R. S., Meyer, J. S., and Quenzer, L. F. (1997). Principles of neuropsychopharmacology. Sunderland, MA: Sinauer Associates; after Jones, R. T. (1990.) NIDA Research Monographs, 99, 30–41. Pharmacokinetics | 2. Distribution Entry of Drugs into the Brain by blood in the circulatory system, including the central nervous system (CNS) Most important factor in determining the rate is lipid solubility (the ability of fat-based molecules to pass through cell membranes) Molecules soluble in lipids pass through the cells that line the capillaries in the CNS, and they rapidly distribute themselves throughout the brain Pharmacokinetics | 3. Metabolism Many drugs are metabolized and deactivated by enzymes Mostly located in the liver Some in blood & brain Enzymes sometimes transform molecules into more active versions Pharmacokinetics | 3. Metabolism Pharmacokinetics 4. Excretion All drugs are eventually excreted (removed from the body) Mostly by kidneys Drug Effectiveness (1 of 2) Wide variance in effectiveness Small dose of an effective drug > large dose of a less effective drug Dose-response curve locates point of maximum effect Opiates (and most drugs) have more than one effect: Analgesic Depress heart rate and respiration  Dose-Response Curves for Morphine The dose-response curve on the left shows the analgesic effect of morphine, and the curve on the right shows one of the drug’s adverse side effects: its depressant effect on respiration. A drug’s margin of safety is reflected by the difference between the dose-response curve for its therapeutic effects and that for its adverse side effects. Drug Effectiveness Therapeutic index measures drug’s margin of safety Ratio of 2 numbers: the dose that produces the desired effects in 50% of the individuals the dose that produces toxic effects in 50% of the individuals ⏬ number = more risky Barbiturates: 2 or 3 Valium: 100+ 👍 2 Reasons for Variability in Drug Effectiveness 1. Different Sites of Action Pre/postsynaptic receptors Transporter molecule Enzymes involved in production or deactivation of neurotransmitters ✨Both have analgesic effects✨ suppresses the reduces production of activity of neurons a chemical involved in the spinal cord in transmitting and brain that are information from involved in pain damaged tissue to perception pain-sensitive neuron 2 Reasons for Variability in Drug Effectiveness 2. Affinity of Drug with its SoA affinity: the readiness with which two molecules join together Drugs vary widely: ⏫ high affinity drug: produce effects at a relatively low concentration ⏬ low affinity drug: must be administered in higher doses to produce the same effect A drug can also have high affinity for some SoA and lower for others same SoA can have different effectiveness because they have different affinities Drug Effectiveness Most desirable drug has high affinity for sites of action producing therapeutic effects and low affinity for sites of action producing toxic side effects Effects of Repeated Administration Types of Effects 1. Tolerance the result of the body’s attempt to Decrease in drug compensate for the effects of the drug effectiveness when Most body systems are regulated so administered repeatedly that they stay at or near an optimal must take larger and value larger amounts of the When drug effects alter the systems drug for it to be for a prolonged time, compensatory effective! mechanisms begin to produce the Seen in many drugs opposite reaction commonly abused (ex: when the person stops taking the heroin) drug, the compensatory mechanisms make themselves felt as withdrawal symptoms, unopposed by the action of the drug Demonstration: Drug of War Effects of Repeated Administration Compensatory Mechanisms with repeated use 1. Decrease in effectiveness of binding with receptors receptors become less sensitive to the drug and affinity for drug decreases or receptors decrease in number (receptor downregulation) 2. The coupling process becomes less effective Receptors + Ion channels Production of second messenger is affected Effects of Repeated Administration 