Linger Pharm Neurotransmitters Flashcards
Sites of Drug Action in the CNS
(1) Action potential in presynaptic fiber;
(2) synthesis of transmitter;
(3) storage;
(4) metabolism;
(5) release;
(6) reuptake into the nerve ending or uptake into a glial cell;
(7) degradation;
(8) receptor for the transmitter;
(9) receptor-induced increase or decrease in ionic conductance;
(10) retrograde signaling.
Monoamine Transporters:
Commonly used drugs such as antidepressants, amphetamines, andcocainetarget monoamine (norepinephrine,dopamine, and serotonin) transporters with different potencies.
Normally, norepinephrine(NE) reuptake back into the noradrenergic neuron occurs via thenorepinephrinetransporter (NET), and subsequently a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT).
Meth and cocaine, e.g., affect these pathways
Monoamine Transporters: Therapeutic applications
ADHD: methylphenidate, amphetamine
Depression: SSRIs, SNRIs, TCAs
Enzymatic Termination of Response
Also enkephalins, endorphins, and other neuropeptides
Therapeutic Applications for AChE inhibitors:
Alzheimer’s disease
Myasthenia gravis
Glaucoma
Chemical warfare: sarin gas
Organophosphate pesticides
Major Classes of Neurotransmitters (NTs)
Amino Acid Transmitters (Glutamate, aspartate, GABA, Glycine)
Peptides (Opioids, Tachykinins)
Small Molecule Transmitters (Ach, Monoamines- catecholamines, serotonin; Histamine)
Endocannabinoids
Neurotransmitter (NT) Receptors
Each chemical signaling molecule has its own receptor(s)
Receptor binding is selective, but not specific
Almost all chemical signaling molecules have several * receptor subtypes:
- In some systems the potential number of receptor variants is enormous
- Consider a receptor composed of five subunits.
- – If there are four distinct subunits (a, b, g, d)
- – And there are five or more variants of each subunit (a1, a2, a3, a4, a5, b1, b2, …etc.)
- – Then how many possible combinations using five subunits are there?
Each receptor subtype is coupled to a specific signaling mechanism and/or has cell type-specific components in the signaling cascade
Neurotransmission at Chemical Synapses
Synaptic vesicle transport to nerve terminal
Neurotransmitter synthesis and packaging into vesicles
Depolarization of the presynaptic nerve terminal by an arriving action potential causes influx of Ca++ via opening of voltage-dependent Ca++ channels
Fusion of vesicles with plasma membrane and release of vesicle contents into synaptic cleft
Binding and activation of postsynaptic receptors
Postsynaptic membrane response
Elimination of transmitter from synapse by reuptake transporter or
Elimination of transmitter from synapse by enzymatic breakdown
Types of Ion Channels and NT Receptors
Voltage-gated channels respond to changes in membrane potential
- Axonal Na+ channels mediate the fast action potential
- Ca++ channels in the presynaptic terminal stimulate NT release
Ligand-gated ion channels (Ionotropic)
G protein-coupled receptors (Metabotropic)
Voltage-gated ion channels
Example: Na+ channels (Nav1.1 – Nav1.9)
Structure: 4 x 6 TM domains
Activated in response to membrane depolarization
Function: propagate action potentials
Ligand-gated ion channels
Example: nicotinic AChRs (nAChRs, neuronal and muscle subtypes)
Structure: pentamer of 5 subunits, each containing 4 TM domains
Activated in response to ligand binding
Function: excitatory neurotransmission, muscle contraction, etc.
Ionotropic
receptors
Multiple subunits; transmembrane domains form an ion channel
Ligand binding causes a conformational change resulting in opening or closing of the channel
Extracellular domain with binding site for NT (also agonist and antagonist binding sites)
Membrane spanning domain that forms the ion channel
Intracellular domains that may interact with other proteins
Mediate fast (msec) synaptic transmission
Metabotropic
Single subunit with seven membrane-spanning domains
Ligand binding stimulates a G protein-coupled signaling cascade and second messengers
Receptor: ligand binding protein
GTP binding protein (a, b, g subunits)
Effector protein (ion channel or enzyme)
Mediate slow (sec to min) synaptic transmission
Ionotropic vs metabotropic-
Excitatory or Inhibitory
Ionotropic:
- Excitatory Postsynaptic Potential (EPSP): Influx of Na+ or Ca++ causes membrane depolarization
- Inhibitory Postsynaptic Potential (IPSP): Efflux of K+ or influx of Cl- causes hyperpolarization
Metabotropic
- Excitatory and inhibitory G protein pathways
Ionotropic
NT Ligands
Glutamate
GABA
Acetylcholine
Serotonin
Glycine
Metabotropic
NT Ligands
Glutamate GABA Acetylcholine Dopamine Norepinephrine Serotonin Histamine Neuropeptides Endocannabinoids
A 75 yo man with atrial fibrillation experiences a stroke when an embolus lodges in the proximal portion of his left middle cerebral artery. He immediately loses his ability to talk and experiences paralysis of his right arm and leg. A small portion of his left cortical hemisphere has substantially reduced blood flow for several hours and is irreversibly damaged. Excess of which neurotransmitter contributes most to the cell death of neurons in this case?
