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Summary Psychopharmacology (PSY3312)
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Detailed summary of all the recommended literature of this course. I passed the course the first time with a 9.0.
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Task 1What is the process of neurotransmission?
Neurotransmission can be described in many ways: anatomically,
chemically, electrically. The anatomical basis of neurotransmission
is neurons and their synapses. The anatomically addressed nervous
system, a complex of “hard-wired” synaptic connections between
neurons. There are axodendritic, axosomatic, dendro-dendritic and
axoaxonic synapses. These are asymmetric since communication is
designed to be in one direction.
The brain is electrochemical in nature—electrical signals within
brain cells (ion fluxes and action potentials) are converted to
chemical signals between cells (synaptic neurotransmission). It is
the chemical nature of the brain that allows it to be the target of
drugs (chemicals) that can affect brain function.
Proteins that are key to each of these stages (such as enzymes and
neurotransmitter receptors) can be targets for psychoactive drugs.
Psychoactive drugs act by stimulating, mimicking, blocking or
otherwise modifying the actions of neurotransmitters.
Proces/ Stages of life of a neurotransmitter (5)
1) Neurotransmitter molecules are synthesized
from precursors under the influence of enzymes.
Biosynthesis
Production of small molecule neurotransmitters occurs through
an enzyme-facilitated process. Increasing or decreasing biosynthesis can facilitate or diminish the function of
neurotransmitters.
Biosynthesis of dopamine: Tyrosine > L-dopa by the enzyme tyrosine
hydroxylase > dopamine by the enzyme dopa decarboxylase.
The drug alpha-methyl-para-tyrosine (AMPT) is an inhibitor of tyrosine
hydroxylase (drug target in this case) > decreases production of
dopamine.
Serotonin > precursor: tryptophan
2) Neurotransmitter molecules are stored in vesicles and prepares them for
release into the synapse.
Storage
The drug reserpine blocks the vesicular monoamine transporter
(VMAT), which is responsible for transporting dopamine and related
neurotransmitters into synaptic vesicles > Blockade of this transporter
prevents the uptake of monoamines > Vesicles are empty > reserpine
inhibits the function of monoamine neurotransmitters, including
dopamine, epinephrine, norepinephrine and serotonin.
3) Action potentials open voltage-gated ion channels, allowing calcium to enter
the terminal. Calcium can then bind to specific proteins to mobilize the
synaptic vesicles. The vesicles then fuse with the presynaptic membrane and
release their neurotransmitter molecules into the synapse.
Release:
Black widow spider venom (latrotoxin) stimulates the release of the
neurotransmitter acetylcholine, which causes excessive stimulation of
muscle fibers.
Botulinum toxin (Botox) irreversibly blocks the release of acetylcholine,
which prevents nerves from activating muscle fibers, effectively
paralyzing the muscles.
4) Released neurotransmitter molecules bind to postsynaptic receptors. Receptors are large protein complexes that
are embedded into the neuronal membrane. There are specific receptors for each major neurotransmitter.
Receptor activation
5) Released neurotransmitter molecules bind with autoreceptors and inhibit subsequent neurotransmitter release.
,6) Released neurotransmitter molecules are deactivated by either reuptake or enzymatic degradation. When a
receptor on a postsynaptic neuron is activated by a neurotransmitter, chemical and/or electrical signals are
generated, which thereby change the functional status of the neuron.
Inactivation/metabolism
Reuptake: via large protein complexes, known as transporters (reuptake sites), located on presynaptic
terminals. These transporters remove the neurotransmitter from the synapse and thereby terminate its
action, preventing it from further activating receptors.
o SSRI’s: block serotonin transporters so serotonin remains in the synapse longer.
Enzymatic inactivation: transforms the neurotransmitter into a compound that can no longer interact with
the receptors.
o Monoamine oxidase inhibitors: block the enzyme that inactivates monoamines.
An electrical impulse in the first neuron is converted to a chemical signal at the synapse > excitation-secretion
coupling. Once an electrical impulse invades the presynaptic axon terminal, it causes the release of chemical
neurotransmitter stored there. Electrical impulses open ion channels – both voltage-sensitive sodium channels
(VSSCs) and calcium channels (VSCCs) – by changing the ionic charge across neuronal membranes. As sodium flows
into the presynaptic nerve through sodium channels in the axon membrane, the electrical charge of the action
potential moves along the axon until it reaches the presynaptic nerve terminal where it also opens calcium channels.
