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.
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.
partial agonist or partial antagonist
A drug that, when bound to a receptor, has less effect than the endogenous ligand would.
dose-response curve (DRC)
A formal plot of a drug’s effects (on the y-axis) versus the dose given (on the x-axis).
When plotted as a graph, the relationship between drug doses and observed effects is called a dose-response curve (DRC). Careful analysis of DRCs reveals many aspects of drugs’ activity and is one of the main tools for understanding pharmacodynamics.
DRCs reveal the effective dose range of a drug and allow comparison of the potencies and efficacies of different drugs
Sometimes a DRC gives us hints that the drug may be binding more than one type of receptor. By directly comparing the DRCs for two drugs, we can determine which drug would be safer to use.
Types of uses of the dose-response curve (DRC)
a. The basic dose-response curve plots increasing drug doses against increasing strength of the response being studied. The dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50).
b. We can assess the relative potencies of two drugs by comparing their ED50 values.
c. We can compare drug efficacies by evaluating maximal responses, rather than doses.
d. The shape of a nonmonotonic DRC is normal up to a point, but then it reverses, and the measured response begins to decrease with larger doses. At that point, the drug is starting to have effects elsewhere than at the drug’s highest-affinity receptors.
e. The therapeutic index is the separation between the effective doses of a drug and the toxic doses.
effective dose
The dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50).
maximal responses
The dose of the drug where the effects start to level off.
We can compare drug efficacies by evaluating maximal responses
nonmonotonic DRC
The shape of a nonmonotonic DRC is normal up to a point, but then it reverses, and the measured response begins to decrease with larger doses. At that point, the drug is starting to have effects elsewhere than at the drug’s highest-affinity receptors.
therapeutic index
The therapeutic index is the separation between the effective doses of a drug and the toxic doses.
A Wide therapeutic index is when the effective doses of a drug and the toxic dose are far apart.
pharmacodynamics
Collective name for the factors that affect the relationship between a drug and its target receptors, such as affinity and efficacy.
dose-response curve (DRC) is one of the main tools for understanding pharmacodynamics.
tolerance
A condition in which, with repeated exposure to a drug, an individual becomes less responsive to a constant dose.
in which successive treatments with a particular drug have decreasing effects
Once established, drug tolerance is believed to be a major cause of withdrawal symptoms, the unpleasant sensations that occur when one stops using a drug.
different ways of creating tolerance
metabolic tolerance functional tolerance down-regulation up-regulation cross-tolerance
metabolic tolerance
The form of drug tolerance that arises when repeated exposure to the drug causes the metabolic machinery of the body to become more efficient at clearing the drug.
in which the body’s metabolic systems and organs (such as the liver) become increasingly effective at eliminating the drug before it has a chance to affect the brain or another target.
functional tolerance
Decreased responding to a drug after repeated exposures, generally as a consequence of up- or down-regulation of receptors.
he target tissue itself may show altered sensitivity to the drug
down-regulation
A compensatory reduction in receptor availability at the synapses of a neuron.
Over the course of repeated exposures to an agonist drug, target neurons often down-regulate (decrease the number of available receptors to which the drug can bind), thereby countering the drug effect.
The effects of an agonist drug augment the effects of the endogenous ligand, enhancing the effect on the postsynaptic cell. The postsynaptic cell may respond by down-regulating (decreasing) the number of receptors it places into the synapse, in order to become less sensitive and more like the pre-drug state.
up-regulation
A compensatory increase in receptor availability at the synapses of a neuron.
a competitive antagonist instead blocks an endogenous substance from having its usual effect, to which the postsynaptic cell may respond by up-regulating (increasing) the number of its receptors in order to become more sensitive and compensate for the lessened effect of the endogenous ligand.
cross-tolerance
A condition in which the development of tolerance for one drug causes an individual to develop tolerance for another drug.
Tolerance to a drug often generalizes to other drugs belonging to the same chemical class.
For example, people who have developed tolerance to heroin tend to exhibit a degree of tolerance to all the other drugs in the opiate category, including codeine, morphine, and methadone.
withdrawal symptom
An uncomfortable symptom that arises when a person stops taking a drug that he or she has used frequently, especially at high doses.
Once established, drug tolerance is believed to be a major cause of withdrawal symptoms, the unpleasant sensations that occur when one stops using a drug.
sensitization
A process in which the body shows an enhanced response to a given drug after repeated doses.
some drug responses can become stronger with repeated treatments, rather than weaker.
opposite of tolerance
this effect is thought to contribute to the drug craving that addicts experience.
This heightened sensitivity may last for a prolonged period and is associated with long-term brain changes, altering the function of the mesolimbocortical DA reward pathway.
route of administration
The amount of drug that reaches the brain and the speed with which it starts acting are determined in part by the drug’s route of administration.
Some routes, such as smoking or intravenous injection, rapidly increase the concentration of drug in the body that is bioavailable. With other routes, such as oral ingestion, drug concentration builds up more slowly over longer periods of time. The duration of a drug effect is largely determined by the manner in which the drug is metabolized and excreted from the body.
INGESTION
INHALATION
PERIPHERAL INJECTION
CENTRAL INJECTION
INGESTION as a route of drug administration
Tablets and capsules
Syrups
Infusions and teas
Suppositories
EXAMPLES AND MECHANISMS
Many sorts of drugs and remedies; depends on absorption by the gut, which is somewhat slower than most other routes
TYPICAL SPEED OF EFFECTS
Slow to moderate
INHALATION as a route of drug administration
Smoking
Nasal absorption
Inhaled powders and sprays
EXAMPLES AND MECHANISMS
Nicotine, cocaine, organic solvents such as airplane glue and gasoline, also used for a variety of prescription drugs and hormone treatments. Inhalation methods take advantage of the rich vascularization of the nose and lungs to convey drugs directly into the bloodstream.
