Chapter 4 - Chemical Basis of Synaptic Transmission Flashcards
Drugs Affect Each Stage of ____________ and ___________
Neural Conduction
Synaptic Transmission
Cholinergic Pathways in the Brain
Two types of ACh receptors:
Nicotinic–most are ionotropic and excitatory
Muscarinic–metabotropic and can be excitatory or inhibitory
Drug tolerance
Drug tolerance can develop–successive treatments have decreasing effects
Metabolic tolerance–organ systems become more effective at eliminating the drug
Functional tolerance–target tissue may show altered sensitivity to the drug
A Neural Pathway Implicated in Drug Abuse
Another pathway may involve the insula, a brain region within the frontal cortex.
People with damage to this area have been able to stop smoking effortlessly.
exogenous substances
animal, vegetable, and mineral compounds from external sources
The brain is an ____________ system
electrochemical
most drugs that affect the nervous system do so by…
altering brain chemistry and synaptic transmission
neurochemistry
The branch of neuroscience concerned with the fundamental chemical composition and processes of the nervous system.
neuropharmacology
Also called psycho-pharmacology. The scientific field concerned with the discovery and study of compounds that selectively affect the functioning of the nervous system.
exogenous
Arising from outside the body.
endogenous
Produced inside the body.
most drugs that affect behavior do so by
altering synaptic neurotransmitter chemical communication process at millions, or even billions, of synapses.
endogenous substances
neurotransmitter
To be considered a classic neurotransmitter, a substance should meet the following criteria:
- The substance exists in presynaptic axon terminals.
- The presynaptic cell contains appropriate enzymes for synthesizing the substance.
- The substance is released in significant quantities when action potentials reach the terminals.
- Specific receptors that recognize the released substance exist on the postsynaptic membrane.
- Experimental application of the substance produces changes in postsynaptic cells.
- Blocking release of the substance prevents presynaptic activity from affecting the postsynaptic cell.
amine neurotransmitter
2 sub families
A neurotransmitter based on modifications of a single amino acid nucleus. Examples include acetylcholine, serotonin, or dopamine.
- Quaternary amines
- Monoamines
amino acid neurotransmitter
A neurotransmitter that is itself an amino acid. Examples include GABA, glycine, or glutamate.
peptide neurotransmitter (neuropeptide) 2 sub families
A neurotransmitter consisting of a short chain of amino acids.
- Opioid peptides
- Other neuropeptides
gas neurotransmitter
A soluble gas, such as nitric oxide or carbon monoxide, that is produced and released by a neuron to alter the functioning of another neuron.
Found widely throughout the body, NO has been implicated in processes as diverse as hair growth and penile erection, in addition to its role in the brain.
the major categories of some of the many neurotransmitters presently known
amine neurotransmitter
amino acid neurotransmitter
peptide neurotransmitter (neuropeptide)
gas neurotransmitter
Examples of AMINES
Quaternary amines
- Acetylcholine (ACh)
Monoamines
- Catecholamines: norepinephrine (NE), epinephrine (adrenaline), dopamine (DA)
- Indoleamines: serotonin (5-hydroxytryptamine; 5-HT), melatonin
Examples of AMINO ACIDS
Gamma-aminobutyric acid (GABA), glutamate, glycine, histamine
Examples of NEUROPEPTIDES
Opioid peptides
- Enkephalins: met-enkephalin, leu-enkephalin
- Endorphins: β-endorphin
- Dynorphins: dynorphin A
Other neuropeptides
- Oxytocin, substance P, cholecystokinin (CCK), vasopressin, neuropeptide Y (NPY), hypothalamic releasing hormones
Examples of gas neurotransmitters
Nitric oxide, carbon monoxide
Even if a substance is known to be a transmitter in one location, proving that it
acts as a transmitter at another location may be ___________
difficult.
Considering the rate at which neurotransmitters are being discovered and characterized, it would not be surprising if there turned out to be ________ _________
several hundred
receptor
Also called receptor molecule. A protein that binds and reacts to molecules of a neurotransmitter or hormone.
neurotransmitters affect their targets by interacting with receptors,
The transmitter molecule binds to the receptor, changing its shape to open an ion channel (as with fast, ionotropic receptors) or altering chemical reactions within the target cell (as with slow, metabotropic receptors)
Receptors add an important layer of complexity in neural signaling, because any given transmitter may affect various kinds of receptors that differ from one another in structure and therefore in how they respond to that neurotransmitter.
receptor
Also called receptor molecule. A protein that binds and reacts to molecules of a neurotransmitter or hormone.
neurotransmitters affect their targets by interacting with receptors,
The transmitter molecule binds to the receptor, changing its shape to open an ion channel (as with fast, ionotropic receptors) or altering chemical reactions within the target cell (as with slow, metabotropic receptors)
Receptors add an important layer of complexity in neural signaling, because any given transmitter may affect various kinds of receptors that differ from one another in structure and therefore in how they respond to that neurotransmitter.
ionotropic receptor
A receptor protein that includes an ion channel that is opened when the receptor is bound by an agonist.
metabotropic receptor
A receptor protein that does not contain an ion channel but may, when activated, use a G protein system to open a nearby ion channel.
receptor subtype
Any type of receptor having functional characteristics that distinguish it from other types of receptors for the same neurotransmitter.
