Neurotransmitters Review

8/8/2019 Neurotransmitters Review

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NEURON

A specialized cell that receives, propagates, and transmits electrochemical impulses

SYNAPSE

Made up of:

Two cell membranes

1. Presynaptic neuron sends the signal (axon)2. Postsynaptic neuron target cell that receives the signal (dendrite)

A synaptic cleft

SYNAPSE Electrochemical

Characterized by the formation of gap junctions that allows ions and organic compounds

to pass

Faster than chemical

CHEMICAL SYNAPSE

Characterized by the presynaptic release of neurotransmitters that diffuse across a

synaptic cleft to bind with postsynaptic receptors

Slower than electrical

SYNAPSE Pharmacology

Many drugs have their site of action in the nervous system in or around the synapse

Sedatives and anesthetics block nerve impulses by altering membrane permeability to

ions

No sodium entry = no action potential

NEUROTRANSMITTER

A chemical messenger that is synthesized within neurons themselves and released by

these same neurons (presynaptic) to communicate with their target cell or neuron(postsynaptic)

Neurotransmitters either stimulate or inhibit electrical impulses in target cells

RECEPTOR a transmembrane protein molecule that a neurotransmitter or drug binds to.

RECEPTORS

Found on cell membrane of both neurons

Specific to a particular neurotransmitter

With receptor subtypes for a particular NT

Neurotransmitter and receptor = key and lock relationship

Locksmith master key

Pharmacologists produce receptor-active drugs

SITES OF DRUG ACTIONS

1. Synthesis of NT

2. Transport of NT down the presynaptic axon

3. Storage in the vesicles

4. Release of NT


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5. Receptor binding

6. NT reuptake

7. NT breakdown by enzyme

Neurotransmitter-Receptor Binding

Binding is brief (milliseconds)

NT is quickly removed from the synaptic cleft by a biochemical process specific to theindividual NT:

1. REUPTAKE

Reabsorption back into the presynaptic axonal terminal for recycling

Performed by a protein reuptake transporter

2. ENZYMATIC BREAKDOWN

NT is destroyed by an enzyme

E.g., Monoamine oxidase (MAO); Acetylcholinesterase

3. MOVEMENT BY DIFFUSION AWAY FROM SYNAPSE

PSYCHOPHARMACOLOGYSites of Drug Actions:

1. Synthesis of the NT

2. Transport of the NT down the

presynaptic axon

3. Storage in the vesicles

4. Release of the NT

5. Receptor Binding

6. NT Reuptake

7. NT Breakdown by enzymes

PSYCHOPHARMACOLOGY

Sites of Drug Actions:

1. Synthesis of the NT

2. Transport of the NT

down the

presynaptic axon

3. Storage in the

vesicles

4. Release of the NT

5. Receptor Binding

6. NT Reuptake

7. NT Breakdown by

enzymes

Abnormal

Neurotransmission

Deficient NT

Deficient Receptors


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Excess NT

Excess Receptors

NEUROTRANSMITTERS

CRITERIA FOR A NEUROTRANSMITTER

1. The molecule is synthesized in the neuron.2. The molecule is present in the presynaptic neuron and is released on depolarization

in physiologically significant amounts.

3. When administered exogenously as a drug, the exogenous molecule mimics the

effects of the endogeneous NT.

4. A mechanism in the neuron or the synaptic cleft acts to remove or deactivate the

NT.

NEUROTRANSMITTERS

CHOLINERGICS

AcetylcholineMONOAMINES

Dopamine

Norepinephrine or

Noradrenaline

Epinephrine or

Adrenaline

Serotonin or 5-HT

Histamine

AMINO ACIDS

Gamma-aminobutyric acid

(GABA)

Glutamate

Glycine

Aspartate

NEUROPEPTIDES

Enkephalins

Endorphins

Dynorphins

Substance P

Somatostatin

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Cholinergic: ACETYLCHOLINESOURCE: Dietary Choline

ACTION: Excitatory or inhibitory

LOCALIZATION: Brain, spinal cord, PNS

Nucleus basalis of Meynert cerebral cortex, limbic system

Reticular system cerebral cortex, limbic system, hypothalamus, thalamus

Myoneural junction, autonomic ganglia, parasympathetic postganglionic neurons

CHOLINERGIC RECEPTOR TYPES:

Muscarinic and Nicotinic Receptors (each with subtypes)

FUNCTION:

CNS: Enhances memory, involved in learning, recall,sleep and mood regulation

PNS: Activates muscles in the peripheral nervous system

Clinical Correlation

What will be the effect if there is a disturbance in the levels of circulating Acetylcholine?