TYPICAL SPEED OF EFFECTS
Moderate to fast
PERIPHERAL INJECTION as a drug route of administration
Subcutaneous
Intramuscular
Intraperitoneal (abdominal)
Intravenous
EXAMPLES AND MECHANISMS
Nicotine, cocaine, organic solvents such as airplane glue and gasoline, also used for a variety of prescription drugs and hormone treatments. Inhalation methods take advantage of the rich vascularization of the nose and lungs to convey drugs directly into the bloodstream.
TYPICAL SPEED OF EFFECTS
Moderate to fast
CENTRAL INJECTION as a route drug of administration
Intracerebroventricular (into ventricular system)
Intrathecal (into spinwal CSF)
Intrathecal (into spinwal CSF)
Intracerebral (directly into a brain region)
EXAMPLES AND MECHANISMS
Central methods involve injection directly into the CNS; used in order to circumvent the blood-brain barrier, to rule out peripheral effects, or to directly affect a discrete brain location.
TYPICAL SPEED OF EFFECTS
Fast to very fast
route of elimination
The duration of a drug effect is largely determined by the manner in which the drug is metabolized and excreted from the body—via the kidneys, liver, lungs, and other routes.
Internal Drug depots
Some drugs may be stored in depots (collecting in fat or bone, for example), only to reemerge and have physiological effects after long periods of time.
bioavailable
Referring to a substance, usually a drug, that is present in the body in a form that is able to interact with physiological mechanisms.
biotransformation
The process in which enzymes convert a drug into a metabolite that is itself active, possibly in ways that are substantially different from the actions of the original substance.
pharmacokinetics
Collective name for all the factors that affect the movement of a drug into, through, and out of the body.
blood-brain barrier
The mechanisms that make the movement of substances from blood vessels into brain cells more difficult than exchanges in other body organs, thus affording the brain greater protection from exposure to some substances found in the blood.
Drugs and the blood-brain barrier
This barrier poses a major challenge for neuropharmacology because many drugs that might be clinically or experimentally useful are too large to pass the blood-brain barrier to enter the brain. To a limited extent this problem can be circumvented by delivering drugs directly into the brain, but that is a drastic step. Alternatively, some drugs can take advantage of active transport systems that normally move nutrients out of the bloodstream and into the brain.
local anesthetic
A drug, such as procaine or lidocaine, that blocks sodium channels to stop neural transmission in pain fibers.
How do drugs that act on the nervous system to produce changes in behavior alter synaptic function?
(2 ways)
Drugs may affect presynaptic events - Some drugs act on the presynaptic terminal, affecting how much neurotransmitter is released into the synaptic cleft.
Other drugs act on the postsynaptic membrane, altering how the target neuron responds to neurotransmitter.
How drugs may affect presynaptic events
three categories and 8 sub categories
Illustrates presynaptic processes that are targeted by CNS drugs, with examples of each kind of drug. The most common presynaptic drug effects can be grouped into three main categories:
effects on transmitter production,
(1) Inhibition of transmitter synthesis
(2) Blockade of axonal transport
(3) Interference with the storage of transmitters
effects on transmitter release
(4) Prevention of synaptic transmission
(5) Alteration of synaptic transmitter release
(6) Alteration of transmitter release through modulation of presynaptic activity
effects on transmitter clearance.
(7) Inactivation of transmitter reuptake
(8) Blockade of transmitter degradation
How drugs may affect presynaptic events:
TRANSMITTER PRODUCTION
Inhibition of transmitter synthesis
A drug may block synthesis enzymes, causing a depletion of transmitter.
affected presynaptic neurons are prevented from having their usual effects on postsynaptic neurons, with sometimes profound effects on behavior.
How drugs may affect presynaptic events:
TRANSMITTER PRODUCTION
Blockade of axonal transport
Drugs that block axonal transport prevent materials from reaching the axon terminals in the first place, likewise causing the terminal to run out of neurotransmitter.
affected presynaptic neurons are prevented from having their usual effects on postsynaptic neurons, with sometimes profound effects on behavior.
How drugs may affect presynaptic events:
TRANSMITTER PRODUCTION
Interference with the storage of transmitters
A third class of drug doesn’t prevent the production of transmitter molecules, but instead interferes with the ability of neurons to store catecholamine transmitters in synaptic vesicles, for later release. This has the effect of depleting transmitter at catecholaminergic synapses and may have a complicated effect on behavior, depending on whether and how much of the leaking transmitter reaches the postsynaptic cell.
How drugs may affect presynaptic events:
TRANSMITTER RELEASE
Prevention of synaptic transmission
Even if a presynaptic terminal has an adequate supply of transmitter stored in vesicles, various agents or conditions can prevent the release of transmitter when an action potential reaches the terminal.
For example, compounds that block sodium channels (like the toxin that makes puffer fish a dangerous delicacy, called tetrodotoxin) prevent axons from firing action potentials, shutting down synaptic transmission with deadly results.
And drugs called calcium channel blockers do exactly as their name suggests, blocking the calcium influx that normally drives the release of transmitter into the synapse.
How drugs may affect presynaptic events:
TRANSMITTER RELEASE
Alteration of synaptic transmitter release
Some toxins prevent the release of specific kinds of transmitters. For instance, the active ingredient in Botox—botulinum toxin.
Tetanus (lock-jaw) bacteria produce a toxin, called tetanospasmin, that interferes with the molecular machinery that causes synaptic vesicles to bind to the presynaptic membrane.
How drugs may affect presynaptic events:
TRANSMITTER RELEASE
Alteration of transmitter release through modulation of presynaptic activity
A different approach involves modifying the systems that the neuron normally uses to monitor and regulate its own transmitter release. For example, presynaptic neurons often use autoreceptors to monitor how much transmitter they have released; it’s a kind of feedback system.
The caffeine that we obtain from coffee and other beverages acts by blocking the autoreceptor effect of an endogenous ligand called adenosine
How drugs may affect presynaptic events:
TRANSMITTER CLEARANCE
Blockade of transmitter degradation
Some drugs interfere with transmitter reuptake by blocking specialized proteins, called transporters, that normally remove neurotransmitter from the cleft for reuse For example, we’ll see that some very common antidepressants inhibit the reuptake of serotonin, allowing the transmitter to accumulate and have a bigger effect on postsynaptic receptors. Such drugs are said to work presynaptically, because the transporters are on the presynaptic terminal.
