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What role do the action potential and calcium play in exocytosis?
by triggering synaptic vesicle exocytosis, thereby releasing the neurotransmitters contained in the vesicles and initiating synaptic transmission
How does the presynaptic cell “know” when it’s released enough neurotransmitter?
The presynaptic cell "knows" when it has released enough neurotransmitter through autoregulation, which involves feedback mechanisms that adjust the amount of neurotransmitter released based on the needs of the postsynaptic cell.
What can happen to a molecule of neurotransmitter after it’s been released and done its job?
It can be cleared from the synaptic cleft by diffusion, reuptake, or degradation
What can happen to a molecule of neurotransmitter after it’s been released and done its job?
Within a neurotransmitter system, are there are multiple receptor subtypes?
Within a neurotransmitter system, there are multiple receptor subtypes. Each neurotransmitter can bind only to a very specific matching receptor. A neurotransmitter binds to a receptor in much the same way a key fits into a lock.
What’s the difference, structurally and functionally, between ionotropic and metabotropic postsynaptic receptors?
Ionotropic receptors are ligand-gated ion channels that open when a neurotransmitter binds to them, allowing ions to flow into or out of the cell. Metabotropic receptors are G protein-coupled receptors that activate a signaling cascade when a neurotransmitter binds to them, leading to the opening or closing of ion channels or other cellular effects.
How do ionotropic and metabotropic receptors differ in terms of how quickly they affect the postsynaptic cells?
Ionotropic receptors affect the postsynaptic cell more quickly than metabotropic receptors. Ionotropic receptors open immediately when a neurotransmitter binds to them, while metabotropic receptors activate a signaling cascade that takes longer to produce an effect.
When might you get desensitization of a receptor?
When it's exposed to a high concentration of a neurotransmitter for an extended period of time. This can cause the receptor to become less responsive to the neurotransmitter, leading to a decrease in the effect of the neurotransmitter on the postsynaptic cell.
Generally speaking, how does metabotropic receptor use chemicals inside the postsynaptic cell to affect what that cell does?
Metabotropic receptors use chemicals inside the postsynaptic cell to affect what that cell does. When a neurotransmitter binds to a metabotropic receptor, it activates a G protein that can activate or inhibit enzymes or ion channels in the cell, leading to a variety of cellular effects.
What sorts of effects can ionotropic and metabotropic postsynaptic receptors have on the postsynaptic cell?
Ionotropic and metabotropic postsynaptic receptors can have different effects on the postsynaptic cell. Ionotropic receptors can cause the cell to become more or less likely to fire an action potential, while metabotropic receptors can activate or inhibit enzymes or ion channels in the cell, leading to a variety of cellular effects.
What are some ways that drugs might interfere with neuronal function?
Some drugs can mimic the effects of neurotransmitters, while others can block the reuptake of neurotransmitters, leading to an increase in their concentration in the synapse. Some drugs can also block the binding of neurotransmitters to their receptors, leading to a decrease in their effect on the postsynaptic cell.
How is the message carried by hormones different from that of neurotransmitters?
Hormones are produced by glands and travel through the bloodstream to affect cells throughout the body, while neurotransmitters are produced by neurons and affect cells in close proximity to the neuron. Hormones also tend to have slower and longer-lasting effects.
