Neurotransmitter
Small molecules that serve as messengers to transmit information between neurons (i.e. 5HT, NE, EPI). Small molecules with point to point transmission. They are released from one neuron and then bind to a receptor.
Neuromodulators
They come from cellular and nonsynaptic sites, yet influence the excitability of the nerve cell (ex. substance P, endorphins). They modulate function of the neuron.
Neurohormones
They can be released from neuronal and nonneuronal cells. They travel in circulation to act at a site distant from release site (ADH, etc). They can travel from brain to kidney.
Neuromediators
Intracellular or secondary messengers (cAMP, Ca++).
Tertiary messengers are phospholipase C and protein kinase C -> they are for cascade process of cell. Oncogenes are quaternary messengers.
Needed For Neurotransmitter
1. Synthesis
2. Storage and release
3. Action
4. Deactivation
Synthesis Of Neurotransmitter
All of the enzymes and precursors must be available in neuron so neurotransmitter can be produced locally.
Storage And Release Of Neurotransmitter
Need to be stored in neuron (usually vesicle). Action potential cause release of neurotransmitter in quantums. How fast neuron firing (modulated by neuromodulators -> fine tune release) tells how much neurotransmitter release.
Action Of Neurotransmitter
Neurotransmitter must have action -> i.e. action in another neuron or cause muscle contraction.
Deactivation Of Neurotransmitter
Examples of neurotransmitter deactivation: enzyme metabolize acetylcholine; have reuptake for catecholamine.
Drugs Affecting Synthesis, Transmission, And Release Of
Acetylcholine
Serotonin
Catecholamine
Drugs Inhibiting Synthesis Of Neurotransmitter
System Drug Action
Ach - Hemicholinium inhibits uptake of choline so no precursor in neuron
Catecholamine Methyltyrosine competitive inhibition of tyrosine hydroxylase
Carbidopa competitive inhibitor of aromatic amino acid decarboxylase
Serotonin p-Chlorophenylalanine competitive inhibitor of tryptophan hydroxylase
Methyltyrosine
Its tradename is Aldemac. It is an antihypertensive. It is stored in neuron, gets released, but no action. So it becomes a false transmitter. It inhibits tyrosine hydroxylase which is the rate limiting enzyme for catecholamine synthesis.
Carbidopa
It works peripherally. It inhibits conversion of L DOPA to dopamine. Carbidopa is used in Parkinson's disease since want the L DOPA you are giving to the patient to shift to the CNS and not in the periphery.
Drug Affecting Storage And Release Of Neurotransmitter
System Drug Action
ACh - Botulinum toxin blocks vesicular release of acetylcholine when action potential comes
Catecholamine - Reserpine prevents vesicular storage
Amphetamine and promotes release of Ephedrine catecholamines
Serotonin -Reserpine prevents vesicular storage
Reserpine
Reserpine not only prevents vesicular storage, but it also depletes vesicle. Reserpine decreases catecholamines since the catecholamines end up getting degraded by enzymes.
Drugs Affecting Catabolism And Reuptake Of
Ach
Catecholamines
Serotonin
Ach Inhibitors (All Block Enzymes)
Reversible
Edrophonium
Pseudoreversible
Physostigmine
Neostigmine
Irreversible
Diisopropyl phosphofluoride (DPF)
Malathion
Reversible Ach Inhibitors
Block for 30 minutes letting Ach build up.
Pseudoreversible Ach Inhibitors
Takes more time to reverse their action.
Irreversible Ach Inhibitors
DPF -> nerve gas.
Malathion -> insecticide.
Enzyme destroyed so have to wait for new enzyme to be produced -> by this time concentration of Ach increases causing paralysis via constant depolarization at receptor site giving death.
Mechanism Of Action Of Acetyl Choline Esterase
Break down of Ach occurs in less than one millisecond: First have bond broken in Ach; then electron shift to esteratic site; then bond made with enzyme; then regenerate enzyme; and then choline taken back to neuron.
Reversible Inhibition Of Acetyl Choline Esterase
Edrophonium binds to both sites and form enzyme inhibition complex increasing Ach at synaptic cleft giving constant depolarization.
Irreversible Inhibition Of Acetyl Choline Esterase
DPF binds to esteratic site giving inactivated phosphorylated enzyme making enzyme useless. If enzyme caught fast (i.e. minutes) before phosphorylation then can use atropine to reactivate enzyme.