How drugs may affect presynaptic events:
TRANSMITTER CLEARANCE
Blockade of transmitter degradation
Other drugs may have a similar effect by inhibiting degradation, the chemical process of breaking down neurotransmitter into inactive metabolites, again allowing the transmitter to accumulate and have a greater effect on the postsynaptic cell. Agents that inhibit the enzyme acetylcholinesterase (AChE), called cholinesterase inhibitors, allow ACh to remain active at the synapse and alter the timing of synaptic transmission. They include certain pesticides and chemical weapons, and they produce prolonged contraction of muscles and resultant paralysis, as well as overactivity of the parasympathetic nervous system.
How drugs may affect presynaptic events:
Effects on Transmitter Production
(3 ways)
In order for the presynaptic neuron to produce neurotransmitter, the axon terminals must receive a steady supply of metabolic raw materials and the enzymes that use these metabolic precursors to synthesize transmitter molecules, vesicles, and other important components.
- Inhibition of transmitter synthesis
Para-chlorophenylalanine inhibits tryptophan hydroxylase, preventing synthesis of serotonin from its metabolic precursor. - Blockade of axonal transport
Colchicine impairs maintenance of microtubules and blocks axonal transport. - Interference with the storage of transmitters
Reserpine blocks the packaging of transmitter molecules within vesicles, thereby allowing the transmitter to be broken down by enzymes.
How drugs may affect presynaptic events:
Effects on Transmitter Release
(3 ways)
- Prevention of synaptic transmission
Tetrodotoxin, found in puffer fish, blocks voltage-gated Na+ channels and prevents nerve conduction. - Alteration of synaptic transmitter release
Calcium channel blockers (e.g., verapamil) inhibit release of transmitters. Amphetamine stimulates release of catecholamine transmitters. Black widow spider venom causes overrelease, and thus depletion, of ACh. - Alteration of transmitter release through modulation of presynaptic activity
Caffeine competes with adenosine for presynaptic receptors, thus preventing its inhibitory effects.
How drugs may affect presynaptic events:
Effects on Transmitter Clearance
(2 ways)
Immediately after being released, transmitter is rapidly cleared from the synapse. Obviously, getting rid of the used transmitter is normally an important step because until it is gone, new releases of transmitter from the presynaptic side won’t be able to have much extra effect. But under certain circumstances, a significant reduction of synaptic transmitter availability may contribute to disorders such as depression.
- Inactivation of transmitter reuptake
Cocaine and amphetamine inhibit reuptake mechanisms, thus prolonging synaptic activity. Certain antidepressants inhibit serotonin reuptake. - Blockade of transmitter degradation
Some drugs (e.g., monoamine oxidaseinhibitors) inhibit enzymes that normally break down neurotransmitter molecules in the axon terminal or in the synaptic cleft. As a result,transmitter remains active longer and to greater effect.
autoreceptor
A receptor for a synaptic transmitter that is located in the presynaptic membrane, telling the axon terminal how much transmitter has been released.
to monitor how much transmitter they have released; it’s a kind of feedback system. Drugs that alter autoreceptor signals provide a false feedback signal, prompting the presynaptic cell to release more or less transmitter.
Botox—botulinum toxin
Some toxins prevent the release of specific kinds of transmitters. For instance, the active ingredient in Botox—botulinum toxin, which is formed by a bacterium that multiplies in improperly canned food—binds to specialized receptors in nicotinic cholinergic membranes and is transported into the cell, where it blocks the Ca2+-dependent release of acetylcholine, resulting in muscle paralysis. The widespread paralysis that occurs after eating contaminated food can be lethal, but when the dilute toxin is selectively injected into facial muscles, the resulting local paralysis reduces wrinkling of the overlying skin.
Tetanus - tetanospasmin
Tetanus (lock-jaw) bacteria produce a toxin, called tetanospasmin, that interferes with the molecular machinery that causes synaptic vesicles to bind to the presynaptic membrane. By blocking exocytosis, particularly at inhibitory synapses in the CNS, tetanospasmin causes the loss of normal inhibitory influences on motoneurons, resulting in strong involuntary contractions of the muscles.
caffeine
A stimulant compound found in coffee, cacao, and other plants.
acts by blocking the autoreceptor effect of an endogenous ligand called adenosine.
So, by blocking adenosine, caffeine increases catecholamine release, resulting in arousal.
adenosine
In the context of neural transmission, a neuromodulator that alters synaptic activity.
Adenosine acts as a neuromodulator: it is normally co-released with primary transmitters to control synaptic activity by inhibiting transmitter release.
(Interestingly, by a different route, the stimulant drug amphetamine also facilitates catecholamine release.)
transmitter reuptake
The reabsorption of synaptic transmitter by the axon terminal from which it was released.
transporters
Specialized receptors in the presynaptic membrane that recognize neurotransmitter molecules and return to the presynaptic neuron for reuse.
degradation
The chemical breakdown of a neurotransmitter into inactive metabolites.
The chemical process of breaking down neurotransmitter into inactive metabolites, again allowing the transmitter to accumulate and have a greater effect on the postsynaptic cell
Drugs may affect postsynaptic events
2 categories and 4 sub categories
Another powerful way for drugs to affect synaptic transmission is to modify the ability of postsynaptic neurons to respond to neurotransmitters.
Effects on Transmitter Receptors
(1) Blockade of receptors
(2) Activation of receptors
Effects on Cellular Processes
(3) Regulation of the number of postsynaptic receptors
(4) Modulation of intracellular signals
Drugs may affect postsynaptic events
Effects on Transmitter Receptors
(2 sub categories)
(1) Blockade of receptors
Antipsychotic drugs block dopamine D2 receptors; curare blocks nicotinic Ach receptors.
(1) Activation of receptors
Nicotine activates ACh receptors. LSD is an agonist at some types of serotonin receptors (such as 5-HT2A receptors).
