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| Link to discussion of synapses and their neurotransmitters. |
Presynaptic neurons
Postsynaptic neurons display receptors to which the neurotransmitter binds.
All of this machinery provides many targets for alteration by exogenous chemicals; that is, psychoactive chemicals introduced into the body. These drugs fall into several distinct families.| Link to discussion of the sympathetic nervous system. |
Nicotine binds to a subset of acetylcholine (ACh) receptors. ACh is a neurotransmitter at synapses early in the pathways of sympathetic stimulation. Although a weak drug in one sense, nicotine is strongly addictive. The use of e-cigarettes, chewing gum and skin patches containing nicotine is designed to satisfy the craving for nicotine while avoiding the serious health effects of other ingredients in cigarette smoke.
Amphetamines and cocaine bind to — thus blocking — transporters used for the reuptake of dopamine (and noradrenaline) into presynaptic neurons. This causes the level of dopamine to rise in the synapses. High levels of dopamine in an area of the brain called the nucleus accumbens appear to mediate the pleasurable effects associated with these (as well as other) psychoactive drugs.
Some amphetamines:| Generic name | Trade name |
| dextroamphetamine sulfate | Dexedrine |
| methylphenidate | Ritalin |
| pemoline | Cylert |
| mixture of 4 amphetamines | Adderall |
Immunity to cocaine addiction? In order to achieve its effects, cocaine must cross the so-called blood-brain barrier. If antibodies are bound to the cocaine molecule, it cannot cross. This has raised the possibility of immunizing people against cocaine. It works in mice.
Sedatives induce sleep.
They includeEthyl alcohol (ethanol) is, by a wide margin, the most widely used drug in most of the world. Its popularity comes not from its sedative effect but from the sense of well-being that it induces at low doses. Perhaps low doses sedate those parts of the brain involved with, for example, tension and anxiety and in this way produce a sense of euphoria. However, higher doses depress brain centers involved in such important functions as pain sensation, coordination, and balance. At sufficiently high doses, the reticular formation can be depressed enough to cause loss of consciousness.
Ethanol increases the release of the neurotransmitter GABA activating GABAA receptors (inhibitory — LINK) and directly inhibits NMDA receptors.
Barbiturates mimic some of the action of ethanol, particularly in their ability to depress the reticular formation (thus promoting sleep) and, in high doses, the medulla oblongata (thus stopping breathing).
Barbiturates bind to a subset of GABA receptors designated GABAA receptors. These are ligand-gated channels that enhance the flow of chloride ions (Cl−) into the postsynaptic neuron, thus increasing its resting potential and making it less likely to fire. By binding to the GABAA receptor, barbiturates (and perhaps ethanol) increase the natural inhibitory effect of GABA synapses. Barbiturates and alcohol act additively — the combination producing a depression greater than either one alone. The combination is a frequent cause of suicide, both accidental and planned.These chemical relatives of cocaine act by blocking the voltage-gated Na+ channels of sensory neurons preventing them from generating action potentials. [Discussion] They are injected or applied topically and block transmission not only in pain-conducting neurons but in others as well (causing general numbness).
Examples:Most of these are volatile hydrocarbons or ethers. Diethyl ether and chloroform are seldom used today, having been replaced by safer alternatives such as isofluorane, a fluorinated ether.
Some, like isofluorane, bind to inhibitory GABA receptors) in the brain hyperpolarizing, and thus decreasing the sensitivity of, postsynaptic neurons.
Others, like ketamine, block the activity of excitatory glutamate receptors.
1,4-Butanediol is a common solvent. When ingested, it is converted into γ-hydroxybutyrate, an increasingly-popular (and illegal) "club drug". γ-Hydroxybutyrate acts on GABAB receptors.
Conversion of 1,4-butanediol to γ-hydroxybutyrate requires the enzyme alcohol dehydrogenase, the same enzyme used to metabolize ethanol. Ingesting both ethanol and 1,4-butanediol delays the effects of the latter.
Opioids also inhibit brain centers controlling coughing, breathing, and intestinal motility. Both morphine and codeine are used as pain killers, and codeine is also used in cough medicine.
Opioids are exceedingly addictive, quickly producing tolerance and dependence. Although heroin is even more effective as a painkiller than morphine and codeine, it is so highly addictive that its use is illegal. Methadone is a synthetic opioid that is used to break addiction to heroin (and replace it with addiction to methadone).