Calcium (Ca2+)
Calcium (Ca2+) is an ion that plays a critical role in neurotransmitter release. When an action potential reaches the presynaptic terminal, it causes voltage-gated calcium channels to open, allowing calcium ions to enter the cell. The influx of calcium triggers the release of neurotransmitter from vesicles in the presynaptic terminal
Exocytosis
Exocytosis is the process by which neurotransmitter is released from the presynaptic terminal into the synaptic cleft. When an action potential reaches the presynaptic terminal, it causes voltage-gated calcium channels to open, allowing calcium ions to enter the cell. The influx of calcium triggers the fusion of neurotransmitter-containing vesicles with the presynaptic membrane, releasing the neurotransmitter into the synaptic cleft
Autoreceptors
Receptors located on the presynaptic terminal that are sensitive to the neurotransmitter released by the neuron. When the concentration of neurotransmitter in the synapse is high, they can inhibit further release of neurotransmitter, helping to regulate the amount of neurotransmitter released
Reuptake
Reuptake is the process by which neurotransmitter is taken back up into the presynaptic neuron after it has been released. Neurotransmitter transporters on the presynaptic membrane are responsible for reuptake. Reuptake helps to clear neurotransmitter from the synapse, allowing for precise control of neurotransmitter signaling
Desensitization
Desensitization of a receptor can occur when it is exposed to a high concentration of a neurotransmitter for an extended period of time. This can cause the receptor to become less responsive to the neurotransmitter, leading to a decrease in the effect of the neurotransmitter on the postsynaptic cell
Metabotropic receptore
Metabotropic receptors use G proteins and second messengers to affect what the postsynaptic cell does. When a neurotransmitter binds to a metabotropic receptor, it activates a G protein that can activate or inhibit enzymes or ion channels in the cell, leading to a variety of cellular effects
Ionotropic receptors
Ionotropic receptors, also known as ligand-gated ion channels, are a type of membrane-bound receptor protein that responds to ligand binding by opening an ion channel and allowing ions to flow into or out of the cell. They are primarily located along the postsynaptic membrane of neurons and are responsible for mediating rapid-onset and rapidly reversible synaptic transmission, generally in millisecond orders. Ionotropic receptors are made up of three, four, or five protein subunits that together form an ion-conducting pore in the center of the protein complex. When a neurotransmitter binds to the receptor, it causes a conformational change that is passed along to the closely associated ion channel, and as a result, the channel properties are altered. The activation of ionotropic receptors produces postsynaptic potentials, which are a result of ion flow through the receptor. Excitatory ionotropic receptors increase sodium permeability across the membrane, whereas inhibitory ionotropic receptors increase chloride permeability. The ion flow through the ionotropic receptors follows the same principles as other ion channels covered so far.
Hormones
chemical messengers produced by endocrine glands that travel through the bloodstream to affect cells throughout the body. Tend to have slower and longer-lasting effects.
Transporters
Transporters are proteins located on the presynaptic membrane that are responsible for reuptake of neurotransmitter after it has been released. They transport neurotransmitter back into the presynaptic neuron, where it can be repackaged into vesicles for later release
Enzymatic breakdown
Enzymatic breakdown is the process by which neurotransmitter is broken down by enzymes in the synaptic cleft. Enzymes like acetylcholinesterase break down neurotransmitter into inactive metabolites, which can be reabsorbed into the presynaptic neuron or cleared from the synapse by glial cells
Receptor subtypes
Different versions of a receptor that are specific to a particular neurotransmitter. Each subtype of receptor has a slightly different structure and function, allowing it to respond to the neurotransmitter in a unique wa
G proteins
G proteins are proteins that are activated by metabotropic receptors when a neurotransmitter binds to them. When activated, G proteins can activate or inhibit enzymes or ion channels in the cell, leading to a variety of cellular effects
Second messengers
Second messengers are small, non-protein molecules that pass along a signal initiated by the binding of a ligand (the “first messenger”) to its receptor. Second messengers include ions, cyclic AMP (cAMP), and inositol phosphates, which are made from phospholipids. Once generated, second messengers can activate enzymes like protein kinases, enabling them to phosphorylate their targets and pass along the signal
Protein kinases
Protein kinases are enzymes that add a phosphate group to a protein, changing its shape and function. They are often activated by second messengers like cAMP and are involved in many signaling pathways in the brain
Endocrine glands
Endocrine glands are glands that produce and secrete hormones into the bloodstream. Hormones travel throughout the body and affect cells in many different tissues and organs
Why does so much research in neuropharmacology involve nonhuman animals?
Nonhuman animals are often used in neuropharmacology research because their brains and nervous systems are similar to those of humans, making them useful models for studying the effects of drugs on the brain. Animal research can also help to identify potential side effects of drugs and to develop new treatments for neurological and psychiatric disorders
Can a researcher do whatever they want to a research animal?
No, researchers cannot do whatever they want to a research animal. Animal research is highly regulated and must follow strict ethical guidelines to ensure the welfare of the animals. Researchers must obtain approval from an institutional animal care and use committee (IACUC) before conducting any animal research, and they must follow specific protocols for animal care and use
What’s the objective of behavioral pharmacology?
