Intro To Neuropharm 2009

Neuropharmacology, 2009 John Schriefer, Ph.D.

Introduction to Neuropharmacology Objectives The student shall be able to: 1.

explain why most mechanisms of action given the neuropharmacologic drugs are approximations.

2.

define what is meant by specific mechanism of action.

3.

describe the various events in synaptic transmission which might be altered by drugs.

4.

describe the consequences of drug-induced alteration of membrane potential.

5.

differentiate between a neurotransmitter and a neuromodulator.

6.

recognize the substances which have been proposed to act as CNS neurotransmitters.

7.

differentiate between ionotropic and metabotrophic receptors.

8.

describe the blood brain barrier and its implications in drug therapy.

9.

describe the function of, and the disorders affecting, the various CNS neuronal systems.

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INTRODUCTION TO NEUROPHARMACOLOGY I.

Neuropharmacology is the study of drugs specifically employed to affect the nervous system.

II.

Mechanism of action A.

Entire mechanism is generally unknown. Approximations of CNS mechanism made from information regarding effects of drugs in isolated systems. CNS as a “Black Box” Extrapolation from biochemical events to behavior is difficult.

B.

III.

Specific Mechanism of Action. A specific drug action affects a recognized protein target, i.e., a receptor, an ion channel, an enzyme, or a transporter.

Site of action A.

Most neuropharmacologic agents produce effects by altering synaptic events

Central nervous system (CNS) neurotransmission and sites of drug action. CNS drugs act primarily by affecting the synthesis, storage, release, reuptake, or degradation of neurotransmitters (NT) or by activating receptors. NT are synthesized from precursors accumulated or synthesized in the neurons. The NT are stored in vesicles whose membranes contain proteins involved in NT release (synaptobrevin and synaptotagmin). The NT are released when an action potential-mediated calcium influx initiates interaction of synaptobrevin and synaptotagmin with neuronal membrane-docking proteins (syntaxin and neurexin). This leads to docking and exocytosis. Synaptic NT may activate presynaptic or post-synaptic receptors (R1, R2, and R3). The action of NT is terminated by reuptake into the presynaptic neuron or by enzymatic degradation.

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Present research concentrates on long-term consequences of alteration of synaptic transmissions. B.

IV.

Alteration of synaptic transmission leads to excitation or inhibition of postsynaptic nerves.

Neurotransmitters A.

Neurotransmitter – a substance which is released locally and causes a change in post-synaptic potential.

B.

Neuromodulator – a substance which acts to modify the response of the synapse to a neurotransmitter.

C.

Substances identified as neurotransmitters. • • • • • • •

Acetylcholine Amino acids Biogenic amines Peptides Purines (ATP, adenosine) Nitric acid Endocanabinoids

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TABLE 18-1. Major Neurotransmitters in the Central Nervous System* Neurotransmitter Acetylcholine

Amino Acids Gammaaminobutyric Acid (GABA) Glutamate and aspartate

Receptors Muscarinic M1, M3, and M5 M2 and M4 Nicotinic

Mechanisms of Signal Transduction ↑ IP3 and DAG. ↓ cAMP; ↑ gK+. ↑ gCa2+, gK+, and gNa+.

Neuronal Tracts Basal ganglia, basal nucleus of Meynert to cerebral cortex; septal area to hippocampus

Excitatory (M1, M3, M5, and nicotinic) or inhibitory (M2 and M4) NT: memory, motor coordination and sensory processing

Ubiquitous

Major inhibitory NT in CNS; motor coordination and neuronal excitability Major excitatory NT in CNS, long-term potentiation (memory), neuronal toxicity and apoptosis, and pain processing Major inhibitory NT in spinal cord; also found in brain stem; motor coordination and neuronal excitability

GABAA GABAB (metabotropic) Ionotropic AMPA and KA NMDA Metab. (MGluR) Strychnineinsensitive Strychninesensitive

