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Chapter 4

Chapter 4 Textbook Notes - Psychopharmacology

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Ayesha Khan

Notes From Reading CHAPTER 4:P SYCHOPHARMACOLOGY (P GS.94-123) Introduction - Ronald Siegal (1989) has suggested that early humans learned to identify drugs by observing the reactions to various plants by their animals - Most psychoactive substances produce their behavioural effects by interacting with the existing chemistry of the nervous system LO1: Differentiate among neurotransmitters, neuromodulators, and neurohormones Neurotransmitters, Neuromodulators, and Neurohormones - Neurotransmitter – A chemical messenger that communicates across a synapse - Neuromodulator – A chemical messenger that communicates with target cells more distant than the synapse by diffusing away from the point of release - Neurohormone – A chemical messenger that communicates with target cells at great distance, often by travelling through the circulation o Often travel in the blood supply to reach their final targets LO2: Summarize the major criteria for identifying a substance as a neurotransmitter Identifying Neurotransmitters - Neurotransmitters are substances released by one cell at a synapse that produce a reaction in a target cell - Neuroscientists generally agree with the following additional criteria: o A neurotransmitters must be synthesized within the neuron o In response to the arrival of an action potential, the substance is released in sufficient quantities to produce an effect on the postsynaptic cell o We should be able to duplicate the action of a suspected neurotransmitter experimentally on a postysynaptic cell o Some mechanism exists that ends the interaction between the neurotransmitter and the postysynaptic cell Types of Neurotransmitters - Major neurotransmitters fall into two classes: - Small-Molecule Transmitters – One of a group of chemical messengers that includes amino acids and amines o Can be further divided into amino acids and amines o Amino Acids – An essential component of proteins - Neuropeptide – A peptide that acts as a neurotransmitters, a neuromodulator, or a neurohormone o Basically chains of amino acids - Table 4.1: Features of Small-Molecule Transmitters and Neuropeptides Small-Molecule Transmitters Neuropeptides Synthesis In axon terminal In cell body; requires transport Recycling of Vesicles Yes No Activation Moderation action potential High action potential frequency frequency Deactivation Reuptake or enzymatic degradation Diffusion away from the synapse Function Fast neurotransmission Neuromodulation LO3: Identify the major locations, functions, synthesis pathways, receptor characteristics, and process of deactivation for actylcholine, dopamine, norepinephrine, epinephrine, serotonin, glutamate, GABA, and adenosine triphosphate LO4: Identiy the major differences among small-molecule, neuropeptide, and gaseous neurotransmitters The Small-Molecule Transmitter - Acetylcholine, five monoamines, several amino acids, and the energy molecule adenosine triphosphate (ATP) and its byproducts Notes From Reading CHAPTER 4:P SYCHOPHARMACOLOGY (P GS.94-123) o Meet all or most of the preceding criteria specified for neurotransmitters and play a vital role in neurotransmission - Acetylcholine (ACh) – A major small-molecule neurotransmitter used at the neuromuscular junction, in the ANS and CNS o Neurons that use Ach as their major neurotransmitter are referred to as cholinergic neurons o Cholingeric neuron obtains the building block choline from dietary fats o A second building block, acetyl coenzyme A (acteyl CoA), results from the metabolic activities of mitochondria (abundantly present in most cells) o The enzyme choline acetyltransferase (ChAT) acts on these two building blocks, or precursors to produce the neurotransmitter acetylcholine o Presence o the enzyme ChAT provides a useful marker for identifying cholinergic neurons because ChAT is found only in neurons that produce Ach - Acetylcholinesterase (AChE) – An enzyme that breaks down the neurotransmitter acetylcholine o AChE is released into the synaptic gap, where it breaks down any Ach in that location o The choline resulting from the breakdown of Ach can then be recaptured by the presynaptic neuron and resynthesized into more Ach o ACh is the primary neurotransmitter at the neuromuscular junction, the synapse between a neuron and a muscle fiber (also essential to the operation of ANS) o Importance in the PNS, cholinergic neurons are widely distributed in the brain – basal forebrain, septum, and brainstem project to the neocortex, hippocampus, and amygdala - Many subtypes of cholinergic receptors are found in the nervous system o Nicotinic Receptor – A postsynaptic receptor that responds to nicotine and ACh o Muscarinic Receptor – A postsynaptic receptor that responds to both ACh and muscarine o Nicotinic and muscarinic receptors differ in their mechanisms of action and lcoations within the nervous system o Nicotinic receptors are fast ionotropic receptors whereas muscarinic receptors are slower metabotropic receptors o Nicotinic receptors are found at the neuromuscular junction, which is logical given the need for speed in muscular responses o Both types are receptors are found in the CNS and ANS - Monoamine – One of a major group of biogenic amine neurotransmitters including dopamine, norespinephrine, epinephrine and serotonin o The five monoamines are further divided into two subgroups: o Catecholamines – A member of a group of related