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
 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 the
individual 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

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

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
  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
 Acetylcholine
MONOAMINES
 Dopamine
 Norepinephrine or
Noradrenaline
 Epinephrine or
Adrenaline
 Serotonin or 5-HT
 Histamine
AMINO ACIDS
 Gamma-amino
butyric acid
(GABA)
 Glutamate
 Glycine
 Aspartate
NEUROPEPTIDES
 Enkephalins
 Endorphins
 Dynorphins
 Substance P
 Somatostatin

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Cholinergic: ACETYLCHOLINE
SOURCE: 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
 PNS: Activates muscles in the peripheral nervous system
 CNS: Enhances memory
 CNS: Involved in learning and recall
 CNS: Involved in sleep and mood
 PNS: Activates muscles in the peripheral nervous system
REDUCED LEVELS
SEEN IN:
 Dementia of the Alzheimer’s Type
(↓ Ach-secreting neurons)
 Myasthenia Gravis
(↓ Ach receptors)
 Down’s Syndrome

DRUGS
1. Acetylcholine precursors
5. Cholinergic Agonist
5. Receptor Antagonist
 Memantine (Namenda)
7. Cholinesterase inhibitors
  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 brain’s reward system

Clinical Correlation
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
 Plays a role in perception of reality
 Involved in the brain’s reward system

INCREASED LEVELS
Schizophrenia
Drug-induced psychosis Other psychoses (e.g., mania)
Drug abuse
Drug dependence

DECREASED LEVELS
Parkinson’s Disease
Depression
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
 Plays a role in perception of reality
 Involved in the brain’s reward system

INCREASED LEVELS
Schizophrenia
Drug-induced psychosis Other psychoses (e.g., mania)
Drug abuse
Drug dependence

DECREASED LEVELS Parkinson’s Disease

Depression
PARKINSON’S DISEASE
 Slowly progressing, degenerative disorder
 Destruction of dopamine-secreting neurons in the basal ganglia
 Dopamine is essential for movement
  ↓ 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:
 α and β 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
Clinical Correlation
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
  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
 Alzheimer’s disease
DRUGS
6. BLOCKADE OF REUPTAKE
 Non-Selective Serotonin and Norepinephrine Reuptake Inhibitor
 Cyclic Antidepressants
 Imipramine (Tofranil)
  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., Alzheimer’s disease, Parkinson’s disease,
Huntington’s 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: Huntington’s, Alzheimer’s, mood disorders
 NEUROTENSIN
  Hypothesis: Schizophrenia
 CHOLECYSTOKININ
 Causes anxiety and triggers panic attacks
 Hypothesis: Schizophrenia, eating disorders, movement disorders
 SOMATOSTATIN
 aka Growth Hormone-Inhibiting Factor
 Implicated in Alzheimer’s and Huntington’s disease
 VASOPRESSIN & OXYTOCIN
 Regulation of mood
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NEUROTRANSMITTER IMBALANCE
and
MENTAL and RELATED DISORDERS

Increased dopamine - Schizophrenia; other psychoses

Decreased dopamine - Parkinson’s disease
Decreased norepinephrine - Depression
Decreased serotonin - Depression
Increased serotonin - Mania
Decreased acetylcholine - Alzheimer’s disease
Decreased GABA - Anxiety disorder