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