↑ gC1↑ gCa2+ and gK+

D1 and D5 D2, D3, and D4

↑ cAMP ↓ cAMP

H1 H2 H3 Adrenergic α1 α2 β1 and β2

↑ IP3 and DAG. ↑ cAMP Unknown

5-HT1 5-HT2 5-HT3 5-HT4

↓ cAMP; ↑ gK+ ↑ IP3 and DAG ↑ gK- and gNa+ ↓ cAMP

Peptides Opioid peptides

δ, κ, and μ

↓ cAMP and gCa2+; ↑ gK+

Widely distributed, especially in brain stem, spinal cord, and thalamus

Tachykinins Neurokinins Substance P

NK1, NK2, and NK3 NK1, NK2, and NK3

↓ gK+; ↑ IP3 and DAG ↓ gK+; ↑ IP3 and DAG

Primary sensory neurons; cell bodies at all levels

Glycine

Biogenic amines Dopamine

Histamine Norepinephrine

Serotonin (5hydroxy-tryptamine, or 5-HT)

Hypocretin 1 and 2

↑ gK+ and gNa+ ↑ gCa2+, gK+, and gNa+ ↓ cAMP; ↑ IP3 and DAG ↑ gCl-

Widely distributed throughout CNS Spinal cord; brain stem

Modulate NMDA Receptors

↑ IP3 and DAG ↓ cAMP ↑ cAMP

Functions

Nigrostriatal, nucleus accumbens, mesolimbic, and tuberoinfundibular; chemoreceptor trigger zone Hypothalamic tracts to entire CNS Locus ceruleus (pons) to thalamus, cerebral cortex, cerebellum, and spinal cord; midbrain to hypothalamus Raphe nuclei (Central brain stem) to forebrain and spinal cord

Inhibitory NT; behavioral and drug reinforcement, emesis, hormone release, mood, motor coordination, and olfaction.

Excitatory NT; sedation, sleep, temperature regulation, and vasomotor function Excitatory (α1 and β1) or inhibitory (α2 and β2) NT; anxiety, cerebellar function, learning, memory, mood, sensory processing and sleep Excitary (5-HT2, 5-HT3, and 5HT4) or inhibitory (5-HT1) NT; appetite, emotional processing, hallucinations, mood, pain processing, and sleep Inhibitory NT, emotions, hearing, motor coordination, neurohormone secretion, pain processing, taste, and vision Excitatory NT; neuromodulation and pain processing involved in sleep/wakefulness

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*AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; cAMP = cyclic adenosine monophosphate; CNS = central nervous system; DAG = diacylglycerol, g = conductance; IP3 = inositol triphosphate; KA = kainate; NK = neurokinin; NMDA = N-methyl-o-aspartate; and NT = neurotransmitter

V.

VI.

VII.

Neurotransmitter receptors A.

Ionotropic receptors (also known as ligand-gated channels) are associated with ion channels, and change ionic conductance.

B.

Metabotropic receptors are coupled with enzymes via G-proteins and other intermediates.

Signal transduction A.

Activation of ionotropic receptors may increase chloride, sodium, potassium, or calcium conductance and cause excitatory or inhibitory membrane potentials.

B.

Activation of metabotropic receptors can lead to synthesis of cAMP, IP3, and DAG which can alter a variety of intracellular pathways. Activation of metabotropic receptors can also modulate voltage gated ion channels.

Blood Brain Barrier A term used to describe diffusional barriers retarding the passage of substances from the central circulation to nerve cells. Characteristics which regulate diffusion of substances through capillaries are 1. 2. 3.

molecular weight lipid solubility ionization at physiological pH

Barrier is a consequence of anatomical differences in CNS capillaries. • • • • • VIII.

less permeable tight junctions fewer pinocytotic sites surrounded by pericytes and astroglial processes carrier mediated transport

Neuronal systems in the CNS A.

Cognitive processing – interpretation of sensory information 1.

results in motor activity, reasoning, forethought 5

2. 3. B.

Memory – ability to recall events 1. 2. 3.

C.

involves limbic structures and frontal lobe cortex disorders include anxiety, mood disorders, and schizophrenia altered by anxiolytics, antidepressants, antipsychotics, and all drugs causing drug dependence

Sensory processing 1. 2. 3.

E.

involves many brain structures disorders referred to as dementia altered by cholinesterase inhibitors and benzodiazepines

Emotional processing – the conscious perception of neuronal activity 1. 2. 3.