These different receptor subtypes may trigger very different responses in target cells, and in many cases they are also distributed differently within the nervous system.
How can drug development capitalize on the existence of receptor subtypes?
Although a given neurotransmitter will interact with all the subtypes of its receptors, it is possible to design drugs that selectively affect only one of the subtypes, thereby producing the specific effects associated with that receptor subtype.
Although a given neurotransmitter will interact with all the subtypes of its receptors, it is possible to design drugs that selectively affect only one of the subtypes, thereby producing the specific effects associated with that receptor subtype.
A substance that binds to receptor molecules, such as those at the surface of the cell.
Three effects of competitive ligands
- A ligand that is classified as an agonist initiates the normal effects of the transmitter on that receptor.
- A receptor antagonist is a ligand that binds to a receptor and does not activate it, thereby blocking it from being activated by other ligands (including the native neurotransmitter).
- An inverse agonist—a less common type of ligand—binds to the receptor and initiates an effect that is the reverse of the normal function of the receptor.
agonist
A molecule, usually a drug, that binds a receptor molecule and initiates a response like that of another molecule, usually a neurotransmitter.
inverse agonist
A substance that binds to a receptor and causes it to do the opposite of what the naturally occurring transmitter does.
competitive ligand
A substance that directly competes with the endogenous ligand for the same binding site on a receptor molecule.
they bind to the same part of the receptor complex that the endogenous transmitter normally would.
noncompetitive ligand or neuromodulator
A substance that alters the response to an endogenous ligand, without interacting with the endogenous ligand’s recognition site.
drugs bind to a part of the receptor complex that does not normally bind the transmitter. Because this sort of drug does not directly compete with the transmitter for its binding site, we say that the drug is a noncompetitive ligand (or neuromodulator) binding to a modulatory site on the receptor.
Noncompetitive ligands may either activate the receptor, thereby acting as noncompetitive agonists, or prevent the receptor from being activated by the transmitter, thus acting as noncompetitive antagonists.
modulatory site
A portion of a receptor that, when bound by a compound, alters the receptor’s response to its transmitter.
co-localization
Also called co-release. Here, the appearance of more than one neurotransmitter in a given presynaptic terminal.
___________ was the first neurotransmitter to be identified
Acetylcholine
acetylcholine (ACh)
A neurotransmitter produced and released by parasympathetic postganglionic neurons, by motoneurons, and by neurons throughout the brain.
acetylcholine was long known to be a transmitting agent in the peripheral nervous system, but it was harder to prove that acetylcholine serves as a transmitter in the central nervous system as well. Now it is recognized that acetylcholine is widely distributed in the brain, and many scientists study its possible relationship to the cognitive deficits seen in Alzheimer’s disease.
cholinergic
Referring to cells that use acetylcholine as their synaptic transmitter.
Widespread loss of cholinergic neurons is evident in Alzheimer’s disease, suggesting that cholinergic systems are crucial for learning and memory. Similarly, the cholinergic antagonist scopolamine interferes with learning and memory in experimental settings.
nicotinic
Referring to cholinergic receptors that respond to nicotine as well as to acetylcholine.
Most nicotinic receptors are ionotropic, responding rapidly and usually having an excitatory effect. Muscles use nicotinic ACh receptors, so antagonists, such as the drug curare, cause widespread paralysis.
muscarinic
Referring to cholinergic receptors that respond to the chemical muscarine as well as to acetylcholine.
Muscarinic ACh receptors are G protein–coupled (metabotropic) receptors, so they have slower responses when activated, and they can be either excitatory or inhibitory (see Figure 3.15B). Muscarinic receptors can be blocked by the drugs atropine or scopolamine, producing pronounced changes in cognition, including drowsiness, confusion, memory problems, and blurred vision.
There are two principal classes of neurotransmitters that, because they are modified amino acids, are called ___________: ___________ and ___________
monoamines: catecholamines and indoleamines.
catecholamines
A class of monoamines that serve as neurotransmitters, including dopamine, dpinephrine, and norepinephrine.
indoleamines
A class of monoamines that serve as neurotransmitters, including dopamine, dpinephrine, and norepinephrine.
dopamine (DA)
A monoamine transmitter found in the midbrain—especially the substantia nigra—and basal forebrain.
