Chapter 4
Majority of illustra3ons in this presenta3on are from Biological Psychology 4th edi3on (© Sinuer Publica3ons) Psychopharmacology
1. Pharmacology comes from a classical Greek word pharmakon, meaning poison in modern Greek it means drug. Logus of course means study. 2. Psychopharmacology is an interdisciplinary field combining psychology with pharmacology and dealing largely with psychotropic drugs, neurohormones, and neurotransmiHers (NTs). 2
Drugs The term drug has many meanings: a. Medica3on to treat a disease. b. A chemical that can be abused. c. An exogenous chemical that significantly alters the func3on of certain bodily cells when taken in rela3vely low doses (chemical that is NOT required for normal cellular func3oning). 3
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NeurotransmiHers Likewise neurotransmiHers can mean: a. Special endogenous chemicals (NTs) released in the brain or glands. b. When these chemicals are exogenously induced as drugs they alter brain and behavior. c. are neurotransmiHers. d.  Where NTs have widespread effect, drugs have localized effect in the brain. 4
Criteria for NTs 1.  Substance must exist in the presynap3c terminals. 2.  Enzymes for synthesis are present in the terminals or cell body. 3.  Nerve impulse (ac3on poten3al) releases significant amounts of the substance. 4.  Substance binds to receptors on the postsynap3c cell. 5
Criteria for NTs 5. Experimental applica3on of the substance produces changes in the postsynap3c cell. 6. Blocking substance makes nerve impulse ineffectual for postsynap3c cell. 6
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Kinds of NTs NeurotransmiHer Amines Amino Acid Quaternary Amines Neuropep3des Pep3de Hormones Gases Mono Amines Acetylcholine Catecholamines Norepinephrine Indolamines Epinephrine Dopamine Serotonin 7
Kinds of NTs NeurotransmiHer Amines Amino Acid Neuropep3des Pep3de Hormones Gases Histamine Gamma-­‐aminobutyric Acid (GABA) Glycine Glutamate 8
Kinds of NTs NeurotransmiHer Amines Amino Acid Neuropep3des Pep3de Hormones Gases Dynorphin A Met-­‐enkephalin β-­‐endorphin Leu-­‐enkephalin 9
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Kinds of NTs NeurotransmiHer Amines Amino Acid Neuropep3des Pep3de Hormones Gases Neuropep3de Y Oxytocin Substance P Cholecystokinin (CCK) Hypothalamic Releasing Hormones Vasopressin 10
Kinds of NTs NeurotransmiHer Amines Amino Acid Neuropep3des Pep3de Hormones Gases Nitric Oxide (NO) Carbon Monoxide (CO) 11
NTs and Receptors NeurotransmiHers can bind to ionotropic and metabotropic receptors in a variety of ways opening or closing them like keys. 12
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Agonists Agonists are chemicals that mimic NT behavior. These can bind to receptors and cause similar effects produced by NTs. 13
Antagonists Agonists are chemicals that work opposite to NTs. These can bind to receptors blocking or deac3va3ng them. 14
Acetylcholine 1.  Acetylcholine (ACh) was first iden3fied by Henry Dale in 1914 and was confirmed as a by OHo Loewi, (1938) through a dream (1921) as a neurotransmiHer, he called vagusstoff (from vagus nerve). OHo Loewi
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Vagusstoff 2. OHo Loewi’s determina3on of vagusstoff was made in the cardiac muscle of the frog. And supported the idea of this chemical release at the synap3c clef. 16
ACh and NS 3.  This vagusstoff or acetylcholine was not only found in PNS but also CNS of many organisms including humans. 4.  Acetylcholine is used in ANS (autonomic ganglia) and the only neurotransmiHer used in the motor division of the soma3c nervous system. 5.  Acetylcholine was extensively studied at the neuromuscular junc3on (NMJ). 17
ACh and Brain 6. Acetylcholine neurons are found in dorsolateral pons, medial septum, & basal forebrain. Its release in brain results in facilitatory effects. And this NT is involved with learning and memory in the CNS. 18