The objective of behavioral pharmacology is to study the effects of drugs on behavior. This field of research aims to understand how drugs affect behavior at the molecular, cellular, and systems levels, and to develop new treatments for neurological and psychiatric disorders
What sort of behavior is measured by the open field test?
The open field test is used to measure exploratory behavior and anxiety in animals. In this test, an animal is placed in a novel environment and its behavior is observed. Measures of exploratory behavior include the number of times the animal crosses a line drawn on the floor, while measures of anxiety include the amount of time the animal spends in the center of the open field versus the periphery
What are the general principles of operant conditioning?
The general principles of operant conditioning involve using rewards and punishments to shape behavior. In operant conditioning, a behavior is followed by a consequence, either a reward or a punishment, which increases or decreases the likelihood of the behavior being repeated in the future
What sort of drug effect is measured by the tail-flick test?
The tail-flick test is used to measure the analgesic (pain-relieving) effects of drugs. In this test, an animal's tail is exposed to a heat source, and the time it takes for the animal to flick its tail away from the heat is measured. The latency to tail flick is a measure of pain sensitivity, and drugs that increase the latency are considered to have analgesic effects
Why is it important in the tail-flick test that the drug being tested does not act as a paralytic?
It is important in the tail-flick test that the drug being tested does not act as a paralytic because paralysis would prevent the animal from flicking its tail away from the heat source, making it impossible to measure pain sensitivity
What kinds of cognitive skills can be measured in nonhuman animals?
Nonhuman animals can be tested for a variety of cognitive skills, including learning, memory, attention, and decision-making. These skills can be measured using a variety of behavioral tasks, such as the Morris water maze, the radial arm maze, and the delayed matching-to-sample task
How do we measure a nonhuman animal’s affective (emotional) state?
A nonhuman animal's affective (emotional) state can be measured using a variety of behavioral and physiological measures, including vocalizations, facial expressions, heart rate, and cortisol levels. These measures can provide insight into an animal's emotional state and can be used to assess the effects of drugs on mood and emotion
In what way does the self-administration method help us gauge the rewarding properties of a drug? What elements of human drug use does this mimic?
The self-administration method involves allowing an animal to self-administer a drug by pressing a lever or performing some other behavior. This method helps researchers gauge the rewarding properties of a drug by measuring how much the animal is willing to work to obtain the drug. This method mimics elements of human drug use, such as the voluntary nature of drug use and the motivation to obtain drugs
How are the goals of neuropharmacology research techniques different from those of the behavioral pharmacology techniques?
The goals of neuropharmacology research techniques are to understand the molecular and cellular mechanisms of drug action in the brain and to develop new treatments for neurological and psychiatric disorders. The goals of behavioral pharmacology techniques are to study the effects of drugs on behavior and to develop new treatments for neurological and psychiatric disorders
What sorts of things can be done with a stereotaxic device and a microelectrode, or cannula?
A stereotaxic device and a microelectrode or cannula can be used to precisely target specific areas of the brain for drug delivery or lesioning. The stereotaxic device allows researchers to position the electrode or cannula in a specific location in the brain, while the microelectrode or cannula allows for precise delivery of drugs or other substances
Why might making a lesion in a nonhuman animal’s brain be useful for investigating brain function?
Making a lesion in a nonhuman animal's brain can be useful for investigating brain function because it allows researchers to study the effects of brain damage on behavior and brain function. Lesions can be made using a variety of techniques, including chemical lesions, electrolytic lesions, and mechanical lesions
How can radioligand binding be used to investigate what receptors are present in an area of the brain?
Radioligand binding can be used to investigate what receptors are present in an area of the brain by labeling a ligand with a radioactive isotope and measuring its binding to receptors in brain tissue. This technique can provide information about the density and distribution of receptors in the brain
How can autoradiography be used to study the distribution of a given receptor type throughout the brain?
Autoradiography can be used to study the distribution of a given receptor type throughout the brain by labeling a ligand with a radioactive isotope and exposing brain tissue to X-ray film. The resulting image shows the distribution of the receptor in the brain
What’s special about the ligand needed for radioligand binding and autoradiography?