Acetylcholine Dopamine GABA Glutamate Serotonin
Glutamate
Glutamate Excitotoxicity
Calcium may trigger apoptosis and a host of degradative intracellular enzymatic processes
This “excitotoxicity” leads to irreversible damage to neurons
Glutamate: The Primary Excitatory NT
Localized throughout the CNS
Glutamate accounts for most fast synaptic transmission in the CNS and spinal cord
Synthesized locally from glucose or from glutamine transported into neurons from surrounding glia
Glial cells surrounding glutamatergic neurons are essential for Glu reuptake and termination of signal
A 73 y/o well-educated woman is brought to the physician by her daughter, who has become concerned about her mother’s behavior. The mother volunteers at the local library shelving books, but for the past few months she has had trouble remembering where the books go. In addition, she often forgets to turn the stove off after cooking her family’s long-time favorite dishes. A drug with which of the following mechanisms of action is most likely to reduce deterioration?
AMPA receptor agonist AMPA receptor antagonist NMDA receptor agonist NMDA receptor antagonist mGluR receptor agonist
NMDA receptor antagonist – memantine
Glutamatergic Receptors: Ionotropic
N-methyl-D-aspartic acid (NMDA)
- Na+/K+/Ca++ channels
- Needs co-agonist glycine
- Channel blocked by Mg++ until depolarized
- Important in ischemia, hypoxia – cell death
- Subtypes: NR1, NR2A-D
Non-NMDA (AMPA/Kainate)
- AMPA receptors mediate the vast majority of excitatory synaptic transmission in the brain
- Na+/K+ channels; some are permeable to Ca++
- Subtypes: GluR1, GluR2, GluR3, GluR4
Glutamatergic Receptors: Metabotropic
Postsynaptic receptors decrease K+ conductance and increase IP3 and DAG
Presynaptic mGluRs act as autoreceptors to inhibit Glu release
- Decrease Ca++ conductance; decrease cAMP
The NMDAR: A Coincidence Detector
A single synaptic input results in the generation of a short-lasting excitatory postsynaptic potential (EPSP) that is mediated entirely by AMPA receptors.
When multiple inputs occur simultaneously, nerve depolarization removes the Mg++ block in NMDA receptor channels and the same single synaptic input generates a longer-lasting EPSP that is mediated by both AMPA and NMDA receptors. Thus, the NMDA receptor can “sense” the activity in adjacent inputs.
Glutamate Pathophysiology
Neural connectivity
- Synaptic plasticity; Learning and memory
Excitotoxicity and Cell Death
- Seizure
- Stroke
- High concentrations of extracellular glutamate whether due to prolonged seizures or * stroke may lead to apoptosis (cell death) of neurons
Neurodegenerative diseases and schizophrenia
Migraine – cortical spreading depression
Which of the following drugs is capable of blocking the NMDA receptor?
LSD Marijuana Phencyclidine (“Angel dust”) Phenytoin Strychnine
Phencyclidine (“Angel dust”)
-also ketamine -these are noncompetitive inhibitors
Marijuana receptor?
cannabinoid
LSD receptor?
usually associated with serotonin
Phenytoin receptor?
voltage-gated sodium channel
strychnine receptors?
many, including glycine receptors
A 35 yo chronic alcoholic, after consuming up to 2 quarts of vodka a day for several weeks, runs out of money and alcohol and presents to the ED in acute alcohol withdrawal. He is extremely agitated, trembling violently, and an hour after arriving at the ED, experiences the first of several grand mal seizures. Phenytoin, a Na+ channel blocker, is given as a loading dose to control his seizures. A drug acting at which of the following receptors is indicated as additional treatment in this EtOH-withdrawal case?