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Myasthenia Gravis Deple3on of ACh in the PNS leads to a number of muscular problems, like Myasthenia Gravis in which the pa3ent suffers from dropping eyelid. When Ach is increased the condi3on is ameliorated. en.wikipedia.org When an intravenous injec3on of edrophonium chloride or neos3gmine is given it reverses eye dropping, by breaking down Acetylcholinesterase (AChE) and increasing ACh. 19
Alzheimer’s Disease hHp://www.nature.com hHp://www.rnw.nl 1.  Reduc3on of ACh in the CNS is implicated in Alzheimer’s disease affec3ng memory and other func3ons. 2.  In this disease Choline acetyltransferase (ChAT) an enzyme is less ac3ve and does not assist in ACh synthesis in the terminal vesicles. 3.  Drugs or enzymes that boost ACh improve Alzheimer pa3ents. 20
ACh Receptors www.scholarpedia.org 1.  ACh ionotropic receptor consists of five subunits. And can be bound by agonists like nico3ne and muscarine 2.  These are fast ac3ng ligand-­‐gated receptors and open channels for Na+ ions. 3.  Most ACh receptors are found in NMJ autonomic ganglia and some in CNS. 21
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ACh and Agonists A number of ACh agonists and antagonists have been studied in detail. Among these agonists nico3ne (tobacco) and muscarine (mushrooms) mimic ACh-­‐like responses. Acetylcholine Nico3ne Mushrooms www.healthline.com www.tobaccoworld.org Tobacco Muscarine 22
Nico3ne Effects 1.  Nico3ne is a s3mulant and increases blood pressure, secre3on of hydrochloric acid in the stomach and motor ac3vity of the bowels. 2.  It binds to ACh receptors, and opens up Na+ channels increasing ac3vity in the muscles through PNS. 23
Muscarinic Effects 1.  There are five different kinds of of ACh metabotropic (muscarinic) receptors (M1-­‐5) and are thus slower than nACh receptors. 2.  These are found in heart, smooth muscle and CNS. 24
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Nico3ne & Muscarine Antagonists 1.  Curare (d-­‐tubocurarine) block nACh receptors thus act like antagonists. 2.  Atropine and scopolamine are muscarine antagonists. en.wikipedia.org en.wikipedia.org Atropine Curare 25
ACh Inac3va3on & Facilita3on 1.  ACh can be inac3vated by blocking Choline reuptake mechanism by Hemicholium. 2.  ACh release is also blocked by botulinum toxin (Botox). Botox blocks ACh release, muscle contrac3ons and wrinkles. 3.  ACh release is facilitated by black widow spider venom (muscle spasms) and Neos3gmine. They both interfere with AChE ac3vity. Black Widow Spider 26
Monoamines Catecholamines consist of dopamine (DA), norepinephrine (NE), and epinephrine (EPI), and Indolamines include serotonin (5-­‐HT) and melatonin they all share chemical structure. www.sciencephoto.com www.3dchem.com www.3dchem.com Dopamine Norepinephrine Epinephrine www.3dchem.com www.3dchem.com Serotonin Melatonin 27
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Dopamine 1.  Over one million neurons in the brain contain DA, this number is extremely small, however DA plays a major role in severe disorders like schizophrenia and Parkinson’s disease. 2.  Dopamine neurons contain several types of DA receptors (DA1-­‐5). 3.  Drugs can affect DA receptors differently. Affinity of an3psycho3c drug haloperidol is twice to DA2 than DA1, thus relieves schizophrenic symptoms. 28
Dopamine 4.  In the brain there are two systems that regulate DA ac3vity. One is mesostriatal system which projects from the substan3a nigra to the caudate nucleus and putamen, and is implicated in Parkinson’s disease. 5.  A disease marked with res3ng tremors to complete paralysis. The condi3on ameliorated with L-­‐dopa. 29
Dopamine 6. The second system is called the mesolimbic system that projects from ventral tegmental area to the limbic system. Over ac3vity of this pathway is implicated in schizophrenia. 30