2. Sensitization the opposite of tolerance, but less common Drug becomes more and more “effective” the more it is administered sensitization may develop for some drug effects then tolerance for others may develop for only some effects : repeated injections of cocaine produces more movement disorders and seizures, but euphoric effects do not show sensitization and may even show tolerance Effects of Repeated Administration 3. Withdrawal Symptoms occur if individual stops taking the drug; similar to mechanisms for tolerance Indicates physical dependence ➔ contributes to compulsive drug taking and substance abuse heroin produces euphoria ➔ withdrawal from it produces dysphoria —a feeling of anxious misery. Heroin: relaxation ➔ withdrawal: agitation Effects of Repeated Administration Placebo Effects Placebo is an inactive substance that may have physiological or psychological effects contain no active drug molecules (incorrect to say that they have no effect) Results from changes in motivation, expectation, or learning Helps investigate behavioral effects of drugs in humans Also used in studies with lab animals administering a drug to an animal causes distress, activates autonomic nervous system, causing the secretion of stress hormones or other physiological effects Placebo studies for new drugs are required by the FDA to determine if drug has significant behavioral effects above and beyond the effects of administering and receiving an inactive substance Homework: Continue Reading Chapter 4 Learning Check #6 Oct 1, Tuesday (after our lecture discussion) Chapter 4 To be continued… Sites of Drug Action Effects on Production of Neurotransmitters Effects on Storage and Release of Neurotransmitters Effects on Receptors Effects on Reuptake and Deactivation of Neurotransmitters Copyright © 2021, 2017, 2013 Pearson Education, Inc. All Rights Reserved Synaptic Transmission: A Timeline 1. Go to our Class Links in Notion 2. Click Synaptic Transmission: A Timeline and duplicate the page as template 3. Work in pairs or trios and move the rows around according to when they happen in synaptic transmission relative to each other  Timeline: Answer Key 1. Neurotransmitters are synthesized 10. Autoreceptors on the terminal buttons are stimulated 2. Vesicle transporters fill synaptic vesicles with neurotransmitters 11. Autoreceptors regulate the synthesis and release of the 3. Synaptic vesicles travel to the neurotransmitter presynaptic membrane 12. Molecules of the neurotransmitter 4. Synaptic vesicles dock in the bind with postsynaptic receptors presynaptic membrane 13. Ion channels in the postsynaptic 5. The Axon fires neuron are opened 6. Voltage-dependent calcium channels 14. Excitatory or inhibitory postsynaptic in the presynaptic membrane open potentials are produced 7. Calcium ions enter the terminal 15. Neurotransmitters undergo reuptake button by terminal membrane transporter 8. Calcium ions interact with the docking molecules proteins 16. Neurotransmitters are deactivated 9. Neurotransmitters are released into by enzymes the synaptic cleft  Most drugs affecting behavior affect synaptic transmission Agonist drugs facilitate postsynaptic effects Antagonists block or inhibit postsynaptic effects Agonists Antagonists  GOng Team A pA NTs Team 1. The class divides into two groups: 2. Open the “It’s Super Effective!” Page in our Notion Class Links 3. Open the deck for your team 4. Play the correct card for each Site of Action 5. The other team scores a point if you misplay A. Effects on Production of Neurotransmitters 1. Neurotransmitters are synthesized Effects on Storage and Release of Neurotransmitters 2. Vesicle transporters fill synaptic vesicles with neurotransmitters Effects on Storage and Release of Neurotransmitters 9. Neurotransmitters are released into the synaptic cleft Effects on Storage and Release of Neurotransmitters Some drugs act as Some drugs act as agonists by binding with antagonists by preventing proteins and triggering release of release of neurotransmitters neurotransmitters from the terminal button  