CHAPTER 4: Introduction to Psychopharmacology

What is pharmacology?

The study of all drugs and their effects on biological systems.

What is psychopharmacology?

The study of drugs that affect the nervous system and behavior.

What are drugs of abuse?

Substances like heroin and cocaine that are often misused for their psychoactive effects

What are therapeutic drugs?

Medications like antidepressants and antipsychotics used to treat mental and neurological disorders.

What is a ligand?

A molecule that binds to a receptor protein (e.g., a drug, neurotransmitter, or hormone).

What is the key difference between neurotransmitters and drugs?

Neurotransmitters are endogenous (produced naturally in the body), while drugs are exogenous (introduced from outside the body).

Where are neurotransmitters synthesized?

Neurotransmitters are synthesized within neurons.

How are the effects of neurotransmitters typically terminated?

Through reuptake into the presynaptic cell or enzymatic degradation in the synapse.

Can both neurotransmitters and drugs bind to ligand-activated receptors?

Yes, both can bind to ligand-activated receptors.

What are the basic principles of pharmacology?

• Route of drug administration

• Individual differences

• Placebo effects

• Tolerance, withdrawal, sensitization, and addiction

• Drug-receptor interactions

• Sites of drug action

What are some examples of drug-receptor interaction concepts?

• Drug affinity

• Dose-response curves

• Therapeutic index

What are two major categories of drug action at receptors?

• Direct and indirect agonists

• Direct and indirect antagonists

What factors influence drug effects in the body?

• Drug concentration in blood supply

• Route of administration (fastest to slowest): injection, inhalation, oral, topical

• Individual differences such as gender, body weight, genetics, and experience (early life stressors, previous drug use)

What is a placebo effect and how is it controlled in experiments?

• Placebo is an inactive substance.

• Effect arises from user’s expectations.

• Can cause real biochemical and physiological effects in the brain.

• Placebo effects can be beneficial or harmful.

• Controlled using double-blind experiments, where neither participants nor experimenters know who gets the placebo.

What are tolerance, withdrawal, and addiction in the context of drug use?

• Tolerance: Decreased effect of a drug after repeated use, requiring higher doses to achieve the same effect.

• Withdrawal: Symptoms that occur when drug use is stopped; usually the opposite of the drug’s effects.

• Addiction: A compulsive, uncontrollable need to continue drug use despite negative consequences.

What must occur for a drug or neurotransmitter to influence the nervous system?

It must bind to specific receptors, and this binding is dependent on the concentration of the drug or neurotransmitter in the area.

What is binding affinity, and how does it affect receptor binding?
A: Binding affinity is how strongly or likely a ligand (such as a drug or neurotransmitter) binds to a receptor.

• At low concentrations, ligands bind to receptors with high affinity first.

• At higher concentrations, ligands may also bind to off-target or secondary receptors.

What is a Dose-Response Curve in pharmacology?

A Dose-Response Curve shows the relationship between the dose of a drug and the magnitude of its effect.

• It helps determine:

  • Effective dose (ED₅₀): dose at which the drug produces half of its maximum effect.

  • Maximum efficacy: the greatest effect a drug can produce regardless of dose.

  • Potency: how much of the drug is needed to produce a given effect.

• At a certain point, increasing the dose does not increase the effect, indicating the maximum response has been reached.

What is the difference between Potency and Efficacy in pharmacology?

• Potency refers to the amount of drug needed to produce a specific effect.

  • Measured by the EC₅₀ (the dose that gives half the maximal response).

  • A lower EC₅₀ means the drug is more potent.

• Efficacy is the maximum effect a drug can produce, regardless of dose.

  • It describes the strength of the response, not the amount needed to produce it.

  • A drug can be highly efficacious but not very potent, or vice versa.

What is the Therapeutic Index (TI) and what does it measure?

• The Therapeutic Index (TI) is the ratio of a drug’s toxic dose (TD₅₀) to its effective dose (ED₅₀).

  • TD₅₀ = Dose that causes toxicity in 50% of subjects.