Drugs may affect postsynaptic events
Effects on Transmitter Receptors
Blockade of receptors
Selective receptor antagonists bind directly to postsynaptic receptors and block them from being activated by their neurotransmitter. This can have immediate and dramatic effects.
Curare, for example, blocks the nicotinic ACh receptors found on muscles, resulting in immediate paralysis of all skeletal muscles, including those used for breathing (which is why curare is an effective arrow poison).
Drugs may affect postsynaptic events
Effects on Transmitter Receptors
Activation of receptors
Selective receptor agonists bind to specific receptors and activate them, mimicking the natural neurotransmitter at those receptors. These drugs are often very potent, with effects that vary depending on the particular type of receptors activated.
LSD is an example, producing bizarre visual experiences through strong stimulation of a subtype of serotonin receptor (5HT2A receptors) found in visual cortex.
Drugs may affect postsynaptic events
Effects on Cellular Processes
2 sub categories
(1) Regulation of the number of postsynaptic receptors
Alcohol up-regulates (increases) the number of receptors for GABA.
(2) Modulation of intracellular signals
Mood-stabilizer lithium has many effects, including changes in second messengers, probably leading to changes in gene expression and receptor density.
Drugs may affect postsynaptic events
Effects on Cellular Processes
Regulation of the number of postsynaptic receptors
When they bind to their matching receptors on postsynaptic membranes, neurotransmitters can stimulate a variety of changes within the postsynaptic cell, such as activation of second messengers, activation of genes, and the production of various proteins. For example, some drugs induce the postsynaptic cell to up-regulate (increase) its receptors, thus changing the sensitivity of the synapse.
Drugs may affect postsynaptic events
Effects on Cellular Processes
Modulation of intracellular signals
Other drugs cause a down-regulation of receptor density. Some drugs directly alter second messenger systems, with wide-spread effects in the brain; this is one of the ways in which the mood-stabilizing drug lithium chloride is believed to act. Future research will probably focus on drugs to selectively activate, alter, insert, or block targeted genes within the DNA of neurons. These genomic effects could produce profound long-term changes in the structure and function of the targeted neurons.
Drugs That Affect the Brain Can Be Divided into Functional Classes
In addition to categorizing drugs on the basis of their cellular effects, we can classify them by their specific effects on behavior and therapeutic applications.
Antipsychotic Antidepressants Anxiolytics (Depressant) Alcohol (Depressant) Opiates Δ9-tetrahydrocannabinol (THC) Stimulants hallucinogens
antipsychotics
A class of drugs that alleviate schizophrenia.
- neuroleptics
- typical neuroleptics
- atypical neuroleptics
neuroleptics
A class of antipsychotic drugs, traditionally dopamine receptor blockers. they act as selective antagonists of dopamine D2 recep-tors in the brain.
typical neuroleptics
A major class of antischizophrenic drugs that share antagonist activity at dopamine D2 receptors. are so good at relieving the symptoms of schizophrenia that a dopaminergic explanation of the disease became dominant.
atypical neuroleptics
A class of anti-schizophrenic drugs that have actions other than the dopamine D2 receptor antagonism that characterizes the typical neuroleptics. The 1990s saw the advent of second-generation antipsychotics, known as atypical neuroleptics, which feature nondopaminergic actions, especially the blockade of certain serotonin receptors.
These atypical neuroleptics, are claimed to reduce additional symptoms that typical neuroleptics generally do not relieve, although this claim has been disputed
antidepressants
A class of drugs that relieve the symptoms of depression.
Increasing synaptic monoamine availability appears to be a key activity of all antidepressants.
- monoamine oxidase (MAO)
- tricyclic antidepressants
- selective serotonin reuptake inhibitor (SSRI)
monoamine oxidase (MAO)
An enzyme that breaks down and thereby inactivates monoamine transmitters.
MAOs break down monoamine neurotransmitters at axon terminals, thereby reducing transmitter activity. By blocking this process, MAO inhibitors allow monoamine neurotransmitters to accumulate at synapses, with an associated improvement in mood.
tricyclic antidepressants
A class of drugs that act by increasing the synaptic accumulation of serotonin and norepinephrine. The second generation of antidepressants—the tricyclics—combat depression by increasing the synaptic content of the monoamines norepinephrine and serotonin. tricyclics block the reuptake of neurotransmitters into presynaptic axon terminals.
selective serotonin reuptake inhibitor (SSRI)
A drug that blocks the reuptake of transmitter at serotonergic synapses.
More recently developed antidepressants
these drugs alleviate depression by selectively allowing serotonin to accumulate in synapses. These newer antidepressants lack some of the undesirable side effects of older drugs, although they have side effects of their own (such as disturbances of sexual function) and can take as long as 6–8 weeks to have full effect.
anxiolytics
A class of substances that are used to combat anxiety.
Sometimes also called tranquilizers, anxiolytics belong to the general category of depressants: drugs that depress or reduce nervous system activity. Alcohol and opiates are perhaps the original anxiolytics, but their anxiety-fighting properties come at the cost of intoxication, addiction potential, and neuropsychological impairment with long-term abuse, so they are not suitable for therapeutic use.
- barbiturate
- benzodiazepine agonists
- Allopregnanolone
- The serotonergic agonist buspirone (Buspar)
depressants
A class of drugs that act to reduce neural activity.
barbiturate
A powerful sedative anxiolytic derived from barbituric acid, with dangerous addiction and overdose potential. Barbiturate drugs (“downers”) were originally developed to reduce anxiety, promote sleep, and prevent epileptic seizures. They are still used for those purposes but are also addictive and easily overdosed, often fatally.
benzodiazepine agonists
A class of antianxiety drugs that bind to sites on GABAA receptors
Nowadays, the safest and most specific anxiolytics are the benzodiazepine agonists, and they are among the most heavily prescribed drugs.
bind to specific sites on GABAA receptors and enhance the activity of GABA. Because GABAA receptors are inhibitory, benzodiazepines help GABA to produce larger inhibitory postsynaptic potentials than would be caused by GABA alone. This has the end result of reducing the excitability of neurons.
Why can many different drugs can interact with GABAA receptor complex?
