Part II Part II
Chapter 5 Chapter 5
The past 20 years have afforded scientists with a greater understanding of the brain.
Extreme changes in psychopharmacology have produced newer medicines with fewer side effects and greater benefi ts than ever before. These changes translate into improved wellness for patients with mental health disorders.
This chapter presents the following:
A basic outline of the currently understood processes by which the brain
communicates
Information to support an improved understanding of the inner brain mechanisms
from synaptic and cellular viewpoints in regard to psychopharmacology
The signaling pathways associated with the six neurotransmitters most commonly
altered in modern psychopharmacological therapy
A strong scientifi c background on which to base psychopharmacological
prescribing practices
NeurotraNsmitters
These are the molecules that mediate intracellular signaling of the brain.
Neurotransmitters are chemicals that communicate their messages to the interior of
the neurons
Through their release from the presynaptic terminal
By diffusing across the synaptic cleft
To further bind to receptors in the postsynaptic membrane
The Relationship
of Psychopharmacology
to Neurotransmitters,
Receptors, Signal Transduction,
and Second Messengers
There are more than several dozen known or suspected neurotransmitters in the
brain.
Theoretically, there may be several hundred neurotransmitters based on the
amount of genetic materials in the neurons.
Neurotransmitters are endogenous molecules; examples include various peptides
and hormones (Table 5.1).
Psychoactive drugs act by increasing, decreasing, or otherwise modulating the
actions of neurotransmitters at their receptor sites.
Ligand
is a generic term referring to either endogenous or exogenous receptor binding partner proteins to which neurotransmitters bind, resulting in changes to downstream cellular processes.
The following six neurotransmitter systems are the major targets for psychotropic
drugs:
Serotonergic neurons
(neurotransmitter = serotonin) originating primarily in the raphe nuclei of the reticular formation extending from the medulla to the midbrain
Noradrenergic neurons
(neurotransmitter = norepinephrine) originating in the locus coeruleus
Dopaminergic neurons
(neurotransmitter = dopamine) originating primarily in the ventral tegmental area
Muscarinic cholinergic neurons
(neurotransmitter = acetylcholine) one of the
principal neurotransmitters in the autonomic nervous system Glutamatergic neurons
(neurotransmitter = glutamate) an amino acid transmit- ter synthesized by the brain from glucose and other nutrients for motor activity GABAergic neurons
(neurotransmitter = gamma-aminobutyric acid [GABA]) an inhibitory amino acid neurotransmitter, which is synthesized from glutamate in the brain and decreases activity in nerve cells
These six neurotransmitters are relatively low-molecular-weight amines or amino
acids.
Multiple neurons that release more than one neurotransmitter may converge at a
single synapse.
Cotransmission involves a monoamine coupled with a neuropeptide.
table 5.1 major Neurotransmitters in the central Nervous system
NeurotraNsmitter effects
Acetylcholine (ACh) Cognition, learning, memory, alertness, muscle contraction Dopamine Pleasure, pain, movement control, emotional response Gamma-aminobutyric acid Psychomotor agitation/retardation, stress, anxiety
Glutamate Memory, energy
Norepinephrine Arousal, dreaming, depressed mood, suicide, apathy, psychomotor agitation/retardation, constricts blood vessels, increases heart rate and blood pressure, affects attention and the sleep—wake cycle Serotonin Mood control, temperature regulation, impulsiveness, aggression,
cognitive problems, depressed mood, suicide, apathy, psychomotor agitation/retardation
NeurotraNsmitters, receptors, sigNal traNsductioN, aNd secoNd messeNgers 53
This natural combination of multiple signaling molecules at the synapse is the
basis for the modern treatment rationale of prescribing drugs affecting multiple neuronal signaling pathways.
siX NeurotraNsmitters most commoNlY aFFected BY psYcHopHarmacologY treatmeNt regimeNs*
Communication within the brain happens in three ways: anterograde, retrograde, or non- synaptic. Chemical neurotransmission is the foundation of psychopharmacology.
Anterograde neurotransmission:
Most predominant means of excitation-coupling and synapses.
Occurs in one direction (i.e., presynaptic to postsynaptic), from the cell body,
down the axon, to the synaptic cleft.
Involves stimulation of a presynaptic neuron causing electrical impulses to be
sent to its axon terminal (may be regarded as “classic” neurotransmission).
Electrical impulses are converted into chemical messengers, known as
neurotransmitters.