  • ED₅₀ = Dose that produces desired effect in 50% of subjects.

• TI = TD₅₀ / ED₅₀

• It is a measure of a drug’s safety:

  • A higher TI means the drug is safer, as there's a larger margin between effective and toxic doses.

  • A lower TI means greater risk of overdose or side effects.

What are some additional layers of complexity in neurotransmission that affect how drugs work?

• Receptors aren’t only on the post-synaptic membrane—they can be presynaptic (e.g., autoreceptors) or located elsewhere.

• Not all receptors are ion channels—some are metabotropic (G-protein coupled) and activate second messenger systems.

• Multiple receptor subtypes exist for many neurotransmitters (e.g., dopamine has D1, D2, etc.).

• Axon terminals can co-release more than one neurotransmitter, adding complexity to synaptic signaling.

What is the difference between agonists and antagonists at the level of the synapse?

• Agonists: Enhance or mimic the effect of a neurotransmitter.

  • Can increase release, block reuptake, activate receptors directly, or inhibit degradation.

  • Example: SSRIs block serotonin reuptake = more serotonin in synapse.

• Antagonists: Reduce or block the effect of a neurotransmitter.

  • Can block receptors, inhibit release, or enhance degradation.

  • Example: Naloxone blocks opioid receptors = prevents opioid effects.

What is an agonist at the level of the receptor?

An agonist is a drug that binds to a receptor and activates it, mimicking the action of the natural (endogenous) neurotransmitter.

• Unbound receptor: Inactive, waiting for a ligand.

• With its matching transmitter: Neurotransmitter binds → receptor activated.

• With an agonist drug: Drug mimics neurotransmitter → receptor activated in the same way.

🔑 Key Point: Agonists promote or mimic neurotransmission by directly activating the receptor.

What is an antagonist at the level of the receptor? What is noncompetitive binding?

An antagonist is a drug that binds to a receptor but does not activate it, effectively blocking the action of the natural neurotransmitter or agonist.

Types:

• Competitive Antagonist: Competes with the neurotransmitter for the same binding site.

• Noncompetitive Antagonist: Binds to a different site (allosteric site) on the receptor, altering the receptor’s shape or function so it cannot be activated, even if the neurotransmitter is bound.

🧪 With an antagonist drug:

• The receptor remains inactive, even when a neurotransmitter is present.

🔑 Key Point: Antagonists inhibit neurotransmission by preventing receptor activation.

What is the difference between orthosteric and allosteric binding at receptors?

• Orthosteric Site:
  The primary binding site on a receptor where the endogenous neurotransmitter (or agonist) normally binds.

• Allosteric Site:
  A secondary binding site on the receptor that modulates the receptor’s activity without directly activating it.

What is a direct agonist?

A drug that binds to the orthosteric site of the postsynaptic receptor and activates it, mimicking the neurotransmitter.

What is a direct antagonist?

A drug that binds to the orthosteric site of the postsynaptic receptor and blocks the neurotransmitter from binding, preventing activation.

What does "indirect" agonist or antagonist mean?

A drug that does not bind to the orthosteric site, but instead influences neurotransmission through other mechanisms (e.g., altering neurotransmitter release, reuptake, or degradation).

At what site do direct agonists and antagonists bind?

The orthosteric site on the postsynaptic receptor.

In the context of this class, what distinguishes direct from indirect drug actions?

• Direct: Binds to orthosteric site of the postsynaptic receptor.

• Indirect: Acts at any other site or influences neurotransmission without directly binding to the orthosteric site.

What is an ionotropic receptor?

A ligand-gated ion channel that opens directly in response to neurotransmitter binding, allowing ions to flow across the membrane. It produces fast, short-lived effects.

What is a metabotropic receptor?

A receptor that activates G-proteins and second messenger systems after binding to a neurotransmitter. It produces slower, longer-lasting, and more widespread effects.

How do ionotropic and metabotropic receptors differ in speed?

• Ionotropic: Fast response

• Metabotropic: Slow response

Do metabotropic receptors form ion channels?

No, they do not form ion channels directly but influence ion channel activity through intracellular signaling.