GABAA receptors have several different binding sites—some that
facilitate and some that inhibit the effect of GABA
orphan receptor
Any receptor for which no endogenous ligand has yet been discovered.
For example, benzodiazepines bind to a unique modulatory site on the receptor complex that is distant from where GABA itself binds. The benzodiazepine-binding site is thus an orphan receptor— a receptor for which an endogenous ligand has not been conclusively identified—and the hunt for its endogenous ligand has been intense.
allopregnanolone
A naturally occurring steroid that modulates GABA receptor activity in much the same way that benzodiazepine anxiolytics do.
Allopregnanolone, a steroid derived from the hormone progesterone, acts on yet another site on the GABAA receptor. Allopregnanolone is elevated during stress and has a calming effect. Alcohol ingestion also increases brain concentrations of allopregnanolone
neurosteroids
Steroids produced in the brain.
Several other progesterone-like neurosteroids (steroids produced in the brain) may act on GABAA receptors to produce anxiolytic, analgesic, and anticonvulsant effects.
Alcohol
The psychoactive effect of alcohol in the nervous system is biphasic: an initial stimulant phase is followed by a more prolonged depressant phase.
Alcohol activates the GABAA receptor–coupled chloride channel, thereby increasing postsynaptic inhibition. This action contributes to social disinhibition, as well as the impairment of motor coordination that occurs after a few drinks.
Alcohol also affects other transmitters. For example, low doses of alcohol stimulate dopamine pathways, and the resulting increase in dopamine may be related to the slightly euphoric feelings that many people experience when having a drink.
Chronic abuse of alcohol damages neurons. Cells of the superior frontal cortex, Purkinje cells of the cerebellum, and hippocampal pyramidal cells show particularly prominent pathological changes. Some of these degenerative effects of chronic alcohol use may be due to a secondary consequence of alcoholism: poor diet. For example, chronic alcoholism is accompanied by severe thiamine deficiency, which can lead to neural degeneration and Korsakoff’s syndrome.
The frontal lobes—especially the superior frontal association cortex—are the brain areas that are most affected by chronic alcohol use. How-ever, some of the anatomical changes associated with chronic alcoholism may be reversible with abstinence.
fetal alcohol syndrome (FAS)
A disorder, including intellectual disability and characteristic facial anomalies, that affects children exposed to too much alcohol (through maternal ingestion) during fetal development.
bingeing
Even in the absence of clear-cut alcoholism, periodic overconsumption of alcohol—known as bingeing—may cause brain damage. After only 4 days of bingeing on alcohol, rats exhibit neural degeneration in several areas of the brain. Damage is especially evident in the olfactory bulbs and in limbic structures connected with the hippocampus, and it is associated with impairments of cognitive ability.
Alcohol bingeing also significantly reduces the rate of neurogenesis—the formation of new neurons—in the adult hippocampus. Alcohol bingeing can depress breathing enough to kill, as happens every year to a few college students.
opium
A heterogeneous extract of the seedpod juice of the opium poppy, Papaver somniferum.
Opiates
The opiates morphine, heroin, and codeine bind to specific receptors—opioid receptors—that are concentrated in certain regions of the brain.
- Morphine
- Heroin
- Codeine
- endogenous opioids
- enkephalins
- endorphins
- dynorphins
morphine
An opiate compound derived from the poppy flower.
the major active substance in opium, is a very effective analgesic (painkiller) that has brought relief from severe pain to many millions of people. Unfortunately, morphine also has a strong potential for addiction
analgesic
Referring to painkilling properties
heroin
Diacetylmorphine; an artificially modified, very potent form of morphine.
has a strong potential for addiction,
opioid receptor
A receptor that responds to endogenous and/or exogenous opiates.
Opioid receptors are found in the limbic and hypothalamic areas of the brain, and they are particularly rich in the locus coeruleus and in the periaqueductal gray—the gray matter that surrounds the aqueduct in the brainstem
periaqueductal gray
The neuronal body-rich region of the midbrain surrounding the cerebral aqueduct that connects the third and fourth ventricles; involved in pain perception.
Injection of morphine directly into the periaqueductal gray produces strong analgesia, indicating that this is a region where morphine acts to reduce pain perception
endogenous opioids
A family of peptide transmitters that have been called the body’s own narcotics. The three kinds are enkephalins, endorphins, and dynorphins.
The discovery of orphan receptors for opiates came as a surprise, and because the presence of these receptors implied that there must be an endogenous ligand produced within the body, it prompted an intense scientific effort to identify endogenous opioids.
enkephalins
One of three kinds of endogenous opioids.
endorphins
One of three kinds of endog-enous opioids.
dynorphins
One of three kinds of endogenous opioids.
marijuana
dried preparation of the Cannabis sativa plant, usually smoked to obtain THC.
Typically inhaled via smoking, marijuana contains dozens of active ingredients, chief among which is the compound Δ9-tetrahydrocannabinol (THC)
The subjective experience of marijuana use is quite variable among individuals: relaxation and mood alteration are the most frequent effects, but stimulation, hallucination, and paranoia also occur in some cases.
Sustained use of marijuana can cause addiction and accelerated cognitive decline, and frequent smoking of marijuana, as with tobacco, can contribute to respiratory diseases.
Adolescents who use marijuana are more likely to develop psychosis in adulthood
that some people are genetically vulnerable to this devastating effect of the drug
As was the case with opiates and benzodiazepines, researchers found that the brain contains cannabinoid receptors that mediate the effects of compounds like THC.
cannabinoid receptors
As was the case with opiates and benzodiazepines, researchers found that the brain contains cannabinoid receptors that mediate the effects of compounds like THC. Cannabinoid receptors are concentrated in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex; other regions, such as the brainstem, show few of these receptors.
endocannabinoid
An endogenous ligand of cannabinoid receptors; thus, an analog of marijuana that is produced by the brain.