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Norepinephrine 1.  The locus coeruleus (LC) gives rise to NE fiber system that connects to spinal cord, cerebellum, brain stem, thalamus, amygdala, and basal cerebrum. 2.  Norepinephrine is synthesized from dopamine within vesicles and is secreted from varicosi3es of LC along fibers. 31
Norepinephrine 3.  Norepinephrine will increase from LC during stress and will alter cogni3ve func3on engaging prefrontal cortex to increase mo3va3on. 4.  Animal models of LC destruc3on and reduc3on in NE suggests its important role in Alzheimer’s disease. 5.  Norepinephrine release from LC is related to REM sleep. 32
Serotonin 1.  Serotonin (5-­‐HT) cells are mostly located in the gut (98%) with only 2% in the brain. 2.  Serotonin cell bodies are located in brainstem raphe nuclei and project to cortex. 3.  Serotonin regulates moods, anxiety and arousal. 4.  Serotonin and NE are implicated in bipolar and other mood disorders. 33
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Glutamate 1.  Glutamate (and aspartate) are two excitatory neurotransmiHers in the brain. 2.  Glutamate binds to many ionotropic receptors like α-­‐amino-­‐3-­‐hydroxy-­‐5-­‐methyl-­‐4-­‐isoxazole-­‐
propionic acid (AMPA), N-­‐methyl-­‐D-­‐aspartate (NMDA), kinate and a few metabotropic receptors. www.mpoullis.net Glutamic Acid 34
Glutamate 3.  Glutamate can cause excitotoxicity killing neurons. Astrocytes clear glutamate from the clef to save neurons. 4.  Interest in glutamate, was greatly increased due its implica3on in memory and long-­‐term poten3a3ng (LTP). 35
Glutamate Ac3on 5. Glutamate (ligand) binds to NMDA receptors when depolariza3on is below 35 mv. This makes NMDA receptors ligand-­‐gated and voltage sensi3ve. Increase in intracellular Ca2+ increase Na+ flux. 36
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γ-­‐amino butyric acid (GABA) 1.  Unlike glutamate, GABA (and Glycine) is an inhibitory NT. There are three classes of GABA receptors (GABAA-­‐C). GABAA and GABAC are ionotropic and GABAB is metabotropic receptor. Glycine Molecule www.cybermedicine2000.com www.cybermedicine2000.com GABAA Molecule 37
GABA 2.  Binding of GABA to its receptor opens up channel to let Cl-­‐ ions to enter the neuron causing hyperpolariza3on. 3.  It is GABA that blocks many excitatory responses in the brain resis3ng seizures. Drugs that block GABA can produce seizures. 38
Neuropep3des, Pep3des & Gases 1.  Opioid pep3des (met-­‐enkephalin, leu-­‐
enkephalin, β-­‐endorphin and dynorphin) mimic opiate drugs like morphine. 2.  Many other pep3des (substance P, neurotensin, cholecytokinin [CCK], neuropep3de Y, vasopressin, oxytosin) act like NTs and hormones. 3.  Finally gases like nitric oxide (NO) and carbon monoxide (CO) act like NTs in neurons. 39
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Neuropsychopharmacology 1.  Neuropsychopharmacology is rapidly developing, field of drugs related to altering behavior. Drugs are extracted from natural sources (plants etc.) or synthesized from ar3ficial means (man-­‐made). 2.  Most of these drugs interact with specific receptors, unlike neurotransmiHers that interact with all receptors. 40
Drug-­‐Receptor Affinity The degree of chemical aHrac3on between a ligand and a receptor is termed as binding affinity. Some drugs bind to receptors more strongly than others. 41
Drug Efficacy Propensity of a ligand (drug) to ac3vate a receptor is called efficacy. Some drugs (agonists) have high efficacy than others. 42
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Dose-­‐Response Curve Dose-­‐response curve is a rela3onship between drug dose and observed effect. Low dosage is ineffectual and high dose lethal. Effec3ve dosage (ED50) is half maximal response. 43
Drug Tes3ng 1.  Dose-­‐response curves can be used to assess different drugs. Effec3ve dosage (ED50) of Drug A is lower than drug B (Lef Figure). 2.  Drug A will bind more than drug B (Right Figure). 44