Can both types of receptors be affected by drugs?

Yes. Both ionotropic and metabotropic receptors can be targets of drugs acting as agonists or antagonists.

What is the primary difference in how ionotropic and metabotropic receptors act?

• Ionotropic receptors cause direct transmitter action by forming ion channels that open immediately when a neurotransmitter binds.

• Metabotropic receptors cause indirect transmitter action by activating intracellular signaling cascades (e.g., G-proteins, second messengers).

Which type of receptor is typically a G-protein coupled receptor (GPCR)?

Metabotropic receptors are often GPCRs.

What is the speed and duration of ionotropic receptor effects?

Fast onset, short-lasting, and localized effects.

What is the speed and duration of metabotropic receptor effects?

Slower onset, longer-lasting, and more widespread effects.

What intracellular mechanisms do metabotropic receptors activate?

They activate second messengers (e.g., cAMP, IP3) through G-protein signaling pathways.

Which receptor type typically controls fast synaptic transmission like in muscle movement?

Ionotropic receptors

Which receptor type is more associated with modulation and regulation of neuron function over time?

Metabotropic receptors

Can the postsynaptic membrane have multiple types of receptors?

Yes, the postsynaptic membrane can contain many types of receptors, including both ionotropic and metabotropic receptors.

Do receptors on the postsynaptic membrane function independently?

No, receptors do not act in isolation. They often interact and influence each other’s function.

What is the Post Synaptic Density (PSD)?

The PSD is a protein-dense region of the postsynaptic membrane that organizes and anchors receptors and signaling proteins, facilitating complex receptor interactions.

Why is receptor interaction on the PSD important?

These interactions allow for fine-tuning of synaptic signaling, integration of multiple signals, and modulation of neuron responses.

Can ionotropic and metabotropic receptors influence each other on the PSD?

Yes. For example, metabotropic receptor activity can modulate the function or trafficking of ionotropic receptors, influencing synaptic strength and plasticity.

Can axon terminals release more than one neurotransmitter?

Yes, axon terminals can release multiple neurotransmitters.

What is neurotransmitter cohabitation?

It refers to the coexistence of different neurotransmitters within the same neuron or terminal, allowing for differential release depending on factors like age, neural activity, or drug exposure.

What is the functional benefit of releasing multiple neurotransmitters?

It allows neurons to send different signals at different firing rates, providing qualitatively different types of information.

What is an example of neurotransmitter co-release?

GABA and glutamate can be co-released from the ventral tegmental area (VTA), showing how inhibitory and excitatory signals can be modulated together.

How can co-release change with experience or conditions?

Co-release can vary with developmental stage, neural activity patterns, and pharmacological manipulation, making it a dynamic signaling mechanism.

What is the most common excitatory neurotransmitter in the brain?

Glutamate

What type of postsynaptic potential does glutamate typically generate?

Excitatory postsynaptic potentials (EPSPs)

What is the most common inhibitory neurotransmitter in the brain?

GABA (Gamma-Aminobutyric Acid)

What type of postsynaptic potential does GABA typically generate?

Inhibitory postsynaptic potentials (IPSPs)

Name four neurotransmitters that are modulatory and project widely in the brain.

Acetylcholine, Dopamine, Norepinephrine, Serotonin

What is the role of neurotransmitters like dopamine and serotonin in the nervous system?

They are modulatory, meaning they influence overall brain activity and are involved in regulating mood, arousal, attention, and motivation.

Why are neurotransmitters like dopamine and serotonin important targets for psychoactive drugs?

Because they affect widespread brain regions and are involved in mood, behavior, and cognition, making them central to the action of many therapeutic and recreational drugs.

What are the two main categories of neurotransmitters based on molecular size?

Small molecule neurotransmitters and neuropeptides

What are examples of small molecule neurotransmitters?

Glutamate, GABA, Acetylcholine, Dopamine, Norepinephrine, Serotonin

What are neuropeptides?

Larger molecules made of chains of amino acids; act as neurotransmitters or neuromodulators

Give two examples of neuropeptides.