Chemical messengers (neurotransmitters) are released to stimulate the receptors
of the postsynaptic neuron.
Communication
within a neuron is mediated by electrical conduction of an action potential from the cell body down the axon of the neuron where it ends at the synaptic cleft.
Communication
between neurons is chemical and mediated by one of the several neurotransmitters described earlier.
Excitation–secretion coupling is the process by which an electrochemical signal
in the first (i.e., presynaptic) neuron is converted from a chemical impulse into the release of a chemical signal at the synapse.
Electrical impulses result from the opening of
ion channels in the neuronal cell
membrane along the axon, causing a change in net charge of the neuron. The difference in charge between the inside of the cell and the outside of the cell is referred to as an action potential.
Voltage-sensitive sodium channels
Voltage-sensitive potassium channels
All this happens very quickly once the electrical impulse enters the presynaptic
neuron.
Occurs predominately in one direction (from the cell body, down the axon, to the
synaptic cleft).
Retrograde neurotransmission:
Postsynaptic neurons can talk back directly and indirectly.
Indirectly through a long neuronal feedback loop
Directly through retrograde neurotransmission from postsynaptic to
presynaptic
Examples of retrograde neurotransmitters synthesized in the postsynaptic neu-
ron, released, and diffused into the presynaptic neuron are
Endocannabinoids (endogenous compounds similar to marijuana, also known
as cannabis) Nitric oxide
*Currently prescribed psychotropic medications are developed to target these neurotransmitter signaling pathways.
Nonsynaptic neurotransmission:
No neurotransmission across a synaptic cleft
Chemical messengers sent by one neuron diffuse to compatible receptor sites
distant to the synapse
receptors
These are proteins to which neurotransmitters bind, resulting in changes to down- stream cellular processes.
Found within plasma membranes and cytoplasm of a cell
Affected by psychoactive drugs
Located on cell membranes of neurons
receptors specific to psychopharmacology
Psychotropic medications are developed to target these various receptor sites.
Serotonin:
binds to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT5A receptors (Table 5.2)
Norepinephrine:
binds to alpha1 and alpha2, beta1, beta2, and beta3 receptors (Table 5.3) Dopamine:
binds to D1, D2, D3, D4, and D5 receptors (Table 5.4)
Acetylcholine: binds to nicotinic (N) and muscarinic (M) receptors (Table 5.5)
table 5.2 serotonin
receptor type DistributioN effects 5-HT1, 5-HT1A,
5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F
Brain, blood vessels, intestinal nerves
Inhibitory: neuronal inhibition, cerebral vasoconstriction
Behavioral effects: addiction, aggression, anxiety, appetite, impulsivity, learning, memory, mood, sexual behavior, sleep 5-HT2, 5-HT2A,
5-HT2B, 5-HT2C
Brain, blood vessels, heart, lungs, smooth muscle control, GI system, blood vessels, platelets
Excitatory: neuronal excitation, vasoconstriction
Behavioral effects: addiction, anxiety, appetite, mood, sexual behavior, sleep 5-HT3 Limbic system, CNS, PNS,
GI system
Excitatory: nausea
Behavioral effects: addiction, anxiety, learning, memory
5-HT4 CNS, smooth muscle, GI
system
Excitatory: neuronal excitation, GI
Behavioral effects: anxiety, appetite, learning, memory, mood
5-HT5, 5-HT5A, 5-HT6, 5-HT7
Brain Inhibitory: may be
linked to BDNF
Behavioral effects: sleep
5-HT6 CNS Excitatory: may be linked to BDNF
Behavioral effects: anxiety, cognition, learning, memory, mood
5-HT7 CNS, blood vessels GI system
Excitatory: may be linked to BDNF
Behavioral effects: anxiety, memory, sleep, mood
BDNF, brain-derived neurotrophic factor; CNS, central nervous system; GI, gastrointestinal; PNS, peripheral nervous system.
