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Summary of the “Principles of Psychopharmacology” text

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I have summarized the text “Principles of Psychopharmacology”. This text should be known for the 'Psychopharmacology' section, taught by Professor D'Hooge. This has already resulted in an exam question, so this is certainly an important text!

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  • January 9, 2023
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  • 2021/2022
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PRINCIPLES OF PSYCHOPHARMACOLOGY

INTRODUCTION
Drugs are chemical compounds that bring some desired change in the body and brain. They are usually used to diagnose, treat,
or prevent illness; to relieve pain and suffering; or to improve some adverse physiological condition.
In this chapter, we focus on psychoactive drugs = substances that alter mood, thought or behavior. They are used to manage
neuropsychological illness and may be abused. We also consider psychoactive drugs that can act as toxins, producing sickness,
brain damage or death.

DRUG ROUTES INTO THE NERVOUS SYSTEM
To be effective, a psychoactive drug must reach its target in the nervous system
Route of administration = the way a drug enters and passes through the body to reach its target
- Drugs can be administered orally, inhaled into the lungs, injected into the bloodstream/brain/muscle, administered
rectally, absorbed from patches applied to the skin




Illustration of these routes of drug administration, summarizes the
characteristics of drugs that allow them to pass through various
barriers to reach their targets

Oral administration
This is easy and convenient, but a complex route:
- To reach the bloodstream, an ingested drug must first be absorbed through the lining of the stomach or small intestine
o Drugs in liquid form are absorbed more readily
o Drugs taken in solid form are not absorbed unless the stomach’s gastric juice can dissolve them
o Whether a drug is a base or an acid, influences its absorption
- Once absorbed by the stomach or intestine, the drug must enter the bloodstream
o This requires for the drug to have additional properties: it must be water soluble because blood has a high
water concentration
o It is then diluted by liters of blood. When the drug leaves the bloodstream, the body’s 35 liters of extracellular
fluid further dilutes is

Administration as gases or aerosols
They penetrate the cell linings of the respiratory tract easily and are absorbed across these membranes into the bloodstream
nearly as quickly as they are inhaled.
- Thus, they reach the bloodstream by circumventing the barriers in the digestive system
- When administered as a gas or in smoke, drugs of abuse, like nicotine, cocaine, and marijuana, are similarly absorbed

Others
The skin has three cell layers designed to be a protective body coat:
- Small molecule drugs like patches, penetrate the skin barrier almost as easily as they penetrate the lungs
- If the drug is directly injected into the bloodstream, there are fewer obstacles that confront the drug
- A psychoactive drug that is directly injected into the brain, is confronted with the least obstacles

With each obstacle eliminated en route to the brain, the drug’s dosage can be reduced by a factor of 10
- 1000 micrograms of amphetamine produces a noticeable behavioral change when ingested orally
- If inhaled into the lungs or injected into the blood, a dose of 100 micrograms produces the same results
- If it is injected into the cerebrospinal fluid, 10 micrograms is enough to produce the same outcome
o The drug is applied directly to target neurons
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,REVISITING THE BLOOD-BRAIN BARRIER
The body presents barriers to the internal movement of drugs: cell membranes, capillary walls, and the placenta.
Blood-brain barrier = the tight junctions between the cells of blood vessels in the brain that block passage of most (harmful)
substances
- It protects the brain ionic balance
- It denies neurochemicals from the rest of the body passage into the brain, where they can disrupt communication
between neurons
- It protects the brain from the effects of many circulating hormones and from toxic and infectious substances
- Injury or disease can sometimes rupture the blood-brain barrier, letting pathogens through

The brain has a rich capillary network, the neurons are very close to capillaries:
- Brain capillaries are composed of a single layer of endothelial cells
- Substances can pass through the clefts between the cells, because endothelial cells in capillary walls aren’t fused
 In most parts of the brain, endothelial walls are fused to form tight junctions, so molecules of most substances
cannot squeeze between them




Brain capillaries’ endothelial cells are surrounded by the end feet of astrocytes attached to the capillary wall
- Glial cells provide a route for the exchange of food and waste between capillaries and the brain’s extracellular fluid and
from there to other cells

The cells of capillary walls in the three brain regions shown in the figure lack a blood-brain barrier
- The pituitary is a source of many hormones secreted into the blood
o Their release is triggered by other hormones carried to the pituitary by the blood
- The absence of a blood brain barrier in the lower brainstem’s area postrema allows toxic substances in the blood to
trigger vomiting
- The pineal gland also lacks a blood-brain barrier, enabling hormones to reach it and modulate the day-night cycles it
controls

To carry out its work, the brain needs, among other substances, oxygen and glucose for fuel and amino acids to build proteins.
Fuel molecules reach brain cells from the blood, just as carbon dioxide and other waste products are excreted from brain cells
into the blood.

Molecules of these vital substances cross the blood-brain barrier in two ways:
1. Small molecules (oxygen and carbon dioxide) can pass through the endothelial membrane
2. Complex molecules (glucose, amino acids and food components) are carried across the membrane by active transport
systems or ion pumps
- = transporter proteins specialized to convey a particular substance

Few psychoactive drug molecules are small enough or have the correct chemical structure to gain access to the CNS. Those few
drugs have an important property, the ability to cross the blood-brain barrier




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, HOW THE BODY ELIMINATES DRUGS
After a drug is administered, the body soon begins to break it down (catabolize) and remove it
- Drugs are diluted throughout the body and are sequestered
- They’re also catabolized throughout the body: kidneys and liver, and in the intestine by bile
- They’re excreted in urine, feces, sweat, breast milk and exhaled

Drugs developed for therapeutic purposes are designed to enhance their survival time in the body, and to increase their chances
of reaching their targets
- The liver is especially active in catabolizing drugs
- Cytochrome P450 enzyme family: liver can break down many different drugs into forms more easily excreted from the
body
o Substances that can’t be catabolized or excreted, build up in the body and become toxic
Ex. Metal mercury can produce severe neurological effects

Drugs eliminated from the body and discharged into the environment are extensive and problematic
- Reingested via food and water by animals and humans
- They affect fertility, embryonic development and the physiology and behavior of adults
- Solution: redesigning waste management systems


DRUG ACTION AT SYNAPSES: AGONISTS AND ANTAGONISTS

Most drugs that produce psychoactive effects work by influencing
chemical reactions at synapses. To understand how drugs work, we must
explore the ways they modify synaptic actions.

This figure summarizes 7 major steps in neurotransmission at a synapse –
each a site of drug action

- A drug can modify seven major chemical processes
- They can result in enhanced or reduced synaptic transmission
- This depends on the fact if the drug’s acts as an agonist or an
antagonist




1. Synthesis of the neurotransmitter can take place in the cell
body, the axon, or the terminal
2. Storage of the neurotransmitter is in granules or in vesicles, or both
3. Release of the transmitter is from the terminal’s presynaptic membrane into the synapse
4. Receptor interaction takes place in the postsynaptic membrane, as the transmitter acts on an embedded receptor
5. Inactivation of excess neurotransmitter occurs at the synapse
6. Reuptake into the presynaptic terminal for reuse is one outcome
7. Degradation of excess neurotransmitter by synaptic mechanisms and removal of unneeded by-products from the
synapse is the other outcome

A drug that affects any of these synaptic functions either increases or diminished neurotransmission:
- Agonists = drugs that increase neurotransmission
- Antagonists = drugs that decrease neurotransmission
- Illustration: the acetylcholine synapse between motor neurons and muscles  a typical synapse




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