Several subtypes of DA receptors have been discovered and have been numbered D1, D2, D3, D4, and D5, in the order of their discovery.
dopaminergic neurons and their projections in the brain, focusing on the mesostriatal pathway and the mesolimbocortical pathway
neurons that release release dopamine are called dopaminergic
mesostriatal pathway
A set of dopaminergic axons arising from the midbrain and innervating the basal ganglia, including those from the substantia nigra to the striatum.
Originates from the mesencephalon (midbrain)—specifically the substantia nigra and nearby areas—and ascends as part of the medial forebrain bundle to innervate the striatum: the caudate nucleus
and putamen.
The mesostriatal DA pathway plays a crucial role in motor control, and significant loss of these neurons produces the movement problems of Parkinson’s disease
mesolimbocortical pathway
A set of dopaminergic axons arising in the midbrain and innervating the limbic system and cortex.
The mesolimbocortical pathway also originates in the midbrain, in the ventral tegmental area (VTA), and projects to the limbic system (amygdala, nucleus accumbens, hippocampus) and the cortex. This system is important in reward and reinforcement, especially via the dopamine D2 receptor subtype
Abnormalities in the mesolimbocortical pathway are associated with some of the symptoms of schizophrenia,
substantia nigra
Literally, “black spot.” A group of pigmented neurons in the midbrain that provides dopaminergic projections to areas of the forebrain, especially the basal ganglia.
striatum
The caudate nucleus and putamen together.
ventral tegmental area (VTA)
A portion of the midbrain that projects dopaminergic fibers to the nucleus accumbens.
norepinephrine (NE)
Also called nor-adrenaline. A neurotransmitter produced and released by sympathetic postganglionic neurons to accelerate organ activity. Also produced in the brainstem and found in projections throughout the brain.
Because norepinephrine is also known as noradrenaline, NE-producing cells are said to be noradrenergic
he two main clusters of neurons in the brainstem releasing
norepinephrine (NE) are …
Locus coeruleus, in the pons,
lateral tegmental system of the midbrain
locus coeruleus
Literally, “blue spot.” A small nucleus in the brainstem whose neurons produce norepinephrine and modulate large areas of the forebrain.
noradrenergic
Referring to systems using norepinephrine (noradrenaline) as a transmitter.
Because norepinephrine is also known as noradrenaline, NE-producing cells are said to be noradrenergic, sympathetic fibers innervating the body are also noradrenergic.
Fibers from the noradrenergic cells of the locus coeruleus project broadly throughout the cerebrum, including the cerebral cortex, limbic system, and thalamus.
The CNS contains four subtypes of NE receptors—α1-, α2-, β1-, and β2-adrenoceptors—all of which are metabotropic receptors.
Given the brain’s wide noradrenergic projections, it’s no surprise that there are noradrenergic contributions to diverse behavioral and physiological processes, including mood, overall arousal, and sexual behavior.
serotonin (5-HT)
A synaptic transmitter that is produced in the raphe nuclei and is
active in structures throughout the cerebral hemispheres.
Serotonin has been implicated in the control of sleep states, mood, sexual behavior, anxiety, and many other functions. Drugs that globally increase 5-HT activity are effective antidepressants;
serotonergic
Referring to neurons that use serotonin as their synaptic transmitter.
Large areas of the brain are innervated by serotonergic fibers, although 5-HT cell bodies are relatively few and are concentrated along the midline in the raphe nuclei of the midbrain and brainstem.
raphe nuclei
A string of nuclei in the midline of the midbrain and brainstem that contain most of the serotonergic neurons of the brain.
The most common transmitters in the brain are ________ ________
amino acids.
The effects of the 4 most common amino acid neurotrglutamateansmitters
Glutamate and aspartate are important excitatory neurotransmitters.
Gamma-aminobutyric acid (GABA) and glycine typically have an inhibitory effect.
glutamate
An amino acid transmitter, the most common excitatory transmitter.
aspartate
An amino acid transmitter that is excitatory at many synapses.
gamma-aminobutyric acid (GABA)
A widely distributed amino acid transmitter, and the main inhibitory transmitter in the mammalian nervous system.
GABA receptors are divided into large classes: GABAA, GABAB, and GABAC receptors. Although they all normally respond to GABA, the subtypes of receptors exhibit quite different properties.
GABA receptors are divided into large classes: …
GABA receptors are divided into large classes: GABAa, GABAb, and GABAc receptors. Although they all normally respond to GABA, the subtypes of receptors exhibit quite different properties.
GABAa receptors are ionotropic, and when activated they produce fast inhibitory postsynaptic potentials. Each GABAA receptor is made up of five protein subunits surrounding a Cl– ion channel that can be widened or narrowed depending on the state of the surrounding complex. By mixing and matching of the various protein subunits that make up the GABAa receptors, the brain may in fact produce dozens of different kinds.
GABAb receptors are metabotropic receptors, typically producing a slow-occur-ring inhibitory postsynaptic potential.