Functions of Acetylcholine:

CNS: Enhances memory, involved in learning and recall, sleep and mood regulation


CNS: Enhances memory

CNS: Involved in learning and recall CNS: Involved in sleep and mood


REDUCED LEVELS

SEEN IN:

Dementia of the Alzheimers Type

( Ach-secreting neurons)

Myasthenia Gravis

( Ach receptors)

Downs Syndrome

DRUGS

1. Acetylcholine precursors

5. Cholinergic Agonist

5. Receptor Antagonist

Memantine (Namenda)

7. Cholinesterase inhibitors


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Donepezil (Aricept)

Rivastigmine (Exelon)

Galantamine (Reminyl)

Tacrine (Cognex)

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Monoamine: DOPAMINE

SOURCE: Tyrosine

ACTION: Excitatory

LOCALIZATION: Brain stem

1. Substantia nigra caudate nucleus-putamen (neostriatum)

Sensory stimuli and movement

2. Ventral tegmental area (VTA) mesolimbic forebrain

Cognitive, reward, and emotional behavior

3. Tubero-infundibular system

Neuronal control of the hypothalamic-pituitary endocrine system

DOPAMINERGIC RECEPTOR SUBTYPES: D1, D2, D3, D4, D5

FUNCTION:

Essential to movement

Influences motivation and emotional behavior

Plays a role in perception of reality

Involved in the brains reward system


What will be the effect if there is a disturbance in the transmission of dopamine?

Functions of Dopamine:

Essential to movement

Influences motivation and emotional behavior



INCREASED LEVELS

Schizophrenia

Drug-induced psychosis Other psychoses (e.g., mania)

Drug abuse

Drug dependence

DECREASED LEVELS

Parkinsons Disease

Depression


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Dopamine Hypothesis of Schizophrenia: Clinical Correlation

Drugs that block dopamine receptors have antipsychotic activity

Drugs that stimulate dopamine activity can, when given in high doses, induce psychotic

symptoms in non-schizophrenic patients

DOPAMINE

DRUGS

1. DOPAMINE PRECURSORS

Levodopa-Carbidopa (Sinemet)

2.

3.

4.

5. DOPAMINE RECEPTOR BLOCKADE (Antagonists)

D2, D3, D4 Blockers

Chlorpromazine (Thorazine)

Haloperidol (Haldol)

Weak D2 Blockers

Clozapine (Clozaril, Leponex)

What will be the effect if there is a disturbance in the transmission of dopamine?

Functions of Dopamine

Essential to movement Influences motivation and emotional behavior



INCREASED LEVELS

Schizophrenia

Drug-induced psychosis Other psychoses (e.g., mania)

Drug abuse

Drug dependence

DECREASED LEVELS Parkinsons Disease

Depression

PARKINSONS DISEASE

Slowly progressing, degenerative disorder

Destruction of dopamine-secreting neurons in the basal ganglia

Dopamine is essential for movement


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dopamine leads to movement disorders

Tremor at rest, sluggish initiation of movement, muscle rigidity

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Monoamine: NORADRENALINE

SOURCE: Tyrosine

ACTION: Excitatory

LOCALIZATION:

Brain stem: locus ceruleus, caudal raphe nuclei

Most prevalent NT

NORADRENERGIC RECEPTORS:

and with several subtypes

FUNCTION

Constricts blood vessels, raising blood pressure

Alertness, attention, concentration, learning, memory, energy, sleep and

wakefulness

Mood regulation

Helps determine motivation and reward


What will be the effect if there is a disturbance in the transmission of noradrenaline?

Functions of Noradrenaline:

Constricts blood vessels, raising blood pressure

Alertness, concentration, attention, learning, memory, energy, sleep and wakefulness

Mood regulation

Helps determine motivation and reward

REDUCED LEVELS

Memory loss

Social withdrawal

Depression

EXCESS LEVELS Anxiety disorders

Monoamine: HISTAMINE

ACTION: Neuromodulator

LOCALIZATION:

Hypothalamus cerebral cortex, limbic system, thalamus


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HISTAMINE RECEPTORS:

H1 receptors production of IP3 and DAG

H2 receptors production of cAMP

H3 receptors regulate vascular tone

FUNCTION:

Controls alertness, gastric secretions, cardiac stimulation, peripheral allergic

responses

Clinical Significance:

Blockade of H1 receptors mechanism of action for allergy medications

Blockade of H1 receptors partly the mechanism for commonly observed side

effects of psychotropic meds (e.g., sedation, weight gain, hypotension)

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Monoamine: SEROTONIN

(5-hydroxytryptamine or 5-HT)

SOURCE: Tryptophan

ACTION: Mostly inhibitory

LOCALIZATION:

Brain stem: caudal raphe nuclei, rostral raphe nuclei

SEROTONERGIC RECEPTORS:

5-HT1 to 5-HT7 with subtypes

FUNCTION

Control of food intake, sleep and wakefulness, sexual behavior, and regulation of

emotions (mood)

Temperature regulation, pain control

What will be the effect if there is a disturbance in the transmission of serotonin?