α2 adrenergic D2 dopaminergic GABAA GABAergic 5-HT3 serotoninergic M1 muscarinic cholinergic
GABAA GABAergic
GABA:
The Primary Inhibitory NT
Localized throughout the CNS
Principal NT of interneurons
Neurons in striatum, globus pallidus, and Purkinje cells of cerebellum
Roles
- Balances excitatory activity of glutamate
- GABA dysfunction leads to hyperexcited states
- GABA-mimetic drugs are used to induce sleep and control anxiety and seizures
A 24 yo medical student experiences extreme anxiety every time he has to sit for an exam (every other day!). Soon after encountering a difficult question on an exam, he develops a sensation that he cannot get enough air, palpitations and chest pain, sweaty palms, and tingling in his extremities. He has been checked by a physician following two recent episodes, but no physical explanation for his symptoms is forthcoming. Which of the following drugs are indicated for treating this patient’s GAD (generalized anxiety disorder) and panic attacks?
Alprazolam Phenobarbital Phenytoin Propranolol Coors light
Alprazolam (Xanax)
or
Propranolol (Inderal)
Drawbacks to alprazolam– dependence, memory problems, etc.
benefit over anti-depressant- works right away
Benzodiazepines
Examples: Alprazolam (Xanax), Diazepam (Valium), Midazolam (Versed), Clonazepam (Klonopin)
Benzodiazepines facilitate GABA-mediated opening of GABAA receptors (Cl- channel)
Indicated for the treatment of generalized anxiety disorder and panic disorders, often in conjunction with psychotherapy
- Antidepressants, SSRIs and SNRIs, are now considered first-line agents for these disorders
Also used for sedation and sometimes for sleep disorders
Ionotropic GABA Receptors
GABAa Receptor Cl- Channel Hyperpolarizes cell, produces IPSP Reduces probably of action potential Highly heterogeneous; over 15 different subunits (α, β, γ, δ, ε, π, θ, and variants)
Metabotropic GABA Receptors
GABAb Receptor
Postsynaptic: increases K+ conductance
Presynaptic: decreases Ca++ conductance
prototype drug: baclofen
A 66 y/o woman is diagnosed with Alzheimer disease, with symptoms being described as mild-to-moderate. What pharmacologic approach is generally considered the most fruitful in terms of alleviating symptoms of early Alzheimer and possibly slowing the course of the underlying brain pathology?
Activate a population of serotonin neurons
Activate a population of adrenergic neurons
Block dopamine release or receptor activation
Inhibit acetylcholinesterase
Inhibit monoamine oxidase
Inhibit acetylcholinesterase
ACh Pathophysiology
Alzheimer’s Disease (AD): Cholinergic neurons exhibit reduced activity in AD; acetylcholinesterase inhibitors are commonly used to treat AD; benefit is modest and may not impact long-term outcomes
Neuromuscular Junction Diseases
- Autoimmune
- Myasthenia gravis: antibodies against nACh receptors; treated with acetylcholinesterase inhibitors and immunosuppressive drugs
- Eaton-Lambert Syndrome: antibodies against presynaptic voltage-gated Ca++ channels; frequently associated with underlying malignancy
- Bacterial
- Botulism: toxin inhibits ACh release from presynaptic terminals
Acetylcholine functions (brain)
Functions
- Wakefulness
- Motor control
- Memory
Drowsiness, sedation, and memory loss can occur when central ACh receptors are blocked
Many CNS drugs have significant affinity for muscarinic ACh receptors
Ionotropic
Acetylcholine Receptors
Nicotinic receptors
Na+/K+ Channels (Excitatory)
neuromuscular junction (NM), postganglionic neurons (NN), CNS (NN)
17 distinct variants of α, β, γ, δ, and ε subunits
Agonist: nicotine, succinycholine
Antagonists: curare-like neuromuscular blockers
Metabotropic
Acetylcholine Receptors
Muscarinic receptors
M1 subtype is excitatory: decreases K+ conductance; increases IP3 and DAG
M2 subtype is inhibitory: increases K+ conductance; decreases cAMP
On cells innervated by postganglionic parasympathetic neurons, on sweat glands, in CNS
Agonists: muscarine, pilocarpine
Antagonist: atropine
A 21 yo college senior rapidly becomes withdrawn and paranoid and develops delusions that her mind is being controlled by extraterrestrial beings. More and more she hears voices that seem to be telling her to do something. She is brought to the ED by her roommate in an extremely agitated, incoherent, combative state. She is given a diagnosis of acute paranoid schizophrenia.