The ligand needed for radioligand binding and autoradiography is special because it must be able to bind specifically to the receptor of interest and must be labeled with a radioactive isotope that can be detected
Explain each of these research techniques: CT, MRI, PET, and fMRI.
CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), and fMRI (functional magnetic resonance imaging) are all imaging techniques used to study the brain. CT use X-rays and MRI use magnetic fieldsto produce detailed images of the brain's structure. PET use radioactive tracers and fMRI use changes in blood flow to measure brain activity.
Behavioral pharmacology
Behavioral pharmacology is a field of research that studies the effects of drugs on behavior. This field aims to understand how drugs affect behavior at the molecular, cellular, and systems levels, and to develop new treatments for neurological and psychiatric disorders.
open field test
The open field test is a behavioral test used to measure exploratory behavior and anxiety in animals. In this test, an animal is placed in a novel environment and its behavior is observed. Measures of exploratory behavior include the number of times the animal crosses a line drawn on the floor, while measures of anxiety include the amount of time the animal spends in the center of the open field versus the periphery.
Operant conditioning
Operant conditioning is a type of learning in which behavior is shaped by rewards and punishments. In operant conditioning, a behavior is followed by a consequence, either a reward or a punishment, which increases or decreases the likelihood of the behavior being repeated in the future.
Analgesia
Analgesia is the reduction or elimination of pain. Drugs that produce analgesia are called analgesics.
tail-flick test
The tail-flick test is a behavioral test used to measure the analgesic (pain-relieving) effects of drugs. In this test, an animal's tail is exposed to a heat source, and the time it takes for the animal to flick its tail away from the heat is measured. The latency to tail flick is a measure of pain sensitivity, and drugs that increase the latency are considered to have analgesic effects.
delayed response test
The delayed response test is a behavioral test used to measure working memory in animals. In this test, an animal is presented with a stimulus and then must remember the stimulus after a delay period before responding.
elevated plus maze
The elevated plus maze is a behavioral test used to measure anxiety in animals. The maze consists of two open arms and two closed arms, and the animal's behavior is observed as it explores the maze. Measures of anxiety include the amount of time the animal spends in the open arms versus the closed arms.
self-administration method
self-administration method involves allowing an animal to self-administer a drug by pressing a lever or performing some other behavior. This method helps researchers gauge the rewarding properties of a drug by measuring how much the animal is willing to work to obtain the drug. This method mimics elements of human drug use, such as the voluntary nature of drug use and the motivation to obtain drugs.
stereotaxic device
stereotaxic device is a tool used to precisely target specific areas of the brain for drug delivery or lesioning. A microelectrode or cannula can be attached to the device to allow for precise delivery of drugs or other substances.
lesion
lesion is an area of damage or destruction in the brain. Lesions can be made using a variety of techniques, including chemical lesions, electrolytic lesions, and mechanical lesions. Lesions can be useful for investigating brain function by studying the effects of brain damage on behavior and brain function.
Radioligand binding
Radioligand binding is a technique used to investigate what receptors are present in an area of the brain by labeling a ligand with a radioactive isotope and measuring its binding to receptors in brain tissue. This technique can provide information about the density and distribution of receptors in the brain.
Autoradiography
Autoradiography is a technique used to study the distribution of a given receptor type throughout the brain by labeling a ligand with a radioactive isotope and exposing brain tissue to X-ray film. The resulting image shows the distribution of the receptor in the brain.
CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), and fMRI (functional magnetic resonance imaging)
all imaging techniques used to study the brain. CT use X-rays and MRI use magnetic fields to produce detailed images of the brain's structure. PET use radioactive tracers and fMRI use changes in blood flow to measure brain activity
What groupings are there for neurotransmitters (NTs)?
Neurotransmitter Groupings:
Small-molecule neurotransmitters
Peptide neurotransmitters
What is the name, abbreviation, and adjective form of each NT.?