D.

disorders referred to as delirium altered by antipsychotics, CNS stimulants, hallucinogens

vision, hearing, olfaction, touch, pain disorders include sleep disorders, chronic pain altered by antidepressants, hallucinogens, anesthetics, analgesics

Motor processing 1. 2. 3.

control of motion and posture disorders include Parkinson’s disease, and degenerating and demyelization diseases altered by antiparkinsonian drugs, CNS stimulants, sedative-hypnotics

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Norepinephrine in the CNS •

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Mechanisms for synthesis, storage, release, and reuptake of noradrenaline in the CNS are essentially the same as in the periphery, as are the receptors. Noradrenergic cell bodies occur in descrete clusters, mainly in the pons and medulla, one important such cell group being the locus ceruleus. Noradrenergic pathways, running mainly in the medial forebrain bundle, and descending spinal tracts, terminate diffusely in the cortex, hippocampus, hypothalamus, cerebellum, and spinal cord. The actions of noradrenaline are mainly inhibitory (β-adrenoceptors), but some are excitatory (α- or β- adrenoceptors). Noradrenergic transmission is believed to be important in o the ‘arousal’ system, controlling wakefulness and alertness o blood pressure regulation o control of mood (functional deficiency contributing to depression). o psychotropic drugs that act partly or mainly on noradrenergic transmission in the CNS include antidepressants, cocaine, amphetamine. Some antihypertensive drugs (e.g., clonidine, methyldopa) act mainly on noradrenergic transmission in the CNS.

Dopamine in the CNS 7

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Dopamine is a neurotransmitter as well as being the precursor for noradrenaline. It is degraded in a similar fashion to noradrenaline, giving rise mainly to DOPAC and HVA, which are excreted in the urine. There are three main dopaminergic pathways. o nigrostriatal pathway, important in motor control o mesolimbic/mesocortical pathways, running from groups of cells in the midbrain to parts of the limbic system, especially the nucleus accumbens, and to the cortex; they are involved in emotion and drug-induced reward systems. o tuberohypophyseal neurons running from the hypothalamus to the pituitary gland, the secretions of which they regulate. There are five dopamine receptor subtypes. D1and D5-receptors are linked to stimulation of adenylate cyclase. D2-, D3- and D4-receptors are linked to inhibition of adenylate cyclase. Most known functions of dopamine appear to be mediated mainly by receptors of the D2 family. Receptors of the D2 family may be implicated in schizophrenia. The D4-receptor shows marked polymorphism in humans. Parkinson’s disease is associated with a deficiency of nigrostriatal dopaminergic neurons. Behavioural effects of an excess of dopamine activity consist of stereotyped behaviour patterns and can be produced by dopamine-releasing agents (e.g., amphetamine) and dopamine agonists (e.g., apomorphine). Hormone release from the anterior pituitary gland is regulated by dopamine, especially prolactin release (inhibited) and growth hormone release (stimulated). Dopamine acts on the chemoreceptor trigger zone to cause nausea and vomiting.

5-Hydroxytryptamine (5-HT in the CNS) •

The processes of synthesis, storage, release, reuptake, and degradation of 5-HT in the brain are very similar to events in the periphery. 8

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Availability of tryptophan is the main factor regulating synthesis. Urinary excretion of 5-HIAA (see text) provides a measure of 5-HT turnover. 5-HT neurons are concentrated in the midline raphe nuclei in the pons and medulla, projecting diffusely to the cortex, limbic system, hypothalamus, and spinal cord, similar to the noradrenergic projections. Functions associated with 5-HT pathways include : o various behavioural responses (e.g., hallucinatory behaviour, ‘wetdog shakes’) o feeding behaviour o control of mood and emotion o control of sleep-wakefulness o control of sensory pathways, including nociception o vomiting. 5-HT can exert inhibitory or excitatory effects on individual neurons, acting either presynaptically or postsynaptically. The main receptor subtypes in the CNS are 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT3. Associations of behavioural and physiological functions with these receptors have been partly worked out. Other receptor types (5-HT4-7) also occur in the CNS, but less is known about their function.