Effects on Storage and Release of Neurotransmitters binding with a particular site on the transporter. synaptic vesicles remain empty ➔ nothing is released when the bind with fusing vesicles eventually proteins directly release their contents triggering the release into the synapse. of the neurotransmitter deactivates the proteins that cause docked synaptic vesicles to fuse with the presynaptic membrane, preventing the release of neurotransmitters from the terminal button  Effects on Receptors 10. Autoreceptors on the terminal buttons are stimulated 11. Autoreceptors regulate the synthesis and release of the neurotransmitter  Effects on Receptors 12. Molecules of the neurotransmitter bind with postsynaptic receptors Effects on Receptors Most important and complex site of action in drugs in the nervous system is on receptors Direct agonist Receptor blocker (direct Binds with and activates a receptor antagonist) Ex: nicotine Binds with postsynaptic receptors but does not open the ion channel or trigger intracellular events Ex: chlorpromazine Effects on Receptors Noncompetitive binding Molecules of the neurotransmitter bind with one site, and other substances bind with the others Indirect agonist Indirect antagonist Ex: Diazepam (Valium) Ex: PCP & Ketamine  Effects on Reuptake and Deactivation of Neurotransmitters 15. Neurotransmitters undergo reuptake by terminal membrane transporter molecules 16. Neurotransmitters are deactivated by enzymes Effects on Reuptake and Deactivation of Neurotransmitters Two processes result in termination of the postsynaptic potential: Molecules of neurotransmitter are taken back into terminal button through process of reuptake Molecules are deactivated by an enzyme Drug Effects on Synaptic Transmission Blue boxes represent agonist (AGO) effects of drugs. Red boxes represent antagonist (ANT) effects of drugs. Examples of drugs in each category are included in the boxes, along with the neurotransmitter system(s) they act on. ACh = Acetylcholine AChE = Acetylcholinesterase (enzyme for ACh deactivation) NT=Neurotransmitter Neurotransmitters and Neuromodulators Amino Acids Acetylcholine (ACh) The Monoamines Peptides Lipids Copyright © 2021, 2017, 2013 Pearson Education, Inc. All Rights Reserved Glutamate GABA Kinds of Neurotransmitters Amino acid neurotransmitters in the brain: Excitatory balance of excitatory and inhibitory effects Glutamate account for most activity of local neuron Inhibitory circuits and between-brain information transmission Gamma-aminobutyric acid, or GABA In the spinal cord and lower brain stem: Secondary Inhibitory NT Glycine Neurotransmitter Systems Amino Acids at least eight amino acids may serve as neurotransmitters in the mammalian CNS! 1. Glutamate Main excitatory neurotransmitter in brain and spinal cord For memory, learning, neural communication Glutaminase (an enzyme) synthesizes Glutamate from its precursor, Glutamine Stored in vesicles by Vesicle Glutamate Transporters released from presynaptic neuron following an action potential 4 Types of Glutamate Receptors Ionotropic: 1. NMDA Receptor 2. AMPA Receptor 3. Kainate Receptor Metabotropic: 4. Metabotropic Glutamate Receptor NMDA Receptor both a voltage- and neurotransmitter-dependent ion channel Has 6+ binding sites! 4 exterior 2 deep within ✓Glutamate ✓Glycine ✓Magnesium must not be attached ✓PCP and Ketamine must not block NMDA Receptor Antagonists Drug AP5 blocks glutamate Alcohol: sudden alcohol binding site withdrawal can cause Impairs certain forms of seizures learning AMPA Receptor Agonist: AMPA most common glutamate receptor play important roles in cellular basis of learning and memory (Synaptic Plasticity) controls a sodium channel so when glutamate attaches, produces EPSPs Fast synaptic transmission! Kainate Receptor has similar Co-localized! effects as AMPA Receptor Glutamate Reuptake & Deactivation transported into presynaptic Deactivated by the cell by excitatory amino enzyme glutamine acid transporters (EAATs!) synthase Glutamate Excitotoxicity: failure to remove glutamate from synapse ➔ prolonged overexcitation will damage neurons Glutamate Release Inhibitor Riluzole (Rilutek) used in ALS treatment reduces glutamate signaling by reducing glutamate vesicle docking with the presynaptic terminal membrane.  