Here are the names, abbreviations, and adjective forms of some of the most common neurotransmitters:
Acetylcholine (ACh): Abbreviation: ACh. Adjective form: cholinergic
Gamma-aminobutyric acid (GABA): Abbreviation: GABA. Adjective form: GABAergic
Glutamate: Abbreviation: Glu. Adjective form: glutamatergic
Glycine: Abbreviation: Gly. Adjective form: glycinergic
Norepinephrine (NE): Abbreviation: NE. Adjective form: noradrenergic
What general function does glutamate serve in the brain? What about GABA? (More specifically, what effect does each have on the postsynaptic membrane potential?)
Glutamate causes depolarization of the postsynaptic membrane potential, while GABA causes hyperpolarization
In what way must excitation and inhibition balance each other in the nervous system?
Excitation and inhibition must balance each other in the nervous system to maintain proper function. Too much excitation can lead to seizures, while too much inhibition can lead to sedation or coma
For each of the neurotransmitters, from what starting chemical is it synthesized?
Glutamate is synthesized from the precursor molecule glutamine
GABA is synthesized from the precursor molecule glutamate
Dopamine is synthesized from the precursor molecule tyrosine
Norepinephrine is synthesized from the precursor molecule dopamine
Serotonin is synthesized from the precursor molecule tryptophan
Acetylcholine is synthesized from the precursor molecule choline
What is the process of NT synthesis (number of steps, whether one NT is synthesized into another NT)
The process of NT synthesis:
Synthesis of enzymes needed for transmitter synthesis in the neuronal cell body
Transport of enzymes to the nerve terminal cytoplasm
Uptake of precursor molecules into the nerve terminal by transporter proteins
Conversion of precursor molecules into neurotransmitters by synthetic enzymes
Loading of neurotransmitters into synaptic vesicles by vesicular transporters
The number of steps involved in NT synthesis can vary depending on the type of NT. Peptide neurotransmitters require more steps than small-molecule neurotransmitters. In general, one NT is not synthesized into another NT
What is the purpose of NT synthesis? Why not just have them be, and stay, already-made in the nervous system?
The purpose of NT synthesis is to produce neurotransmitters that can be released into the synapse to communicate with other neurons. If neurotransmitters were already present in the nervous system, they would be constantly activating receptors and causing unwanted effects
What is the purpose of a rate-limiting enzyme in NT synthesis?
Rate-limiting enzymes control the rate of NT synthesis by regulating the production of key precursors. This ensures that the synthesis of neurotransmitters is tightly regulated and occurs at the appropriate rate
In what part of the neuron are the NTs we talked about synthesized?
NTs are synthesized in the presynaptic terminal
How are NT molecules loaded into presynaptic vesicles?
specialized transporters that use energy to move the molecules against their concentration gradient
What happens if you block this process of NT molecules being loaded into presynaptic vesicle (say, with reserpine)?
depletion of neurotransmitters in the synapse and a decrease in neurotransmission
What is the purpose of presynaptic autoreceptors?
They help regulate neurotransmitter release by inhibiting further release when the concentration of neurotransmitter in the synapse is high
What happens if you activate autoreceptors (say, with clonidine)?
decrease neurotransmitter release and decrease neurotransmission
What is the purpose of NT reuptake and how does it happen?
The purpose is to remove neurotransmitters from the synapse and terminate their action. It occurs when transporters on the presynaptic terminal membrane move neurotransmitters back into the presynaptic terminal
What happens if you inhibit reuptake (say, with an SSRI like Prozac)?
It can increase the concentration of neurotransmitters in the synapse and prolong their action
What enzyme breaks down monoamines? What about acetylcholine?
Monoamines are broken down by the enzyme monoamine oxidase (MAO), while acetylcholine is broken down by the enzyme acetylcholinesterase (AChE)
What happens if you inhibit an enzyme that breaks down a neurotransmitter?
It can increase the concentration of that neurotransmitter in the synapse and prolong its action
Why is it useful to know about the monoamine metabolites?
Monoamine metabolites can be useful in diagnosing certain neurological disorders, as their levels can indicate the activity of monoamine neurotransmitter systems
What is a NT “system”?
A neurotransmitter "system" refers to a group of neurons that use the same neurotransmitter to communicate with each other
Between what structures does the nigrostriatal dopaminergic pathway travel?
The nigrostriatal dopaminergic pathway travels between the substantia nigra and the striatum
What kind of symptoms might you get if you activate or deactivatethe nigrostriatal dopaminergic pathway?