NeurotraNsmitters, receptors, sigNal traNsductioN, aNd secoNd messeNgers 55
table 5.3 Norepinephrine
receptor type DistributioN effects
Alpha1 Brain, heart, smooth muscle Excitatory: vasoconstriction, smooth muscle contraction
Alpha2 Presynaptic neurons in brain, pancreas, smooth muscle
Inhibitory: vasoconstriction,
gastrointestinal relaxation presynaptically
Beta1 Heart, brain Excitatory: increased heart rate
Beta2 Lungs, brain, skeletal muscle Excitatory: bronchial relaxation, vasodilation, smooth muscle relaxation Beta3 Adipose tissue Excitatory: stimulation of effector cells
table 5.4 dopamine
receptor type DistributioN effects
D1 Brain, smooth muscle Excitatory: possible role in
schizophrenia and Parkinson’s D2 Brain, cardiovascular system, presynaptic
nerve terminals
Inhibitory: possible role in schizophrenia
D3 Brain, cardiovascular system, presynaptic nerve terminals
Inhibitory: possible role in schizophrenia
D4 Brain, cardiovascular system, presynaptic nerve terminals
Inhibitory: possible role in schizophrenia
D5 Brain, smooth muscle Excitatory: possible role in
schizophrenia and Parkinson’s
table 5.5 acetylcholine
receptor type DistributioN effects
M1 Ganglia, secretory glands Excitatory: CNS excitation, gastric acid secretion
M2 Heart, nerves, smooth
muscle
Inhibitory:
cardiac inhibition, neural inhibition
M3 Glands, smooth muscle,
endothelium, secretory glands
Excitatory: smooth muscle contraction, vasodilation
M4 CNS, PNS, smooth muscle,
secretory glands
Inhibitory
M5 CNS Inhibitory
NM Skeletal
muscle, neuromuscular junction
Excitatory: neuromuscular transmission
NN Postganglionic cell body dendrites
Excitatory: ganglionic transmission CNS, central nervous system; PNS, peripheral nervous system.
GABA
binds to GABAA and GABAB receptors (Table 5.6) Glutamate
binds to AMPA, kainate, and NMDA receptors (Table 5.7)
sigNal traNsductioN
Signal transduction is the movement of signals from the outside of a cell to the inside.
Signal
→ receptor → change in cell function
Plays a very specific role through messaging and activation of an inactive molecule
Starts a reaction that cascades through chemical neurotransmission via numer-
ous molecules
Long-term effects of late gene products and many more messages
Can occur over the time course of minutes, hours, days, or weeks
Effects may be temporary or permanent
Signal transduction translates into the following diverse biological responses:
Gene expression
Synaptogenesis
secoNd messeNgers
Second messengers are synthesized and activated by enzymes, and help mediate intra- cellular signaling in response to a ligand binding to its receptor.
Relay and amplify signals received by receptors such as cyclic adenosine mono-
phosphate (cAMP), inositol trisphosphate (IP3), used for signal transduction in biological cells and Ca2+.
eNdogeNous NeurotraNsmitters See Table 5.8.
table 5.6 gaBa
receptor type DistributioN effects GABAA Central nervous system Inhibitory GABAB Autonomic nervous system Excitatory GABA, gamma-aminobutyric acid.
table 5.7 glutamate
receptor type DistributioN effects
AMPA CNS Excitatory
Kainate CNS Excitatory
NMDA CNS Excitatory
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CNS, central nervous system; NMDA, N-methyl-D-aspartate receptor.
NeurotraNsmitters, receptors, sigNal traNsductioN, aNd secoNd messeNgers 57
table 5.8 endogenous Neurotransmitters
NeurotraNsmitter receptor sigNal traNsDuctioN secoND messeNger
Acetylcholine Muscarinic G-protein linked cAMP or IP3
Nicotinic Ion channel linked Calcium
Dopamine D1, D2, D3, D4, D5 G-protein linked cAMP or IP3
alpha1, beta2 G-protein linked cAMP or IP3
GABA GABAA Ion channel linked and
ligand-gated ion channels
Calcium
GABAB G-protein linked cAMP or IP3
Glutamate AMPA, Kainate, and NMDA
Ion channel linked Calcium
Metabotropic G-protein linked cAMP or IP3
Norepinephrine alpha1, alpha2 G-protein linked cAMP or IP3
beta1 G-protein linked cAMP or IP3
Epinephrine alpha1, alpha2 G-protein linked cAMP or IP3
beta1, beta2 G-protein linked cAMP or IP3 Serotonin 5-HT1A, 5-HT1B, 5-HT1D,
5-HT1E, 5-HT1F
G-protein linked cAMP or IP3
5-HT2, 5-HT2A, 5-HT2B, 5-HT2C
G-protein linked cAMP or IP3
5-HT3 Ion channel linked Calcium
5-HT4 G-protein linked cAMP or IP3
5-HT5A G-protein linked cAMP or IP3
59