Review: Ionic Movements During Postsynaptic Potentials 2nd Amino Acid NT: GABA Inhibitory neurotransmitter with packaged into vesicles widespread distribution in brain by the vesicle GABA and spinal cord transporter produced from a precursor (glutamic acid) by the action of an enzyme (glutamic acid decarboxylase, or GAD) GABA-secreting Neurons present in large numbers in the brain inhibitory influence is essential to help keep brain stable poorly functioning GABA-secreting neurons or receptors ➔ Seizures GABA Receptors GABAA Receptor Most important receptor for behavior Ionotropic controls Chloride channels Has 5+ binding sites GABA Binding Site is the primary site Agonist: Antagonist: Muscimol Bicuculline Hyperpolarizing (inhibitory) GABA Receptors: Binding Sites Benzodiazepine Site binds with class of drugs benzodiazepines Anxiolytics: Valium & Xanax Sleep Medications: Ambien and Lunesta Barbiturates Binding Site older class of sedative and antianxiety drugs with narrow therapeutic index (2-3) Steroid-binding Site Unknown Site: Alcohol GABA: Reuptake and Deactivation GABA Transporter Removed from the synapse Tiagabine (Gabitril) GABA transporter antagonist used to increase availability of GABA and reduce the likelihood of seizures GABA aminotransferase enzyme that deactivates GABA Vigabatrin (Sabril) blocks the activity of GABA amino-transferase to increase the amount of GABA available in the synapse used for seizure and epilepsy treatment  Table 4.1 Neurotransmitter Systems (1 of 2) Neurotransmitter Examples of CNS Functions Examples of PNS Functions Glutamate Excitatory; interacts with other N/A neurotransmitter systems N/A GABA Inhibitory, interacts with other N/A neurotransmitter systems Acetylcholine Learning, memory, REM Regulates muscle sleep contraction Dopamine Voluntary movement, N/A attention, learning, reinforcement, planning, problem solving Table 4.1 Neurotransmitter Systems (2 of 2) Neurotransmitter Examples of CNS Examples of PNS Functions Functions Norepinephrine/ Vigilance Autonomic nervous system Epinephrine regulation (regulate heart rate, blood pressure etc.) Serotonin Mood regulation, Involved in the enteric nervous eating, sleep, system (digestive tract) dreaming, arousal, impulse control Histamine Wakefulness Immune response Opioids Reinforcement, pain Pain modulation modulation Endocannabinoids Appetite regulation Immune response Acetylcholine (ACh) the first neurotransmitter to be discovered! Found outside the CNS in locations that are easy to study functions in both CNS & PNS In CNS, found in specific In PNS, it’s the primary locations and pathways neurotransmitter to control Dorsolateral Pons muscle contraction (REM sleep) Basal Forebrain or motor neurons release ACh to signal muscle cells nucleus basalis (facilitate learning) Medial Septum (memory formation) Acetylcholinergic Pathways in Rat Brain This schematic figure shows the locations of the most important groups of acetylcholinergic neurons and the distribution of their axons and terminal buttons. Figure 4.12 Synthesis of Acetylcholine Acetylcholine (ACh) Receptors Ionotropic Receptor Metabotropic Receptor aka nicotinic receptor aka muscarinic receptor stimulated by nicotine stimulated by muscarine (reinforcing effect) (found in the mushroom rapid-acting, excitatory Amanita muscaria) found in muscle fibers in actions are slower and the PNS & axoaxonic more prolonged synapses in brain A lot in the CNS Antagonist: Atropine Acetylcholine (ACh) Reuptake and Deactivation Deactivated by the enzyme acetylcholinesterase (AChE), present in the postsynaptic membrane AChE inhibitors used to treat myasthenia gravis Neostigmine: ACh that is released will have a more prolonged effect on the remaining receptors Hemicholinium-3: research drug that blocks the choline transporter, reducing ACh production The Monoamines