As calcium flows into the presynaptic nerve terminal, it causes synaptic vesicles anchored to the inner membrane to
spill their chemical contents into the synapse. The way is paved for chemical communication by previous synthesis of
neurotransmitter and storage of neurotransmitter in the first neuron’s presynaptic axon terminal.
Classic neurotransmission begins with an electrical process by which neurons send electrical impulses from one part
of the cell to another part of the same cell via their axons.
Retrograde neurotransmission: from the postsynaptic neuron to the presynaptic neuron. For example,
endocannabinoids, nitric oxide and neurotrophic factors.
Neurotransmission without a synapse is called volume neurotransmission (nonsynaptic diffusion
neurotransmission). The transmission can occur at any compatible receptor within the diffusion radius. This is part of
the chemically addressed nervous system: how chemical signals are coded, decoded, transduced, and sent along
the way.
The first example of volume transmission is dopamine action in the prefrontal cortex. Here there are very few
dopamine reuptake transport pumps (DATs) to terminate the action of dopamine. The dopamine is free to spill
over from that synapse and diffuse to neighboring dopamine receptors and stimulate them.
Another example is at the sites of autoreceptors on monoamine neurons. At the somatodendritic end of the
neuron are autoreceptors that inhibit the release of neurotransmitter from the axonal end of the neuron. These
autoreceptors apparently receive neurotransmitter from dendritic release.
Neurons have dendrites at their receiving end, and axons extending from the cell body. At the end of the axon
(terminal) is a gap called the synapse.
Glia cells support neurons in a structural and nutritional way. The cells remove debris when damage occurs, serve
other housekeeping functions, synthesize myelin, facilitate electrical signaling in neurons, respond to
neurotransmitters and modulate neurotransmission.
Tripartite synapse: includes the presynaptic neuron, the postsynaptic neuron and synapse associated glia.
Binding affinity: the strength of the binding interaction between a single biomolecule (e.g. protein or DNA) to its
ligand/binding partner (e.g. drug or inhibitor).
Reversable binding <> Irreversible binding
Receptors: large protein molecules located on the surface of or within cells, are the initial sites of action of
biologically active agents such as NT, hormones, and drugs (all referred to as ligands).
Extracellular receptors: Receptors on exterior cell surface (most drugs and NT). Relay information through the
membrane to affect intracellular processes. Changes depend on whether the receptor is coupled with an ion
channel or with a G protein.
Intracellular receptors: in the cytoplasm or in the nucleus. Most hormones use this receptor. Binding alters cell
function by triggering changes is expression of genetic material within the nucleus.
Receptors recognize specific molecular shapes:
, Receptor agonists: molecules that can bind to a particular receptor protein to initiate a cellular response
(activate neurotransmitter receptors). Molecules with the highest affinity attach most readily to the receptor.
o Morphine > opioid receptors
Receptor antagonists: produce no cellular effect after binding,and prevent an “active” ligand from binding by
“blocking” the receptor.
o Naloxone (Narcan) > used for opioid overdoses since it rapidly reverses the effects of drugs that activate
these receptors.
Partial agonists: less efficacious than agonists (more effect then agonist but less then antagonist).
Inverse agonists: initiate a biological action when bound that’s opposite to that produced by an agonist.
Autoreceptors: regulate the biosynthesis and release of the neurotransmitter. They serve as a type of
“thermostat,” sensing the amount of neurotransmitter in the synapse.
Hence, drugs can vary in efficacy along a continuum, ranging from full agonists (max efficacy) to inverse agonists
(inverse efficacy).
Receptors are modified in number, and in sensitivity:
Up-regulation – increase in receptors
Down-regulation – decrease
It takes 1-2 weeks of altered activity to initiate a modification in number, while a change in sensitivity due to 2nd
messenger induced function is more rapid.
Receptor subtype – the receptor proteins of a given drug may have different characteristics in different target
tissues.
Ligands: any molecule that binds to a receptor with some selectivity. Binding or attachment of the
specific ligand is temporary. Once the ligand dissociates from the receptor, it has opportunities to attach again.
Receptor proteins have a normal life cycle. How much intracellular activity occurs depends on:
Number of interactions with the receptor.
Ability of ligand to alter the shape of the receptor, which reflects its efficacy.