GABAC receptors are ionotropic with a chloride channel, but they differ from other GABA receptors in certain details of their subunit structure.
glycine
An amino acid transmitter, often inhibitory.
glutamatergic
Referring to cells that use glutamate as their synaptic transmitter.
Glutamatergic transmission employs what are called AMPA, kainate, and NMDA receptors, which are ionotropic. Because NMDA-type glutamate receptors are active in a fascinating model of learning and memory, they have been studied very closely.
There are also several metabotropic glutamate receptors (mGluR’s), which act more slowly because they work through second messengers. Glutamate is also associated with excitotoxicity, a phenomenon in which neural injury, such as a stroke or trauma, provokes an excessive release of glutamate that overexcites cells, eventually killing them.
excitotoxicity
The property by which neurons die when overstimulated, as with large amounts of glutamate.
opioid peptide
A type of endogenous peptide that mimics the effects of morphine in binding to opioid receptors and producing marked analgesia and reward.
The actions of gas neurotransmitters like NO are different from those of the classic transmitters in several important ways.
List and explain three
First, nitric oxide is produced in cellular locations other than the axon terminals, especially the dendrites, and molecules of nitric oxide are not held in or released from vesicles; the substance simply diffuses out of the neuron as soon as it is produced.
Second, the released NO doesn’t interact with membrane-bound receptors on the surface of the target cell, but rather it diffuses into the target cell and stimulates the production of second messengers.
And third, NO can serve as a retrograde transmitter: diffusing from the postsynaptic neuron back to the presynaptic neuron, where it stimulates changes in synaptic efficacy that may be involved in learning and memory.
nitric oxide (NO)
A soluble gas that serves as a retrograde gas neurotransmitter in the nervous system.
nitric oxide, or NO (distinct from nitrous oxide, or laughing gas, which is N2O).
retrograde transmitter
A neurotransmitter that diffuses from the postsynaptic neuron back to the presynaptic neuron.
Recall that any given neurotransmitter interacts with a variety of different subtypes of receptors. This principle is crucial to neuropharmacology because…
unlike the transmitter, which will act on all its receptor subtypes, a drug can be targeted to interact with just one or a few receptor subtypes.
Why can so selectively activating or blocking specific subtypes of receptors have widely varying effects?
The various subtypes of receptors generally differ in their distribution within the brain, and they also serve very different cellular functions.
For example, treating someone with doses of serotonin would activate all of her serotonin receptors, regardless of subtype, and produce a variety of nonspecific effects. But drugs that are selective antagonists of 5HT3 receptors, showing little activity at other subtypes of serotonin receptors, produce a powerful and specific anti-nausea effect.
Apparently, evolution tinkers with the structure of ________ more than ___________.
Receptors
transmitters
The binding at a receptor sight is usually ________.
When the drug or transmitter breaks away from the receptor, the receptor ….
temporary
returns to its unbound shape and functioning.
Drug molecules _____ seek out particular receptor molecules
Don’t
A drug molecule that has more than one kind of action in the body exhibits this flexibility because …
Because it affects more than one kind of receptor molecule.
For example, some drugs combat anxiety at low doses without producing sedation (relaxation, drowsiness), but at higher doses they cause sedation, probably because at those doses they activate additional types of receptors.
binding affinity
Also called simply affinity. The propensity of molecules of a drug (or other ligand) to bind to receptors.
The degree of chemical attraction between a ligand and a receptor
A drug with high affinity for a particular type of receptor will selectively bind to that type of receptor even at low doses, and it will stay bound for a relatively long time. Lower-affinity drugs will bind fewer receptor molecules.
If a particular drug has a low affinity for a receptor, then it will ….
then it will quickly uncouple from the receptor. To bind half the receptors at any given time, a higher concentration of the drug is needed.
If a drug has a high affinity
for a receptor then …
the two will stay together for a longer time, and a lower concentration of drug will be sufficient to bind half the receptors.
If equal concentrations of the two
drugs are present then…
the high-affinity drug will be bound to more receptors at any given time. If the drugs have an equivalent effect on the receptors, then the higher-affinity drug will be more potent
efficacy
Also called intrinsic activity. The extent to which a drug activates a response when it binds to a receptor.
After binding, the propensity of a ligand to activate the receptor to which it is bound is termed its efficacy (or intrinsic activity): agonists have high efficacy and antagonists have low efficacy. Partial agonists are drugs that produce a middling response regardless of dose.
So, it is a combination of _______and________ that determines the overall action of a drug.
affinity
efficacy
where it binds and what it does
To some extent we can compare the effectiveness of different drugs by comparing their affinity for the receptor of interest.
Within certain limits, administering larger doses of a drug increase in receptor binding also increases the response to the drug; in other words …
greater doses tend to produce greater effects.