Produced by several systems of neurons in the brain Modulate functions of widespread regions of brain, either increasing or decreasing brain functions Table 4.4 Classification of the Monoamine Neurotransmitters Catecholamines Indolamine Ethylamine Dopamine Serotonin Histamine Norepinephrine Epinephrine similar molecular structures → some drugs affect the activity of all of the systems to some degree Along with ACh, belong to “Classical” Neurotransmitters a family of relatively small molecules (compared to Peptide neurotransmitters) The Monoamines: Dopamine Produces both excitatory and inhibitory postsynaptic potentials, depending on the postsynaptic receptor Affects movement, attention, learning, and reinforcing effects of drugs The Monoamines: Dopamine Three most important dopamine pathways originate in midbrain structures 1. Nigrostriatal system 2. Mesolimbic system 3. Mesocortical system Degeneration of dopaminergic neurons that connect the substantia nigra with the caudate nucleus causes Parkinson’s Disease Figure 4.14 Dopaminergic Pathways in a Rat Brain This schematic figure shows the locations of the most important groups of dopaminergic neurons and the distribution of their axons and terminal buttons. Source: Adapted from Fuxe, K., Agnati, L. F., Kalia, M., et al. (1985). Dopaminergic systems in the brain and pituitary. In E. Fluckinger, E. E. Muller, and M. O. Thomas (Eds.), Basic and clinical aspects of neuroscience: The dopaminergic system. Berlin: Springer–Verlag. 1. Nigrostriatal System 2. Mesolymbic System 3. Mesocortical System The Three Major Dopaminergic Pathways Name Origin Location of terminal Behavioral effects (location of buttons cell bodies) Nigrostriatal Substantia Neostriatum Control of movement system nigra (caudate nucleus and putamen) Mesolimbic Ventral Nucleus accumbens, Reinforcement system tegmental amygdala, and (reward) area hippocampus Mesocortical Ventral Prefrontal cortex Short-term system tegmental memories, planning, area strategies for problem solving Synthesis of the Catecholamines Dopamine: Production, Storage, and Release Producing catecholamines (dopamine & norepinephrine) requires several enzymatic steps Precursor is tyrosine, essential amino acid obtained from diet People with Parkinson’s disease are often given the drug L-DOPA, which can cross blood–brain barrier for conversion to dopamine Dopamine Receptors Metabotropic types of receptors D1, D2, D3, D4, and D5 chlorpromazine blocks D2 receptors and alleviate hallucinations in schizophrenia Effects of Low and High Doses of Apomorphine a D2 agonist has a greater affinity for presynaptic D2 receptors than for postsynaptic D2 receptors At low doses, apomorphine serves as a dopamine antagonist. At high doses, it serves as an agonist. Dopamine: Reuptake Dopamine transporters remove dopamine from the synapse Several drugs serve as dopamine agonists: Block Dopamine Reuptake Block Dopamine Reuptake + cocaine Transporters run in reverse methylphenidate (Ritalin) amphetamine methamphetamine Dopamine: Deactivation Deactivation of catecholamines is regulated by an enzyme called monoamine oxidase (MAO) deprenyl: inhibits the particular form of monoamine oxidase (MAO-B) found in dopaminergic terminal buttons prevents the deactivation of dopamine, more dopamine is available in the terminal buttons serves as a dopamine agonist used to treat the symptoms of Parkinson’s disease Chapter 4 To be continued…  Review Glutamate GABA Acetylcholine Catecholamines Indolamine Ethylamine Dopamine Serotonin Histamine Norepinephrine Epinephrine Peptides Lipids Pathway Function Production, Storage, and Release Receptors Agonist & Antagonist Drugs Reuptake and Deactivation Norepinephrine (NE) noradrenaline = norepinephrine adrenaline = epinephrine Pathways: found in both the CNS and PNS act as hormones in the PNS Almost every region of the brain receives input from noradrenergic neurons Primary effect of activation is an increase in vigilance: attentiveness to events in the environment Figure 4.18 Noradrenergic Pathways in a Rat Brain This