The discovery of cannabinoid receptors touched off an intensive search for an endogenous ligand, and several such compounds—termed endocannabinoids—were identified. Interestingly, endocannabinoids can function as retrograde messengers, conveying messages from the postsynaptic cell to the presynaptic cell. This retrograde signal is thought to modulate the release of neurotransmitter by the presynaptic nerve terminal. The most studied endocannabinoid is anandamide.
The study of endocannabinoids will aid the search for drugs that share the beneficial effects of marijuana: relieving pain, lowering blood pressure, combating nausea, lowering eye pressure in glaucoma, and so on.
anandamide
An endogenous substance that binds the cannabinoid receptor molecule.
The most studied endocannabinoid is anandamide, which has diverse
functional effects, including alterations of memory formation, appetite stimulation, reduced sensitivity to pain, and protection from excitotoxic brain damage
Stimulants
Stimulants are excitatory. They therefore have an alerting, activating effect. Many naturally occurring and artificial stimulants are widely used. Some stimulants act directly by increasing excitatory synaptic potentials. Others act by blocking normal inhibitory processes. - Khat - Caffeine - amphetamine - nicotine - cocaine - methylphenidate (Ritalin) - amphetamine
khat
Also spelled qat. An African shrub that, when chewed, acts as a stimulant.
nicotine
A compound found in plants, including tobacco, that acts as an agonist on a large class of cholinergic receptors.
Exposed to the large surface of the lungs, the nicotine from cigarettes enters the blood and brain much more rapidly than does nicotine from other tobacco products. Nicotine in-creases heart rate, blood pressure, secretion of hydrochloric acid in the stomach, and intestinal activity. In the short run, these effects make tobacco use pleasurable. But these neural effects on body function, quite apart from the effects of tobacco tar on the lungs, make prolonged tobacco use very unhealthful. Smoking and nicotine ex-posure in adolescence has a lasting impact on attention and cognitive development, likely as a consequence of impairments of glutamatergic synapses in the prefrontal cortex
Nicotinic receptors
Nicotinic receptors drive the contraction of skeletal muscles and the activation of various visceral organs, but they are also found in high concentrations in the brain, including the cortex. This is one way in which nicotine enhances some aspects of cognitive performance.
cocaine
A drug of abuse, derived from the coca plant, that acts by potentiating catecholamine stimulation.
either chewed or brewed as a tea—to increase endurance, alleviate hunger, and promote a sense of well-being. This use of coca leaves does not seem to cause problems. The artificially purified coca extract cocaine, however, is a powerfully addictive alkaloid stimulant that has harmed millions of lives.
Heavy cocaine use raises the risk of serious side effects like stroke, psychosis, loss of gray matter, and severe mood disturbances. Like other psychostimulants, cocaine acts by blocking monoamine transporters, especially those for dopamine, slowing reuptake of the transmitters and therefore boosting their effects.
chronic cocaine use can provoke symptoms similar to psychosis. Cessation of cocaine use often produces very uncomfortable withdrawal symptoms: initial agitation and powerful drug cravings, followed by depression and an inability to enjoy anything else in life. Cerebral glucose metabolism is decreased for months after cocaine use is discontinued and may contribute to that depression.
dual dependence
Dependence for emergent drug effects that occur only when two drugs are taken simultaneously.
in which the interaction of two (or more) drugs produces another addictive state. For example, cocaine metabolized in the presence of ethanol (alcohol) yields an active metabolite called cocaethylene, to which the user may develop an additional addiction
amphetamine
A molecule that resembles the structure of the catecholamine transmitters and enhances their activity.
losely resembles that of the catecholamine transmitters (norepinephrine, epinephrine, and dopamine). Amphetamine and the even more potent methamphetamine (“meth” or “speed”) cause the release of these transmitters from presynaptic terminals even in the absence of action potentials, and when action potentials do reach the axon terminals, amphetamine also potentiates the subsequent release of transmitter.
Once transmitter has been released, amphetamine further enhances activity in two ways:
(1) by blocking the reuptake of catecholamines into the presynaptic terminal and
(2) by providing an alternative target for the enzyme (monoamine oxidase) that normally inactivates them.
Over the short term, amphetamine causes increased vigor and stamina, wakefulness, decreased appetite, and feelings of euphoria.
Addiction and tolerance to amphetamine and methamphetamine develops rapidly, requiring ever larger doses leading to sleeplessness, severe weight loss, and general deterioration of mental and physical condition.
Prolonged use of amphetamine may lead to symptoms that closely resemble those of paranoid schizophrenia: compulsive, agitated behavior and irrational suspicious-ness. In fact, some amphetamine users have been misdiagnosed as having schizophrenia. Amphetamine acts on the autonomic nervous system to produce high blood pressure, tremor, dizziness, sweating, rapid breathing, and nausea. Worst of all, people who chronically abuse speed display symptoms of brain damage long after they quit using the drug.
hallucinogens
A class of drugs that alter sensory perception and produce peculiar experiences. The effects of lysergic acid diethylamide (LSD, or acid) and related substances like mescaline (peyote) and psilocybin (“magic mushrooms”) are predominantly visual. Users often see fantastic images with intense colors, and they are often aware that these strangely altered perceptions are not real events. Hallucinogenic agents are diverse in their neural actions. But many act as serotonin receptor agonists or partial agonists.
- (LSD) lysergic acid diethylamide
- Mescaline
- Psilocybin
- Salvia
- (PCP) phencyclidine
- Ketamine
- MDMA
- (3,4-methylenedioxymethamphetamine)
Why is the the term hallucinogen is a misnomer?
Because, whereas a hallucination is a novel perception that takes place in the absence of sensory stimulation (hearing voices, or seeing something that isn’t there), the drugs in this category tend to alter or distort existing perceptions.
LSD
lysergic acid diethylamide
(acid)
Also called acid. Lysergic acid diethylamide, a hallucinogenic drug.
LSD Flashbacks
Former users of LSD sometimes report experiencing flashbacks—that is, having experiences as if they had taken a dose of the drug, even though they are drug-free.
Salvia
Salvia is unusual among hallucinogens because it acts on the opioid kappa receptor.
phencyclidine (PCP)
Also called angel dust. An anesthetic agent that is also a psychedelic drug.