MonoAmine Oxidase (MAO)
It is responsible for breakdown of catecholamines.
Monoamine Oxidase Inhibitors
Isozyme Selective Substrate Inhibitor
Type A MAO Serotonin, Clorgyline
Norepinephrine
Type B MAO Phenylethylamine Pargyline
Clorgyline
It increases neurotransmitter at synaptic cleft. Clorgyline is an antidepressant drug. With clorgyline, find NorEp in neuron, so higher concentration of NorEp within neuronal vessel.
Dopamine And Tyramine
They are good substrates for type A and type B MAO.
Neurotransmitter Reuptake Inhibition
Neurotransmitter Drug
NorEp Cocaine, Desipramine
Dopamine Cocaine, Amphetamine
Serotonin Amitriptyline, Imipramine
Cocaine
Gives explosive release of NorEp.
Desipramine
This is a tricyclic antidepressant. Increases NorEp at synaptic cleft.
(Depression occurs due to decrease in concentration of catecholamines).
Amitriptyline And Imipramine
They are both tricyclic antidepressants.
(Serotonin is also involved in the genesis of depression. If have increased serotonin concentration in synaptic cleft, then can reverse effects of depression).
Neurotransmitter
Have synthesis, storage, release, and then effect at receptor site.
Drugs Affecting Synthesis Of Neurotransmitter
Hemicholinium affect Ach synthesis and Methyltyrosine affect catecholamine synthesis.
Drugs Affecting Storage Of Neurotransmitter
By preventing storage of catecholamines, reserpine causes the catecholamines to be destroyed by MAO after release.
Drugs Affecting Reuptake Of Neurotransmitter
Catecholamine reuptake is blocked by cocaine, amphetamine, and tricyclic antidepressants -> leads to a high concentration of catecholamines in the synaptic cleft.
Pharmacology Of Neurotransmitter Receptors
Drugs that act as receptors.
Receptor subtypes.
Regulation of receptors.
Definition Of Agonist And Antagonist
Agonist
Drug that mimic action of neurotransmitter at the receptor site.
Antagonist
Drug that blocks action of neurotransmitter at receptor site.
Definition Of Receptor Types And Subtypes
Receptor type is defined by neurotransmitter that interacts with the receptor. A receptor type can be subdivided into subtypes on the basis of selective agonists and antagonists (i.e. five different muscarinic receptors, two different nicotinic receptors).
Classification Of Acetylcholine Receptors
cholinergic receptor
nicotinic receptor muscarinic receptor
nicotinic 1 nicotinic 2
receptor receptor
Agonists And Antagonists For Cholinergic Receptor Subtypes
Receptor Agonist Antagonist Anatomic Localization
muscarinic muscarine atropine parasympathetic end organ
pilocarpine
nicotinic nicotine tubocurarine -
nicotinic 1 DMPP hexamethonium autonomic ganglia
nicotinic 2 PTMA decamethonium striated muscle
Classification Of NorEp and Ep Receptor
Adrenergic Receptor
adrenergic adrenergic
1 2 1 2
Activate adenylate Increase calcium Inhibition of
cyclase (mediated by mobilization via adenylate
Gs) calcium channel and cyclase
phospholipase C (mediated by
(mediated by Gp) Gi)
Increase in cAMP (a
second messenger)
Functions Of Adrenergic Receptor
Receptor Location Effect
1 Adipocyte Lipolysis
Heart Tachycardia
2 Vascular Smooth Muscle Relaxation
Lung Bronchodilation
1 Vascular Smooth Muscle Contraction
2 Adipocyte Inhibition of lipolysis
Platelet Aggregation
Presynaptic autoreceptor NorEp release
Agonists And Antagonists For Adrenergic Receptor Subtypes
Receptor Agonist Antagonist
adrenergic Isoproterenol Propranolol
1 Tazolol Practolol
2 Terbutaline Butoxamine
adrenergic Phenylephrine Prazosin
2 Clonidine Yohimbine
Clonidine
Antihypertensive agent. It reduces blood pressure by affecting autoreceptors.
Classification Of Dopamine Receptors
Six subtypes of dopamine receptors. There are two important subtypes (D1 and D2).