biogenic amines that includes dopamine, epinephrine, and norepinephrine o Indoleamines – One of a subgroup of monoamines including serotonin and melatonin o All monoamines are subject to reuptake from the synaptic gap following release o Within the axon terminal, monoamines that are not encased in vesicles are broken down by the action of monoamine oxidase (MAO) - Catecholamine synthesis begins with the amino acid tyrosine o All neurons containing a catecholamine also contain the enzyme tyrosine hydroxylase (TH) o When TH acts on tyrosine, the end produce is L-dopa – A substance produced during the synthesis of catecholamines that is also administered as a treatment for Parkinson’s disease o The production of dopamine requires one step following the synthesis of L-dopa  A major monoamine and catecholamine neurotransmitter implicated in motor control, reward, and psychosis o The enzyme dopa decarboxylase acts on L-dopa to produce dopamine o Dopamine is converted to norepinephrine by the action of the enzyme dopamine β- hydroxylase (DBH)  A major monoamaine and catecholamine neurotransmitter o This last step takes place within the synaptic vesicles Notes From Reading CHAPTER 4:PSYCHOPHARMACOLOGY (PGS .94-123) o The catecholamine epinephrine is produced by the reaction between norepinephrine and the enzyme phenylethanolamine N-methyltransferase (PNMT)  One of the monoamine/catecholamine neurotransmitters; aka adrenaline o PNMT exists in the intracellular fluid of the axon terminal of neurons that use epinephrine o Once the norepinephrine is synthesized within synaptic vesicles, it must be released back into the intracellular fluid, where it is concerted by PNMT into epinephrine which is transported back into vesicles - Dopamine is widely distributed throughout the brain and is particularly involved ith systems mediating movement, reinforcement and planning o Projections from the substantia nigra of the midbrain to the basal ganglia of the cerebral hemispheres provide an important modulation of motor activity o The mesolimbic system (involved in feeling reward and addiction) arises in the ventral tegmentum of the midbrain and projects to various parts of the limbic system, incl. the hippocampus, the amygdala and the nucleus accumbens o Another group of dopaminergic neurons in the ventrl tegmentum projects to parts of the frontal lobe of the cerebral cortex (participate in higher-level cognitive functions, including the planning of behaviour) - Multiple receptor subtypes also exist for dopamine, labeled D1 through D5 (in order of their discovery) o All of these receptors are of the slow metabotropic variety o D2 receptors (and prob D3 and D4 receptors) serve as both postysynaptic receptors and presynaptic autoreceptors o The D2 receptor class has been implicated in both reward and psychotic behaviour - Epinephrine and norepinephrine were formerly referred to as adrenalin and noradrenalin, respectively o Epinephrine plays a limited role as a CNS neurotransmitter o The “adrenalin rush” we associate with stress actually results from the release of epinephrine from the adrenal glands located above the kidneys in the lower back into the blood supply o Neurons that secrete norepinephrine are found in the pons, medulla, and hypothalamus o The most significant source of norepinephrine is the locus coeruleus of the pons o Projections from the locus coeruleus go to the spinal cord and nearly every major part of the brain o In the PNS, norepinephrine is found at the postganglionic synapses of the SNS (involved in arousal) - There are at least four receptor types that respond to either norepinephrine or epinephrine o Found in both the CNS and target organs that respond to SNS activity and neurohormones o All these receptors are metabotropic - Indoleamins are similar enough in chemical structure to the catecholamines to share the umbrella term of monoamine yet are different enough to warrant their own subheading o Includes melatonin and serotonin – A major monoamine and indoleamine neurotransmitter believed to participate in the regulation of mood, sleep and appetite - The synthesis of serotonin begins with the amino acid tryptophan, which is obtained from dietary sources to convert tryptophan into serotonin o Most of these neurons are located in the raphe nuclei of the brainstem o Their projections travel to the spinal cord, the cerebellum, the limbic system and the neocortex - After acetylcholine and the monoamines, the next category of small-molecule transmitters is the amino acid neurotransmitters o Glutamate – A major excitatory amino acid neurotransmitter  Among the 20 basic amino acids that are used to build other proteins o Gamma-Aminobutyric Acid (GABA) – A major inhibitory amino acid neurotransmitter Notes From Reading CHAPTER 4:P SYCHOPHARMACOLOGY (PGS.94-123) - Glutamate is the most frequently used excitatory neurotransmitter in the CNS o Synthesized from α-ketoglutarate and once released, is taken up by both neurons and astrocytes - Glutamate receptors can be either ionotropic or metabotropic o The three glutamate receptors are the N-methyl-D-asparate (NMDA) receptor, the alpha- amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor and the kainite receptor o Both AMPA receptor and kainite receptor operate by controlling a sodium channel o When these receptors bind a molecule of glutamate, a sodium channel opens, and an EPSP is produced o NMDA receptor are unique in that they are both voltage-dependent and ligand-dependent  will not open unless glutamate is present AND the postsynaptic