Functions of Serotonin:

Control of food intake, sleep and wakefulness, sexual behavior, and regulation of emotions

(mood)

Temperature regulation, pain control

REDUCED LEVELS

Depression

Risk for suicide

Alzheimers disease

DRUGS

6. BLOCKADE OF REUPTAKE

Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor

Cyclic Antidepressants

Imipramine (Tofranil)


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Selective Serotonin Reuptake Inhibitor (SSRI)

Fluoxetine (Prozac)

Sertraline (Zoloft)

7. BLOCKADE OF ENZYME BREAKDOWN

Monoamine Oxidase Inhibitor (MAOI)

Phenelzine (Nardil)

BIOGENIC AMINE HYPOTHESIS

of

MOOD DISORDERS

Based on the observation that tricyclic drugs and the MAOIs are effective in alleviating the

symptoms of depression

serotonin = depression

serotonin = mania

However, drugs that affect both NE and serotonin are effective in treating depression.

Also, drugs that affect primarily serotonin are also effective in treating depression.

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Amino Acid: GLUTAMATE

SOURCE: Glucose and Glutamine

ACTION: Excitatory

LOCALIZATION:

Cortex, thalamus, striatum

GLUTAMATERGIC RECEPTORS: 5

NMDA, AMPA, kinase receptors, AP4, and ACPD

N-methyl-D-aspartate (NMDA) receptor

allows passage of Na, K, and Ca

involved in learning and memory

Clinical Significance:

Glutamate release is stimulated by nicotine.

EXCITOTOXICITY hypothesis that excessive stimulation of glutamate receptors

leads to prolonged and excessive intraneuronal concentrations of Ca and NO. Such

conditions activate many enzymes (especially proteases) that are destructive to

neuronal integrity.

Too much NMDA receptor activity kills neurons (neurotoxic at high levels: Stroke, hypoglycemia, sustained hypoxia or ischemia

Degenerative diseases (e.g., Alzheimers disease, Parkinsons disease,

Huntingtons disease)

Too little NMDA receptor activity induces psychosis

Schizophrenia


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Amino Acid:

GAMMA-AMINOBUTYRIC ACID (GABA)

SOURCE: Glutamate

ACTION: Inhibitory

LOCALIZATION:

Widespread in the CNS

Major inhibitory NT in the brain

GABAERGIC RECEPTORS:

GABA A, B, C with several subtypes

FUNCTION:

Modulates other NT systems (rather than direct stimulus)

Mediator for the inhibitory feedback loop

Thought to suppress seizure activity, anxiety, mania

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NEUROPEPTIDES

ACTION: Neuromodulators

Enhance, prolong, inhibit, or limit the effects of principal neurotransmitters

PROPERTIES: Unlike the other NTs, peptides must be made in the cell body, where the genetic

information for making them resides

Preprohormones prohormones final hormones

From the cell body, transported down the axon for storage in the vesicles and

release in the synapse

Replenishing released neuroactive peptides takes a comparably long time

ENDOGENOUS OPIOIDS

Regulation of stress, pain and mood

Enkephalins Endorphins

Dynorphins

SUBSTANCE P

Mediation of the perception of pain

Hypothesis: Huntingtons, Alzheimers, mood disorders

NEUROTENSIN


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Hypothesis: Schizophrenia

CHOLECYSTOKININ

Causes anxiety and triggers panic attacks

Hypothesis: Schizophrenia, eating disorders, movement disorders

SOMATOSTATIN

aka Growth Hormone-Inhibiting Factor

Implicated in Alzheimers and Huntingtons disease

VASOPRESSIN & OXYTOCIN

Regulation of mood

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NEUROTRANSMITTER IMBALANCE

and

MENTAL and RELATED DISORDERS

Increased dopamine - Schizophrenia; other psychoses

Decreased dopamine - Parkinsons disease

Decreased norepinephrine - Depression

Decreased serotonin - Depression

Increased serotonin - Mania

Decreased acetylcholine - Alzheimers disease

Decreased GABA - Anxiety disorder

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Neurotransmitters Review