Blockade of which of the following receptor systems is indicated to treat her schizophrenia?
Dopamine D1 Dopamine D2 GABAA GABAB Serotonin 5-HT3
Dopamine D2
Dopamine Pathophysiology
SN → striatum regulates voluntary movement
- Substantia nigra DA neurons degenerate in Parkinson’s disease
VTA “reward pathway” mediates
- Drug addiction
- – Cocaine blocks DA uptake
- – Amphetamines increase DA release
Psychiatric disorders
- Schizophrenia involves increased DA activity
- Classical antipsychotics work (in part) by blocking dopamine D2 receptors
Dopamine Receptors
All five subtypes are metabotropic GPCRs
D1-like family (D1,D5) is stimulatory: increases cAMP
D2-like family (D2, D3, D4) is inhibitory
- Presynaptic receptors decrease Ca++ conductance
- Postsynaptic receptors increase K+ conductance and decreases cAMP
The patient is treated with the anti-psychotic drug, haloperidol, an antagonist with high affinity for dopamine D2 receptors. Her agitation, hallucinations, and delusions quickly dissipate but she develops muscular rigidity, becomes quite akinetic and from time to time exhibits dystonic postures. She is switched to olanzapine. On this drug, her hallucinations, delusions, and agitation remain under control but her motor symptoms subside.
Blockade of which neurotransmitter system is most likely mediating the effects of olanzapine?
Dopamine Norepinephrine Serotonin Glutamate GABA
Serotonin
During an annual physical exam, an internist notes that a 65 yo woman appears depressed. She admits to persistent feelings of hopelessness. She feels she is nothing but a burden to her husband. She doesn’t seem to enjoy anything anymore. She sleeps poorly, tending to wake up at 3-4 am. Her appetite is diminished and she has lost 10 lb over the past 2 months. She has frequent crying spells. She denies suicidal ideation but wishes she could just quietly die.
Which of the following drugs is indicated for treating this patient?
Methylphenidate Haloperidol Fluoxetine Clonidine Flumazenil
Fluoxetine (Prozac) - SERT Blocker – SSRI
Methylphenidate is what?
(Ritalin) - Central stimulant, DA & NE releaser & uptake blocker
Haloperidol is what?
(Haldol) - D2 antagonist
Clonidine - is what?
central a2-adrenergic agonist
Flumazenil is what?
Benzodiazepine GABAA receptor antagonist
Serotonin (5-Hydroxytryptamine, 5-HT)
Mediates affective processes such as aggressive behavior and arousal
Descending pain pathways
Sensory enhancement
Depression is associated with decreased 5-HT function
- Treated with SSRIs
Ectasy (MDMA), LSD and other hallucinogens probably act in part by interacting with 5-HT receptors
Ionotropic Serotonin Receptors
5-HT3 receptor
Non-selective cation channel (Excitatory)
Metabotropic Serotonin Receptors
5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, 5-HT7
Over a dozen subtypes
5-HT1 is inhibitory
5-HT2A is excitatory
5-HT4 is excitatory
Norepinephrine
Modulates sleep, wakefulness, attention, and feeding behaviors
Roles in learning and memory, anxiety and pain, and mood
A neuron can make more than 250,000 synapses, and that cell can have one axon branch in thecerebralcortex and another in thecerebellarcortex
Neuropeptides vs Conventional NTs
synthesis: cell body vs presynaptic terminal
storage: large dense-core vesicles vs. small synaptic vesicles
release: colocalized wtih conventional NTs vs by separate sets of neurons
inactivation: uncharacterized vs. reuptake or enzymatic degradation
Endogenous Opioid Peptides
Endorphins, Enkephalins, and Dynorphins
Morphine-like compounds involved in pain pathway
Potent pain relievers, such as morphine, oxycodone, and fentanyl, bind to opioid receptors
Receptors for the opioid peptides are present in the brain and peripheral tissues
Receptor subtypes and peptide selectivity: µ (endorphins), δ (enkephalins), and κ (dynorphins)
one last thing
check out the slide on alpha/ Gi/ etc. receptors and stuff. one of the last slides.