Signal transduction: the electrical or chemical change in the cell produced by the activation of a receptor. There are
two main broad types of neurotransmitter receptors, each with a distinct signal transduction mechanism. There are
also hormone-linked systems, and neurotrophin-linked systems.
Signal transduction cascades triggered by chemical neurotransmission involve numerous molecules, starting with
neurotransmitter first messenger, and proceeding to second, third, fourth, and more messengers. The initial events
occur in less than a second, but the long-term consequences are mediated by downstream messengers that take
hours to days to activate yet can last for many days or even for the lifetime of a synapse or neuron.
Each molecular site within the cascade of transduction of chemical and electrical messages is a potential location for
a malfunction associated with a mental illness; it is also a potential target for a psychotropic drug.
Ionotropic receptors (ligand-gated ion channels/neurotransmitter-gated ion channels): Mediates the simplest signal
transduction mechanism and are large protein complexes with a central ion channel.
Neurotransmitter activates the receptor > ion channel opens >
specific ions flow through the channel.
Because ions are unequally distributed between the inside and the
outside of a neuron, electrical charges flow across the membrane,
and these charges directly excite or inhibit the neuron.
Fast receptors: the opening of the ion channel is a direct response
to binding of the neurotransmitter.
The ion channel in an ionotropic receptor may be selective for
sodium, potassium, chloride, or calcium.
Calcium not only produces an electrical change (an excitatory
effect), but can also activate specific enzymes in the neuron,
initiating biochemical cascades that can modify the neuron in
multiple ways.
Made of multiple protein subunits, so the pharmacology and
function of the receptors can vary depending on the specific
subunits that make it up.
, Metabotropic receptors (G-protein-coupled receptors (GPCRs)/7-transmembrane receptors): are large proteins that
fold within and across the neuronal membrane, containing an external binding site for the neurotransmitter, and an
internal tail that interacts with intracellular signaling molecules.
Rather than multiple subunits, a single protein makes up a metabotropic receptor. However, there may be
different variants of the protein, resulting in receptors that differ in pharmacology and function.
Process: neurotransmitter activates metabotropic receptor > conformational change in the receptor modifies an
associated protein complex (G-protein) > dissociation of the G-protein complex > allowing G-protein subunits to
then trigger other events in the neuron.
For example, a subunit of a G-protein may trigger the opening of an ion channel, allowing the flow of specific
ions into or out of the neuron.
Second messenger system: In addition to activating an ion channel, a subunit of a G-protein can activate an
enzymatic cascade that modifies the neuron in a longer-term manner—for example, by inserting receptors into
the neuronal membrane or by activating the biosynthesis of new molecules that will modify the function of the
neuron.
Second messengers can activate third messengers, which can alter gene transcription in the cell. This can lead to
increased or decreased production of key proteins, such as an enzyme or neurotransmitter receptor.
Excitation or inhibition of the cell is dependent on the type of ion channel that is activated. Nearly all
neurotransmitters have multiple receptor types, allowing for a large number of effects of a neurotransmitter.
Forming a second messenger
Every signal transduction cascade passes its
message from an extracellular first messenger to
an intracellular second messenger. In the case of
G-protein-linked systems, the second messenger
is a chemical, but in the case of an ion channel-
linked system, the second messenger can be an
ion such as calcium.
There are four key elements and four steps in the
G-proteins second-messenger system: The first-
messenger neurotransmitter, A receptor for the
neurotransmitter, G protein capable of binding
both to certain conformations of the
neurotransmitter receptor and to an enzyme
system that can synthesize the second
messenger and the enzyme system itself for the
second messenger.
There are four steps in this process:
1) Neurotransmitter binds to its receptor.
2) This changes the conformation of the
receptor so it can now fit with the G
protein.
3) The binding of the G protein to this new
conformation of the receptor-
neurotransmitter complex.
4) The G protein is now capable of binding to an enzyme. The enzyme then synthesizes the second messenger.
Pharmocokinetics and pharmacodynamics
Pharmacology: the scientific study of the actions of drugs and their effects on a living organism.
Neuropharmacology: concerned with drug-induced changes in the functioning of cells in the nervous system.
Psychopharmacology: emphasizes drug-induced changes in mood, thinking and behavior
Neuropsychopharmacology: the goal is to identify chemical substances that act on the nervous system to alter
behavior that is disturbed because of injury, disease, or environmental factors.
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