Drug Dose Range Every drug at some dosage level becomes lethal. The wider the range a drug has between effec3ve ED50 and lethal dosage (LD50 ), the safer the drug is. Drug represented by blue curves, is safer than one shown by yellow curves. 45
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Drug Tolerance 1.  Repeated use of a drug leads to tolerance. Metabolic tolerance is a biochemical tolerance that increases the metabolites such that they become less effec3ve. Liver generally eliminates such metabolites before tolerance occurs. 2.  Func3onal tolerance leads to down-­‐regula3ng receptors in the target neurons if an agonist con3nues to occupy neuronal environment. 46
Other Drug Effects 1.  Cross Tolerance: Tolerance to one drug that generalizes to other drugs. 2.  Sensi3za3on: Drug craving caused by changes in the brain and receptor up regula3on. 3.  Withdrawal Symptoms: Unpleasant cogni3ve sensa3on associated with drug cessa3on. 47
Drug Administra3on 48
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Drugs Affec3ng Presynap3c Sites 1.  Synthesis of transmiHers is inhibited (enzymes) at the axon. 2.  Axonal transport is impaired (microtubles) by Colchicine. 3.  Ac3on poten3als are blocked by tetrodotoxin. 49
Drugs Affec3ng Presynap3c Sites 4.  Reserpine inhibits uptake of transmiHers into vesicles. 5.  Ca++ channel blockers (verapamil) inhibit NT release. 6.  Modula3on (caffeine) of transmiHer release by presynap3c receptor. 50
Drugs Affec3ng Presynap3c Sites 7.  Inac3va3on (amphetamine) of transmiHer reuptake thus prolonging synap3c ac3vity. 8.  Blockade of transmiHer degrada3on. MAOIs block enzymes that degrade NTs. Thus NT prolongs at the synapse. 51
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Drugs Affec3ng Postsynap3c Sites 1.  Inac3va3on of enzyme in the clef to prolong transmiHer ac3vity. 2.  Altera3on (alcohol) of postsynap3c receptors (GABA) to increase inhibi3on. 3.  Blockade (curare) of nAChrs. 52
Drugs Affec3ng Postsynap3c Sites 4.  Ac3va3on (nico3ne) ac3vates ACh receptors. 5.  Ac3va3on (lithium) of second messengers cyclic AMP. 53
Classes of Drugs (Analgesics) 1.  Poppy flowers produce opium. Opium contains morphine, a powerful pain-­‐killer (analgesic) and is addic3ve. Likewise heroin (ar3ficial form of morphine) is also analgesic and addic3ve. 2.  Hughes and Kosterlitz (1975) iden3fied two pep3des that bound to opioid receptors and called them enkephalins. Enkephalins like morphine relieved pain and were addic3ve. Poppy Flowers 54
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Analgesics: Opiates 3.  Other endogenous morphine (endorphins) and dynorphin were also discovered that were endogenous to the brain. 4.  Pert and Snyder (1973) discovered opiate receptors in the limbic system, hypothalamus, locus coeruleus, and periaqueductal gray. Morphine bound to receptors in these regions. 55
Analgesics: Cannabinoids 1.  The second class of analgesics is based on tetrahydrocannabinol (THC) main ingrediant in marijuana and hashish extracted the cannabis plant. 2.  In 1992 an endogenous cannabanoid ligand was discovered (anandamide). 3.  Cannabanoid receptors are found in substan3a nigra, hippocampus, cerebellum and the cortex. 56
Depressants 1.  Throughout human history alcohol has been the easiest drug to concoct. It is a tension reducer. 2.  Alcohol has a biphasic effect on the brain. An ini3al s3mula3ng phase and longer depressant phase later on. 3.  Prolonged usage of alcohol damages nerve cells. Purkinje cells (cerebellum), pyramidal neurons (hippocampus) show such damage. Thus motor and memory losses over the pa3ent’s life3me. 57
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Depressants 4.  Alcoholism and dietary deficiency (thiamine) leads to Korsakoff’s syndrome. 5.  Low dosage of alcohol s3mulate dopamine pathways (euphoria) and perhaps opiate receptors in numbing pain. 6.  Alcohol’s depressive effect is because of its interac3on with GABAA receptors which are involved with inhibi3on in the brain. 58