(commonly known as PCP or angel dust) was developed in 1956 as a potent analgesic and anesthetic agent. Classified as a dissociative drug because it produces feelings of depersonalization and detachment from reality, it was soon dropped from use in anesthesia because it also causes agitation, excitement, delirium, hostility, and disorganization of perceptions. PCP continues to be used as a street drug, principally because of its hallucinogenic actions. But even at relatively low doses, PCP also produces numerous undesirable side effects, including combativeness and catatonia (stupor and immobility). Higher doses or repeated use can lead to long-lasting profound confusion, or convulsions and coma. The similarity
between PCP’s effects and psychosis has led some researchers to propose PCP as a chemical model of schizophrenia.
PCP antagonizes the NMDA receptor, perhaps at a special binding site, and it stimulates release of the transmitter dopamine
dissociative drug
A type of drug that produces a dreamlike state in which consciousness is partly separated from sensory inputs.
ketamine
A dissociative anesthetic drug, similar to PCP, that acts as an NMDA receptor antagonist.
(nicknamed Special K), is a less potent NMDA antagonist that is used as a dissociative anesthetic agent. PET studies indicate that ketamine increases metabolic activity in the prefrontal cortex
ketamine in high doses produces transient psychotic symptoms in volunteers.
MDMA
Also called Ecstasy. A drug of abuse, 3,4-methylenedioxymethamphetamine.
Ecstasy is the street name for the hallucinogenic amphetamine derivative MDMA.
Major actions of MDMA in the brain include an increase in the release of serotonin, stimulation of 5HT2A receptors, and changes in the levels of dopamine and certain hormones, such as prolactin. Exactly how these activities account for the subjective effects of MDMA—positive emotions, empathy, euphoria, a sense of wellbeing, and colorful visual phenomena—remains to be established.
Several possible psychiatric and cognitive consequences of chronic MDMA use have been described, including memory disturbances
(Wareing et al., 2000) and depression (Sumnall and Cole, 2005). However, shorter-term MDMA treatment is also being studied in clinical settings, as a possible therapy for treatment-resistant posttraumatic stress disorder.
Researchers have proposed numerous models of substance abuse and addiction
that vary in their emphasis on ____________, ____________, and ___________ factors
Researchers have proposed numerous models of substance abuse and addiction
that vary in their emphasis on physiological, behavioral, and environmental factors
dependence
DSM Diagnosis
Also called addiction. The strong desire to self-administer a drug of abuse.
dependence is a more severe disorder than substance abuse
The essential feature of dependence on psychoactive substances (e.g.,
alcohol, tobacco, cocaine, marijuana) is a cluster of cognitive, behavioral, and physiological symptoms indicating that the person continues use of the substance despite significant substance-related problems.
To be diagnosed as dependent, a person must meet a certain number of criteria relating to patterns of consumption, craving, expenditure of time and energy in serving the addiction, and impact on the other aspects of the person’s life.
substance abuse
A maladaptive pattern of substance use that has lasted more than a month but does not fully meet the criteria for dependence.
maladaptive patterns of substance use have persisted at least a month or have occurred repeatedly
dysphoria
Unpleasant feelings; the opposite of euphoria.
nucleus accumbens
A region of the fore-brain that receives dopaminergic innervation from the ventral tegmental area.
insula
A region of cortex lying below the surface, within the lateral sulcus, of the frontal, temporal, and parietal lobes.
People suffering damage to the insula were able to effortlessly quit smoking, indicating that this brain region is also involved in addiction.
cue-induced drug use
An increased likelihood to use a drug (especially an addictive drug) because of the presence of environmental stimuli that were present during previous use of the same drug.
Environmental stimuli can then become risk factors for deepening addiction or relapse: simply being in a setting where a person previously used drugs can trigger drug craving in that person.
It is not limited to longer-term users; in rats, exposure to environmental stimuli that were present during their very first cocaine treatment.
THE MORAL MODEL
perspective on drug abuse
The earliest approach to explaining drug abuse was to simply blame the substance abuser for a failure of moral character or a lack of self-control.
Explanations of this sort often have a religious aspect and hold that only divine help will free a person from addiction.
Applications based on the moral model can occasionally be effective.
Any comprehensive model of drug abuse has to answer several difficult questions:
(4)
(1) What social and environmental factors in a person’s life cause her to start abusing a substance?
(2) What factors cause her to continue?
(3) What physiological mechanisms make a substance rewarding?
(4) What is addiction, physiologically and behaviorally, and why is it so hard to quit?
THE DISEASE MODEL
perspective on drug abuse
According to the disease model, the person who abuses drugs requires medical treatment rather than moral exhortation or punishment. This view also justifies spending money to research drug abuse in the same way that money is spent to research other diseases. However, the term disease is usually reserved for a state in which we can identify an abnormal physical or biochemical condition that initiates the problem. No abnormal physical or biochemical condition has been found in the case of drug addiction, and the disease model is mute with respect to initial development of addiction, although mounting evidence suggests that some people are genetically more susceptible to addiction than others. Nevertheless, this model continues to appeal to many, and an intensive effort is under way to identify the physiological “switch” that establishes addiction after exposure to a drug.
A related formulation of the disease model views drug abuse as a type of self-medication, in which the addict is drawn to specific drugs in an effort to compensate for a deficiency of a corresponding endogenous substance: taking opiates to compensate for a lack of endorphins, for example.
he Terminology of Substance-Related Disorders
For definitions of mental disorders, psychiatrists, psychologists, and neuroscientists rely on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
Dependence (commonly called addiction) is a more severe disorder than substance abuse.
Males are three times more likely than females to be diagnosed, at some point in life, with substance abuse or dependence
THE PHYSICAL DEPENDENCE MODEL
perspective on drug abuse
The physical dependence model, sometimes called the withdrawal avoidance model, argues that people keep taking drugs in order to avoid unpleasant withdrawal symptoms.
The specific withdrawal symptoms depend on the drug, but they are often the opposite of the effects produced by the drug itself.