membrane is depolarized at the same time o Since NMDA and AMPA receptors are usually found near one another on the same postsynaptic membrane, sodium moving through the nearby AMPA receptors will depolarize the postsynaptic cell - GABA serves as the major inhibitory neurotransmitter of the CNS o Synthesized from glutamate through the action of the enzyme glutamic acid decarboxylase (GAD) o GABA A receptors are ionotropic chloride channels, which allow negatively charged chloride ions to enter the cell o GABA B receptors are metabotropic potassium channels, which allow positively charged potassium ions to leave the cell - Adensosine triphosphate (ATP) and its byproducts, particularly adenosine, also act as neurotransmitter in the CNS and in connections between autonomic neurons and the vas deferens, bladder, heart, and gut o Adenosine – A byproduct of adenosine triphosphate (ATP) that functions as a neurotransmitter o ATP frequently coexists in high concentrations in vesicles containing other neurotransmitters, particularly the catecholamines LO5: Provide examples of major neuropeptides Neuropeptides - There are at least 40 different peptides that act as neurotransmitters, neuromodulators and neurohormones - Neuropeptides often coexist in the same neuron with a small-molecule neurotransmitter and modify its effects - Among the neuropeptides are substances P, which is involved in the perception of pain, and the endogenous morphines (endorphins), substances manufactured in the body that act on the same receptors as opiate drugs Gaseous Neurotransmitters - Some gases transfer information from one cell to another o Nitric Oxide (NO) – A gas that performs a type of signaling between neurons - NO is involved with neural communication, the maintenance of blood pressure, and penile erection - NO plays an important role in the communication between the thalamus and the cerebral cortex o In turn influences the amount of snsory input processed by the highest levels of the brain - Gaseous molecules diffuse through membrane without needing vesicles or a release mechanism o Act on receptors located within cells rather than on receptors embedded in the membrane - Gaseous transmitters break down very quickly without needing the action of enzymes - Appear to transfer information from the postsynaptic neuron to the presynaptic neuron (rather than the other way around) Drug Actions at the Synapse Notes From Reading CHAPTER 4:P SYCHOPHARMACOLOGY (P GS.94-123) - Many drugs produce their psychoactive effects through actions at the synapse - Drugs can affect synthesis of neurotransmitter, storage or neurotransmitters within the axon terminal neurotransmitter release reuptake or enzyme activity following release and interactions with either pre- or postsynaptic receptor sites LO6: Differentiate between agonists and antagonists Agonists and Antagonists - Drugs can boost or reduce the activity of a neurotransmitter - Agonist – Substance that promotes the activity of a neurotransmitter - Antagonist – Substance that reduces the action of a neurotransmitter - The outcome of the action of an agonist or antagonist depends on the normal effects of the neurotransmitter - If a neurotransmitter generally has an inhibitory effect on the postsynaptic neuron, the action of an agonist would increase the amount of inhibitory input, resulting in reduced postsynaptic activity - The action of an antagonist at this same synapse, interfering with the inhibitory neurotransmitter, would result in greater than normal postsynaptic activity Neurotransmitter Production - Substances that promote increased production will act as agonists, whereas substances that interfere with production will act as antagonists - To boost the rate of neurotransmitter synthesis is to provide larger quantities of basic building blocks, or precursors, for the neurotransmitter - Serotonin levels can be raised by eating high carbohydrate meals, which result in more tryptophan crossing the blood-brain barrier to be synthesized into serotonin - Drugs can exert antagonistic effects by interfering with the synthesis pathways of neurotransmitters LO7: Provide examples of drugs that produce effects by influencing neurotransmitter production, neurotransmitter storage, neurotransmitter release, receptor activity, reuptake and enzymatic degradation Neurotransmitter Storage - Certain drugs have an antagonistic effect by interfering with the storage of neurotransmitters in vesicles within the neuron - For example: the drug Reserpine – A substance derived from a plant that depletes supplies of monoamines by interfering with the uptake of monoamines into synaptic vesicles; used to treat high blood pressure but often produces depression o As a result, abnormally small quantities of monoamine neurotransmitters are available for release in response to the arrival of action potentials o Reserpine is rarely prescribed today Neurotransmitter Release - Drugs often modify the release of neurotransmitters in response to the arrival of an action potential - Black widow spider venom is a cholinergic agonist promoting greater than normal release of ACh at the neuromuscular junction o Greater release of ACh overstimulates muscle fibers, leading to convulsions o Convulsions are followed by muscle paralysis - Powerful toxins produced by Clostridium botulinum bacteria, found in spoiled food prevent the release of ACh at the neuromuscular junction and at synapses of the ANS o Botulism – A fatal condition produced by bacteria in spoiled f
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