Dopamine Receptor
Dopamine 1 Receptor (D1) Dopamine 2 Receptor (D2)
(Two types: D2, D2)
Activation of adenylate Inhibitory or no effect on
cyclase adenylate cyclase
Release of parathyroid Clinical efficacy of
hormone antipsychotic drugs
Inhibition of dopamine
release through
presynaptic autoreceptors
(usually D2)
Two Divisions Of Dopamine 2 Receptor
D2 is on post synaptic site. Antipsychotic drugs block D2.
D2 is on autoreceptors.
Agonists And Antagonists For Dopamine Receptors
Receptor Agonist Antagonist
Dopamine Apomorphine Thioridazine
D1
D2 Bromocriptine Haloperidol
Sulpiride
Haloperidol And Sulpiride
They are antipsychotics.
Classification Of Histamine Receptors
Histamine Receptor
Histamine 1 Receptor Histamine 2 Receptor
Bronchoconstriction Gastric Secretion
Contraction of gut
Agonists And Antagonists For Histamine Receptors
Agonist Antagonist
Histamine 1 2 Methylhistamine Diphenhydramine (Benadryl)
Histamine 2 4 Methylhistamine Cimetidine
Cimetidine
It is used for inhibiting gastric secretion.
Classification Of GABA Receptors
GABA Receptor
GABA A Receptor GABA B Receptor
Chloride ionophore
GABA A Receptor
Stimulation of it by GABA cause chloride channel to open.
Benzodiazepines And Barbiturates
These are antianxiety drugs that facilitate effect of GABA by opening channel wider letting more chloride through.
Agonists And Antagonists For GABA Receptors
Receptors Agonist Antagonist
GABA Kojicamine
GABA-A Muscimol Bicuculline
GABA-B Baclofen
Classification Of Endorphin Receptors
Endorphin (Opiate) Receptor
Receptor Receptor Receptor
Inhibition of adenylate
cyclase via Gi subprotein
Reduces cAMP to reduce pain
Gs Protein
Stimulating Gs protein leads to increase in cAMP which is responsible for mechanism of dependence.
Agonists And Antagonists For Endorphin Receptors
Agonist Antagonist
Endorphin Endorphin Naloxone
Receptor Morphine Naloxone
Receptor Enkephalins Naloxone
Receptor Dynorphin A Naloxone
Ketocycloazocine
Receptor
It is inhibited by c/s maloxasone.
Regulation Of Receptor Density
Up regulation.
Down regulation.
Up Regulation And Supersensitivity
Up Regulation: An increase in the number or density of receptor binding sites (i.e. receptor in plasma membrane may bubble to surface).
Supersensitivity: An increased response to a neurotransmitter or agonist drug.
Down Regulation And Desensitization
Down Regulation: A decrease in the number or density of receptor binding sites.
Desensitization: A decreased response to a neurotransmitter or agonist drug.
Consequences Of Receptor Up Regulation
Increase in maximum response (receptor is limiting factor in response).
Decrease in concentration of agonist needed to produce half maximal response (receptor is not limiting factor in response) (have increase in receptors).
Nerve Terminal And Synapse Diagrams
Normal (neuron releases NT to synaptic cleft).
Denervation Supersensitivity (not enough NT being released).
Overactivity (too much NT being released).
Denervation Supersensitivity
When increase number of receptor due to less NT release (i.e. antipsychotics block NT release increasing the number of receptors).
Overactivity
Too much NT released decreasing amount of receptors.
Neurotransmitters And Their Receptors (Medical Insights)
Disorder Disorder Type
Parkinsons Neurotransmitter
Myasthenia gravis Decrease in concentration of nicotinic receptors due to auto
antibody produced for the nicotinic receptor
Schizophrenia ?
Affective disorder ?
The Four Most Serious Mental Illnesses
Schizophrenia
Depression
Mania
The anxiety states
These disorders involve disturbances in thought, self awareness, perception, and affect social interaction.
Psychiatric Disorders Are Grouped According To Which Of The Four Major
Mental Faculties Are Affected
1. Disorders of thinking and cognition
(schizophrenia and delirium)
2. Disorders of mood
(affective disorder and anxiety)
3. Disorders of social behaviors
(character defects and personality disorders)
4. Disorders of learning, memory, and intelligence
(mental retardations and dementia)
Mental Illness
5% of U.S. population has at some time had some type of mental illness.