Whereas most drugs of abuse produce pleasurable feelings, withdrawal usually induces the opposite: dysphoria.
The model does a good job of explaining why addicts will go to great lengths to obtain their addicted drug, but it has an important shortcoming: it can’t explain how the addiction gets established in the first place. Why do some people, but not all, start to abuse a drug before physical dependence (tolerance) has ever developed? And how is it that some people can become addicted to some drugs even in the absence of clear physical withdrawal symptoms?
THE POSITIVE REWARD MODEL
perspective on drug abuse
The positive reward model of addictive behavior proposes that people get started with drug abuse, and become addicted, because the abused drug provides powerful reinforcement. Using a self-administration apparatus that allows animals to administer drugs to themselves, it is possible to quantify the motivation of animals to consume drugs.
Furthermore, even animals that are not already morphine-dependent learn to press a lever for morphine, and they will happily self-administer doses of morphine that are so low that no physical dependence ever develops. Animals will also furiously press a lever to self-administer cocaine and other stimulants that do not produce withdrawal symptoms as marked as those that opiates produce.
Experiments using drug self-administration thus suggest that by itself, the physical dependence model is inadequate to explain drug addiction, although physical dependence and tolerance may contribute to drug hunger.
Many addictive drugs cause the release of dopamine in the nucleus accumbens, just like more-conventional rewards such as food, sex, or winning money. interestingly, dopamine release is also linked to
pathological gambling. As we mentioned previously, dopamine released from axons originating from the ventral tegmental area
(VTA), part of the mesolimbocortical dopaminergic pathway, has been widely implicated in the perception of reward. Then the addictive power of drugs may come from their artificial stimulation of this pathway. When the drug hijacks this system, providing unnaturally powerful reinforcement, the user learns to associate the drug-taking behavior with that pleasure and begins seeking out drugs more and more until life’s other pleasures fade into the background.
These higher-order cognitive aspects of addiction depend on glutamatergic inputs from the prefrontal cortex, integrating aspects of memory, attention, and self-control to regulate the functioning of the dopamine reward system.
Cocaine produces long-lasting changes in dopaminergic circuitry, as well as other neurotransmitter systems in the nucleus accumbens, which seems to further augment the pleasure associated with drugs while decreasing the pleasure experienced from other behaviors. The drug’s “pathological” reinforcement of associated behaviors leads to exclusive, compulsive drug seeking. If natural activities like conversation, eating, and even sex no longer provide appreciable pleasure, addicts may seek drugs as the only source of pleasure available to them.
4 models of substance abuse and addiction
THE POSITIVE REWARD MODEL
THE PHYSICAL DEPENDENCE MODEL
THE DISEASE MODEL
THE MORAL MODEL
Why people differ in their vulnerability to drug abuse?
4 general categories
The individual and environmental factors that account for this differential susceptibility are the subject of active investigation; they fall into several general categories:
- Biological factors - Sex is a significant variable; males are more likely to abuse drugs than are females. There is also evidence for genetic predisposition.
- Family situation - Family breakup, a poor relationship with parents, or the presence of an antisocial sibling are associated with drug abuse.
- Personal characteristics - Certain traits, such as aggressiveness and poor emotional control, are especially associated with drug abuse. Strong educational goals and maturity are associated with lower likelihood of drug abuse.
- Environmental factors - A high prevalence of drug use in the community, and especially in the peer group, predisposes an individual toward drug abuse.
What are the ways that drug abuse and dependence can be prevented or treated?
(5 medication strategies)
Many of those who become dependent are able to overcome their addiction without outside help: more than 90% of ex-smokers and about half of those who recover from alcoholism appear to have quit on their own. Others gain great benefit from counseling or social interventions such as 12-step programs. For those who require medical intervention, several categories of medication are available, including the following:
- Drugs for detoxification - For example, benzodiazepines and drugs that suppress central adrenergic activity help reduce withdrawal symptoms during the early drug-free period.
- Agonist or partial agonist - analogs of the addictive drug Analogs partially activate the same mechanisms that the addictive drug activates, to help wean the individual. For example, the opioid receptor agonist methadone reduces heroin appetite and lessens withdrawal symptoms; similarly, nicotine patches.
- Antagonists to the addictive drug - Specific antagonists block the effects of an abused drug, but they also may produce harsh withdrawal symptoms.
- Reward-blocking medications - block the positive reward associated with drugs of abuse, primarily by using dopamine receptor blockers. One problem with this approach is the tendency of treatments to produce a generalized loss of pleasurable feelings.
- Anticraving medications - These medications reduce the appetite for the abused substance.
Behavioral method of drug treatment
Behavioral methods often center on educational programs, peer-support systems, and therapy techniques that aim to break the learned associations between drug use, contexts, and reward.
Problem with non-medical drug treatment
These approaches require a significant investment on the part of the substance abuser: he must be motivated, willing to tolerate considerable discomfort, and able to commit the time required to complete the therapy. A rapid, long-lasting, easy-to-administer pharmacological treatment would be more likely to succeed for higher-risk, low-compliance individuals.
Drug vaccination
Scientists have long had tools for bending the immune system to their will so that it produces highly selective antibodies that seek out and destroy targeted substances—in it’s simplest form, that’s what we call vaccination. It turns out that it may be possible to develop vaccines against drugs like cocaine, heroin, and nicotine too.
Here the strategy is to prompt the individual’s immune system to produce antibodies that remove the targeted drugs from circulation before they ever reach the brain. The problem is that the immune system evolved to recognize large foreign proteins, not small molecules such as cocaine. The solution is to conjugate (join) molecules of the drug with a larger protein and get the immune system to react to the new combination. Just as with other forms of vaccination, the immune system has a “memory” for cocaine vaccine and continues to make the anti-cocaine antibodies. Now, when cocaine enters the bloodstream, the antibodies immediately bind to the drug molecules, forming large conglomerates that cannot reach the brain and are subsequently cleared from the body.
vaccination
Injection of a foreign substance, such as deactivated viruses or conjugated molecules of drugs of abuse like cocaine, in order to provoke the production of antibodies against the foreign substance.