Opioids bind to so-called mu (µ) receptors . These G-protein-coupled receptors are located on the subsynaptic membrane of neurons involved in the transmission of pain signals. Their natural ligands are two pentapeptides (containing five amino acids):
Release of enkephalins suppresses the transmission of pain signals. (Little is to be gained by having the perception of pain increase indefinitely in proportion to the amount of damage done to the body. Beyond a certain point, it makes sense to have a system that decreases its own sensitivity in the face of massive, intractable pain.)
By binding to mu (µ) receptors, opioids like morphine enhance the pain-killing effects of enkephalin neurons. Opioid tolerance can be explained, at least in part, as a homeostatic response that reduces the sensitivity of the system to compensate for continued exposure to high levels of morphine or heroin. When the drug is stopped, the system is no longer as sensitive to the soothing effects of the enkephalin neurons and the pain of withdrawal is produced.
Mu (µ) receptors are also found on the cells in the medulla oblongata that regulate breathing. This accounts for the suppressive effect opioids have on breathing.
Tranquilizers act like sedatives in reducing anxiety and tensions.
Most belong to a group called benzodiazepines and include such commonly-prescribed drugs as Xanax® and Ativan®.
The benzodiazepines act on interneurons that use the inhibitory neurotransmitter GABA. By binding to GABAA receptors on the postsynaptic membrane, they enhance the action of GABA at the synapse. [Further discussion]
This is the same receptor to which barbiturates (and perhaps ethanol) bind. Thus although benzodiazepines seem safe enough when used alone, combining them with ethanol or barbiturates can be (and often has been) lethal.
These drugs block the reuptake of noradrenaline, dopamine, and serotonin causing an increase in the level of these neurotransmitters in the synapse.
Examples:| Generic name | Trade name |
| imipramine | Tofranil® |
| clomiprimine | Anafranil® |
| amitriptyline | Elavil® |
Although tricyclics are still prescribed for pain relief, their role as antidepressants has largely been taken over by the serotonin reuptake inhibitors (SRIs).
These drugs inhibit the reuptake of serotonin but not of noradrenaline.
Examples:| Generic name | Trade name |
| fluoxetine | Prozac® |
| paroxetine | Paxil® |
| sertraline | Zoloft® |
Although all these drugs quickly increase the amount of serotonin in the brain, there is more to the story than that. Unlike most psychoactive drugs, antidepressants do not relieve the symptoms of depression until a week or more after dosing begins. During this period, the number of serotonin receptors on the postsynaptic membranes decreases. How this translates into relief of symptoms is not yet understood.
Because they act on the reuptake of both serotonin and noradrenaline (norepinephrine), this category of antidepressants is also known as dual reuptake inhibitors.
Examples: venlafaxine (Effexor®) and duloxetine (Cymbalta®).
Bupropion (Wellbutrin®) is a novel drug that blocks the reuptake of noradrenaline and dopamine. Although it does not interfere with the uptake of serotonin, it also appears to be an effective antidepressant.
This drug (Strattera®) selectively interferes with the reuptake of noradrenaline. It is used in children with attention deficit/hyperactivity disorder (ADHD).
Psychedelic drugs distort sensory perceptions, especially sight and sound.
Some such asThe photograph (courtesy of Dr. Richard Evans Schultes) shows the peyote cactus in flower. The cactus head contains several psychedelic chemicals, of which mescaline is the most important. Dried cactus heads ("mescal buttons") have been used since pre-Columbian times in the religious ceremonies of native peoples in Mexico. About a century ago, this religious use spread to some tribes in the United States and Canada who, in 1922, became incorporated into the Native American Church.
Other psychedelic drugs are synthetic. These includeUsed (illicitly) by humans (called "crystal" or "angel dust"), it can produce a wide variety of powerful reactions resembling those of stimulants as well as psychedelics.
Unlike the other psychedelics, it binds to (and inhibits) NMDA receptors (in the hippocampus and other parts of the forebrain).The main psychoactive ingredient in marijuana is delta-9-tetrahydrocannabinol (Δ9-THC). It binds to
THC produces
Unlike sedatives and opioids, however, tolerance to THC does not occur. In fact, the drug is excreted so slowly from the body that, with repeated use, a given response is achieved by a lower dose.
The natural ligands of the CB receptors are the endocannabinoidsWhat are these natural ligands doing? They probably will turn out to have multiple effects, but the clearest ones so far are their effects on
Rimonabant (Acomplia®), a drug that blocks the ability of the body's natural CB1 ligands to bind the CB1 receptor was sold for a time in Europe as an appetite suppressant. (Because of its side effects, it was never approved for use in the U.S. and was removed from the European market in 2008.)
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