Acetylcholine in the CNS • •

Synthesis, storage, and release of acetylcholine in the CNS are essentially the same as in the periphery. Acetylcholine is widely distributed in the CNS, important pathways being: o basal forebrain (magnocellular) nuclei, which send a diffuse projection to most forebrain structures, including the cortex o septohippocampal projection 9

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o short interneurons in the striatum and nucleus accumbens. Certain neurodegenerative diseases, especially dementia and Parkinson’s disease, are associated with abnormalities in cholinergic pathways. Both nicotinic and muscarinic acetylcholine receptors occur in the CNS. The former mediate the central effects of nicotine. Nicotinic receptors are mainly located presynaptically; there are few examples of transmission mediated by postsynaptic nicotinic receptors. Muscarinic receptors appear to mediate the main behavioural effects associated with acetylcholine, namely effects on arousal, and on learning and short-term memory Muscarinic antagonists (e.g., hyoscine) cause amnesia. Acetylcholinesterase released from neurons may have functional effects distinct from cholinergic transmission.

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Excitatory amino acids (EAAs) •

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EAAs, namely glutamate, aspartate, and possibly homocysteate, are the main fast excitatory transmitters in the CNS. Glutamate is formed mainly from the tricarboxylic acid cycle intermediate α-oxoglutarate, by the action of GABA aminotransferase. There are four main EAA receptor subtypes: o NMDA o AMPA o kainate o metabotropic. NMDA-, AMPA-, and kainate-receptors are ionotropic receptors regulating cation channels; metabotropic receptors are Gprotein-coupled receptors and act through intracellular second messengers. There are many molecular subtypes within each class. The channels controlled by NMDA-receptors are highly permeable to Ca2+ and are blocked by Mg2+. AMPA- and kainate-receptors are involved in fast excitatory transmission; NMDA-receptors mediate slower excitatory responses and, through their effect in controlling Ca2+ entry, play a more complex role in controlling synaptic plasticity (e.g., longterm potentiation). Competitive NMDA-receptor antagonists include APS and other experimental compounds; the NMDA-operated ion channel is blocked by dizocilpine, as well as by the psychotomimetic drugs ketamine and phencyclidine. CNQX is a selective AMPA receptor antagonist. NMDA-receptors require low concentrations of glycine as a coagonist, in addition to glutamate; 7-chlorokynurenate blocks this action of glycine. NMDA-receptor activation is increased by endogenous polyamines, such as spermine, acting on a modulatory site that is blocked by ifenprodil. The entry of excessive amounts of CA2+ produced by NMDAreceptor activation can result in cell death; excitotoxicity. Metabotropic receptors are G-protein-coupled receptors, linked to inositol trisphosphate formation and intracellular Ca2+ release. They play a part in glutamate-mediated synaptic plasticity and excitotoxicity. Specific agonists and antagonists are known. EAA receptor antagonists are being developed for clinical use.

Inhibitory amino acids: GABA and glycine •

GABA is the main inhibitory transmitter in the brain. 11

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It is present fairly uniformly throughout the brain; there is very little in peripheral tissues. GABA is formed from glutamate, by the action of GAD (glutamic acid decarboxylase). Its action is terminated mainly by reuptake, but also by deamination, catalysed by GABA transaminase. There are two types of GABA receptor, GABAA and GABAB. GABAA-receptors, which occur mainly postsynaptically, are directly coupled to chloride channels, opening of which reduces membrane excitability. Muscimol is a specific GABA agonist, and the convulsant bicuculline is an antagonist. Other drugs that interact with GABAA-receptors and channels include: o benzodiazepine tranquillizers, which act at an accessory binding site to facilitate the action of GABA o convulsants such as picrotoxin, which block the anion channel o neurosteroids, including endogenous progesterone metabolites, and other CNS depressants, such as barbiturates, which facilitate the action of GABA. GABAB receptors are G-protein-coupled receptors, linked to inhibition of cAMP formation. They cause pre- and postsynaptic inhibition by inhibiting calcium channel opening and increasing K+ conductance. Baclofen is a GABAB-receptor agonist used to treat spasticity. GABAB antagonists are not yet in clinical use. Glycine is an inhibitory transmitter mainly in the spinal cord, acting on its own receptor, structurally and functionally similar to the GABAA-receptor. The convulsant drug strychnine is a competitive glycine antagonist. Tetanus toxin acts mainly by interfering with glycine release.

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