schematic figure shows the locations of the most important groups of noradrenergic neurons and the distribution of their axons and terminal buttons. Source: Adapted from Cotman, C. W., and McGaugh, J. L. (1980.) Behavioral neuroscience: An introduction. New York: Academic Press. Norepinephrine Production and Storage Synthesized from dopamine by the enzyme dopamine β-hydroxylase occurs in vesicles themselves Norepinephrine Release through axonal varicosities Norepinephrine Receptors 4 types that are sensitive to both norepinephrine and epinephrine blocks the adrenergic All metabotropic autoreceptor produces symptoms Agonist at the Found in neurons in CNS and of anxiety norepinephrine increases heart rate autoreceptor various organs of body and blood pressure Reduces heart rate and blood pressure Norepinephrine Reuptake and Deactivation Norepinephrine transporter removes excess norepinephrine from the synapse Excess norepinephrine in the terminal buttons is deactivated by monoamine oxidase, type A Some MAOIs are used to treat depression, but have side effects newer drugs such as selective serotonin, norepinephrine, and dopamine reuptake inhibitors have replaced them Serotonin AKA 5-HT, or 5- hydroxytryptamine plays role in regulation of mood; control of eating, sleep, dreaming, arousal; and pain regulation Serotonin Pathways Found in nine clusters, most located in the raphe nuclei of the midbrain, pons, and medulla Released from varicosities, like norepinephrine Serotonergic Pathways in a Rat Brain Serotonin Production Serotonin Receptors At least 9 different types of serotonin receptors All Metabotropic except for Ionotropic 5-HT3 controls chloride channel, produces inhibitory postsynaptic potential play a role in nausea and vomiting a 5-HT3 antagonist reduces nausea side effects of chemotherapy and radiation for the treatment of cancer Serotonin Reuptake and Deactivation Serotonin transporter removes 5-HT from the synapse  Serotonin: Drugs Drugs that inhibit uptake of serotonin play important role in treatment of mental illness Fluoxetine (Prozac) used to MDMA (ecstasy) has treat depression, some types excitatory and hallucinogenic of anxiety disorders, and effects. It can selectively obsessive-compulsive disorder damage serotonergic neurons and cause some cognitive deficits. Histamine Pathways Found in only one place in the plays important role in brain: the tuberomammillary wakefulness nucleus, located in the posterior hypothalamus Histamine Production & Storage Produced from the amino acid precursor histidine by the action of the enzyme histidine decarboxylase Stored in vesicles and released following an action potential Histamine Receptors CNS contains H1, H2, H3, and H4 receptors Antihistamines act as antagonists at histamine receptors Block role in wakefulness ➜ produce drowsiness diphenhydramine New antihistamines don’t cross the BBB so there are no direct effects on the brain Peptides: Production, Storage, and Release Peptides are two or more amino acids linked by peptide bonds Produced from precursor molecules large polypeptides broken into smaller neurotransmitter molecules by special enzymes Peptides are released from all parts of terminal button No mechanism for reuptake and recycling, just deactivated Peptides: Receptors Opiate drugs used for Several neural systems centuries, but receptors not activated when opioid discovered until 1970s receptors are stimulated Natural ligands for Analgesia receptors called Inhibition of defensive enkephalins responses such as (endogenous opioid) fleeing and hiding 3 Different Types of Reinforcement (can Opioid Receptors lead to opioid abuse) µ (mu) δ (delta) Κ (kappa) Naloxone—used clinically to reverse overdose Lipids Substances derived from lipids can transmit messages within or between cells endocannabinoids: responsible for effects of THC (active ingredient in marijuana) Lipid neurotransmitters appear to be synthesized on demand, produced or released as needed Not stored in synaptic vesicles (since it’s lipid soluble, it would integrate into the membrane)