Endorphins and Substance P

How are small molecule neurotransmitters synthesized and stored?

Synthesized in the axon terminal and stored in small, clear vesicles

How are neuropeptides synthesized and stored?

Synthesized in the cell body and transported down the axon in large, dense-core vesicles

How are neurotransmitters also classified functionally?

As excitatory, inhibitory, or modulatory

Which neurotransmitter is primarily excitatory in the CNS?

Glutamate

Which neurotransmitter is primarily inhibitory in the CNS?

GABA

What are modulatory neurotransmitters and what do they do?

Neurotransmitters like dopamine, serotonin, acetylcholine, and norepinephrine that modulate the activity of neural circuits rather than directly causing excitation or inhibition.

Where are small-molecule neurotransmitters synthesized?

In the axon terminal

What types of receptors can small-molecule neurotransmitters act on?

Ionotropic and/or metabotropic receptors

Do small-molecule neurotransmitters typically act on only one type of receptor?

No, they often act on multiple receptor subtypes

How are small-molecule neurotransmitters removed from the synaptic cleft?

Through reuptake or enzymatic degradation

Why do small-molecule neurotransmitters act quickly?

Because they are synthesized locally in the axon terminal and packaged into vesicles near the release site

What is the principal excitatory neurotransmitter in the CNS?

Glutamate

What type of postsynaptic potentials does glutamate produce?

EPSPs (Excitatory Postsynaptic Potentials)

What analogy is commonly used to describe glutamate's excitatory effect?

The “gas pedal” of the brain

What are the two principal ionotropic glutamate receptors?

AMPA and NMDA

What type of receptors are mGluRs (metabotropic glutamate receptors)?

G-protein-coupled receptors (metabotropic)

What can result from excessive glutamate transmission?

Epilepsy, seizures, and neurotoxicity (damage or death of neurons)

What ion does the AMPA receptor gate?

Na⁺ (sodium)

Is the AMPA receptor excitatory or inhibitory?

Excitatory

What makes the NMDA receptor unique among glutamate receptors?

It requires both glutamate binding and membrane depolarization to activate.

What ion blocks the NMDA receptor at resting membrane potential?

Magnesium (Mg²⁺)

What ions flow through the NMDA receptor when activated?

Na⁺ (sodium) and Ca²⁺ (calcium)

What are the three requirements for NMDA receptor (NMDAR) activation?

1. Glutamate binding

2. Glycine (or D-serine) co-agonist binding

3. Membrane depolarization to remove Mg²⁺ block

How many orthosteric binding sites does the NMDA receptor have?

Two — one for glutamate and one for glycine (or D-serine)

What ion blocks the NMDA receptor at resting membrane potential?

Mg²⁺ (Magnesium)

What type of receptor is the NMDA receptor?

Ionotropic glutamate receptor

Which ions flow through the NMDA receptor once it is activated?

Na⁺ (sodium) and Ca²⁺ (calcium)

What ion does the AMPA receptor (AMPAR) gate?

Na⁺ (sodium)

What type of postsynaptic potential does AMPAR generate?

Fast excitatory postsynaptic potentials (EPSPs)

What are the activation requirements for NMDA receptor (NMDAR)?

1. Glutamate binding

2. Glycine (or D-serine) co-agonist binding

3. Membrane depolarization to relieve Mg²⁺ block

Which receptor is faster in mediating synaptic transmission, AMPAR or NMDAR?

AMPAR (quick activation and deactivation)

What ions flow through NMDA receptors once activated?

Na⁺ (sodium) and Ca²⁺ (calcium)

Why is NMDA receptor activation considered "coincidence detection"?

Because it requires both ligand binding and postsynaptic depolarization to open.

Where is glutamate synthesized in the neuron?

In the axon terminal from the precursor glutamine.

What enzyme converts glutamine to glutamate?

Glutaminase

Where does the neuron get glutamine from?

From astrocytes through the glutamate-glutamine cycle.

How is glutamate packaged into synaptic vesicles?

By vesicular glutamate transporters (VGLUTs).