There Are Now Reliable Clinical Criteria For Classifying Mental Illnesses
Natural history (clinical course and outcome)
Response to specific treatment
Causality (etiology and pathogenesis)
Schizophrenia Symptoms
1. Bizarre delusions (i.e. hearing voices )
2. Prominent hallucinations, usually auditory
3. Disordered thoughts, incoherence, flattening of affect (i.e. ask person the date and person talks about something else; i.e. person might get stuck in talking about the past)
4. Loss of contact with reality
Two Psychotic Periods
1. Nonpsychotic period
See the negative symptoms. See negative social function: 1. person withdrawn; and 2. person want to be left alone.
2. Psychotic period
See hallucinations, delusions, bizarre behavior, and cationic states (muscular rigidity).
Antipsychotic Drugs Block Dopamine Receptors
It is now thought that an excess of dopamine transmission could be an important part of the pathogenesis of schizophrenia.
Dopamine Receptors
There are now at least six dopamine receptors (D1, D2, D2, D3, D4, and D5), and these are divided into two major groups: 1. D1 and D5; and 2. D2, D3, and D4.
Reserpine
It causes depletion of catecholamine stores -> causes remission in the psychotic states. Exasperate condition by enhancing dopamine store by using cocaine or amphetamines.
Antipsychotic
Neuropeptides that block dopamine receptors.
D1 and D5
They are coupled to Gs -> stimulates adenylate cyclase to cause decrease of cAMP. In striatum, cortex, and hippocampus, they have effects on motor condition. Gives stiffness -> the positive stimulus of muscular rigidity. Learning and memory functions disrupted (gives difficulty with organizing thoughts).
D2
It decreases cAMP in midbrain, caudal nucleus, and limbic system (for emotional behavior). D2 concentrated in nucleus circumfrens, amygdala, hippocampus, and part of the cerebral cortex -> causes a decrease in higher thinking.
D2
Linked to ((Gi)). Act as inhibitory autoreceptors which control release of dopamine. There may be a major defect in D2 receptor (gate keeper for dopamine concentration) -> then flood of dopamine to synapse.
D2
Correct information about D2: the D2 is the autoreceptor; the D2 is linked to Gp protein.
D2
D2 is linked to Gp protein -> involved with calcium. D2 stimulate Gp protein increasing phosphoinositide turnover.
Six Types Of Synaptic Dopamine Receptors
D1 and D5 D2 D2 D3 and D4
Molecular seven membrane seven membrane seven membrane seven membrane
structure spanning spanning spanning spanning
region region region region
Effect on increases decreases increases decreases
cAMP phospho (D)
inositide
turnover
Agonists
dopamine
apomorphine
Antagonists
phenothiazines
thioxanthenes
butyrophenones
clozapine
Blockage Of D2 And D2
Responsible for action of typical antipsychotic drugs.
D3 and D4 Receptors
Linked to Gi protein. Decrease cAMP. Located in limbic system and cerebral cortex -> gives decrease in cAMP levels. The atypical antipsychotics (i.e. clozapine) bind to D3 and D4.
Neuroanatomical Model Of Schizophrenia
Normal State Schizophrenia
Prefrontal Prefrontal
Cortex Cortex
-
Limbic
Area Limbic
- System
Brain Stem Brain Stem
DA Neuron DA Neuron
Schizophrenia
Increase in dopamine system. Increase in mesolimbic system (D2, D3, D4). Decrease in mesocortical system.
Four Major Pathways (s/a Tracks) Of Dopamine
1. Mesocortical System (higher thinking areas)-> positive symptoms of schizophrenia.
2. Mesolimbic system (emotional effects)-> negative symptoms of schizophrenia.
3. Tubuloinfidibulum -> neuroendocrine function.
4. Nigrostriatal (globus pallidus, basal ganglia, cortex) -> motor system. (involved in Parkinson disease).
Schizophrenia
In normal state, mesocortical system feed back on mesolimbic system and brain stem -> disruption in balance in this system is schizophrenia leading to feedback inhibition giving disinhibition and get overactivity in mesolimbic pathway.
Other pathways -> neurotransmitter involved: when looking at antipsychotic drug -> effect in cholinergic, glutanergic, serotonergic ((5HT1)), and histaminergic sites.