Depressants 7. Abs3nence from alcohol leads to brain recovery in gray maHer (cortex) and reduc3on in lateral ventricular volume. 59
Anxioly3cs 1.  Anxioly3cs (Anxiety and Greek ly8cos “able to loosen”) are drugs ameliorate disabling emo3onal distress, like fear and terror. 2.  Benzodiazepines (Valium etc.) are anxioly3c and enhance GABA receptors ac3vity to increase inhibi3on. 3.  Hormone allopregnanolone suspected to be endogenous anxioly3c is increased by alcohol. 60
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S3mulants 1.  Nico3ne: Found largely in tobacco s3mulates nico3nic receptors at the neuromuscular junc3ons (NMJ). Also in the CNS. 2.  Cocaine: Derived from coca leaves is used as a local anesthe3c and also relieves depression. Increases dopamine in the synapse. 3.  Amphetamines: Causes heightened alertness, and even euphoria and wards off boredom. 61
Hallucinogens 1.  Lysergic Acid Diethylamide (LSD): •  Potent drug that causes hallucina3ons was discovered in 1938 by Hoffmann. •  In the 1950s scien3sts thought that it would provide a model for psychosis. •  Why LSD causes hallucina3ons is not understood? •  Former users report flashbacks resembling hallucina3ons. Memory or plas3c changes? 62
Hallucinogens 2. Phencyclidine (PCP): •  Also called angel dust, is a potent analgesic and anesthe3c. •  Dropped from use because of side effects (delirium, disorganized percep3on, hos3lity etc). •  Toxic reac3ons (four Cs) comba3veness, catatonia, convulsions (or coma), confusion. •  May provide useful model of schizophrenia. 63
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Hallucinogens 3. Peyote and Mushrooms: •  Peyote seed and mushrooms can alter states of consciousness resembling hallucina3ons. Fewer side effects. •  Eminent scien3sts advocated their use. Carlos Castaneda Mushroom Timothy Leary 64
Recrea3onal Drugs All drugs used in recrea3onal form have devasta3ng effects on the brain. Drugs like Ecstasy, hallucinogenic amphetamine can reduce serotonin axons in the brain within a single dose. 65
Drug Abuse Any comprehensive model of drug abuse should be able to answer the following ques3ons. 1.  What social and environmental factors lead the individual to start abusing the drug? 2.  What factors make her con3nue? 3.  What physiological factors makes a substance rewarding? 4.  What is addic3on in behavioral and physiological terms, and why it is so hard to quit? 66
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Drug Models 1.  The Moral Model: The abuser lacks morals and thus self-­‐control. Train self-­‐control (punishment?). 2.  The Disease Model: Drug abuser is diseased thus needs the drug. Needs treatment rather than moral punishment. 3.  The Physical Dependence Model: Drugs are con3nued because their cessa3on cause unpleasant withdrawal symptoms. 67
Drug Models 4. The Posi3ve Reward Model: Proposes animals and humans engage in drug ac3vity for its reward-­‐like consequences. 68
Individual Differences Individuals differ in their suscep3bility to be becoming drug addicts because of many factors. 1.  Biological Factors: men are more likely to abuse drugs than women. 2.  Family Situa3on: Family breakup, poor parental rela3onships, an3social siblings lead to drug abuse. 3.  Personal Characteris3cs: Aggressiveness and poor emo3onal leads to drug abuse. 4.  Environmental Factors: Prevalence of drug use in community. 69
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Drug Abuse Preven3on & Treatment 1.  Detoxifica3on: Drugs like benzodiazepines reduce early withdrawal symptoms of drug abusers. 2.  Agonists: Agonists can wean the individual form drugs, e.g., methadone reduces heroin appe3te. 3.  An3craving Medica3ons: Drugs that reduce appe3te for the abused substance, e.g., naltrexone reduces alcohol pleasure. 70
Drug Abuse Preven3on & Treatment 4. Immuniza3ons: Trigger the immune system to produce an3bodies that remove targeted drugs from circula3on. 71
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