Activating the nigrostriatal dopaminergic pathway can lead to symptoms such as increased movement and decreased tremors. Inhibiting the pathway can lead to symptoms such as decreased movement and increased tremors
Between what structures does the mesolimbic dopaminergic pathway travel?
The mesolimbic dopaminergic pathway travels between the ventral tegmental area (VTA) and the nucleus accumbens (NAc)
What midbrain structure gives rise to axons that release NE broadly throughout the brain? What behavioral effect does the NE release have?
The midbrain structure that gives rise to axons that release NE broadly throughout the brain is the locus coeruleus. The NE release has a variety of behavioral effects, including increased arousal, attention, and vigilance
What midbrain structures give rise to axons that release serotonin in the brain?
The midbrain structures that give rise to axons that release serotonin in the brain are the dorsal and median raphe nuclei
Explain how broadly throughout the brain the different NT systems send axons (and, thus, their NT).
Different NT systems send axons broadly throughout the brain, allowing for widespread communication between neurons. For example, the mesolimbic dopamine pathway sends axons to the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus
What NT is involved in the basal forebrain cholinergic system? About where in the brain is the basal forebrain?
The NT involved in the basal forebrain cholinergic system is acetylcholine. The basal forebrain is located deep within the cerebral hemispheres and is largely inhibitory, with tonical suppression of behavioral actions
What is the designations of the receptor subtypes? Which are ionotropic or metabotropic?
Receptor subtypes are designated by a combination of letters and numbers. Ionotropic receptors are designated by a combination of letters and numbers, while metabotropic receptors are designated by a combination of letters and numbers followed by the letter "m"
In what way is the NMDA receptor more complex than the others?
The NMDA receptor is more complex than other receptors because it requires the binding of both glutamate and glycine to open its ion channel. It is also voltage-dependent and requires depolarization of the postsynaptic membrane potential to become activated
What is it about the GABA A receptor that makes combining drugs like alcohol and barbiturates so dangerous?
The GABA A receptor is dangerous to combine with drugs like alcohol and barbiturates because they all enhance the activity of the receptor, leading to excessive inhibition of the nervous system and potentially fatal respiratory depression
Monoamines
Monoamines are a class of neurotransmitters that are derived from a single amino acid and include dopamine, norepinephrine, and serotonin
Dopamine (DA)
Dopamine (DA) is a monoamine neurotransmitter that is involved in reward, motivation, and movement
Norepinephrine (NE)
Norepinephrine (NE) is a monoamine neurotransmitter that is involved in arousal, attention, and vigilance
Catecholamines
Catecholamines are a class of monoamine neurotransmitters that include dopamine, norepinephrine, and epinephrine
Serotonin (5-HT)
Serotonin (5-HT) is a monoamine neurotransmitter that is involved in mood, appetite, and sleep
Acetylcholine
Acetylcholine is a neurotransmitter that is involved in muscle movement, attention, and memory
Amino acids
class of neurotransmitters that include glutamate and GABA. Glutamate is the primary excitatory neurotransmitter in the brain, while GABA is the primary inhibitory neurotransmitter
Precursors
molecules that are used to synthesize neurotransmitters. For example, tyrosine is a precursor for dopamine and norepinephrine, while tryptophan is a precursor for serotonin
Enzymes
proteins that catalyze chemical reactions. Enzymes are involved in the synthesis and breakdown of neurotransmitters
Rate-limiting enzymes
enzymes that control the rate of a chemical reaction. In the context of neurotransmitter synthesis, rate-limiting enzymes regulate the production of key precursors
Transporters
proteins that move molecules across cell membranes. Vesicular transporters are transporters that move neurotransmitters into vesicles for storage and release. Reuptake transporters are transporters that move neurotransmitters back into the presynaptic terminal to terminate their action
Autoreceptors
receptors located on the presynaptic terminal that are sensitive to the neurotransmitter being released. They help regulate neurotransmitter release by inhibiting further release when the concentration of neurotransmitter in the synapse is high
Monoamine oxidase (MAO)
molecules that are produced when neurotransmitters are broken down. The levels of metabolites can indicate the activity of neurotransmitter systems
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