Neurotransmitters and Drugs

Common Neurotransmitters and Their Actions

Determining Neurotransmitter Effects

• Excitatory Neurotransmitters:
  • Open Na^+ or Ca^{++} chemical-gated channels.
  • Positive ions (Na^+ or Ca^{++}) enter the cell.
  • The cell membrane potential is depolarized (becomes more positive).
  • Depolarization brings the voltage closer to threshold (-55mV), increasing the likelihood of an action potential (AP).
• Inhibitory Neurotransmitters:
  • Open K^+ chemical-gated channels.
  • Positive ions (K^+) exit the cell.
  • The cell membrane potential is hyperpolarized (becomes more negative).
  • Open Cl^- channels.
  • Negative ions (Cl^-) enter the cell
  • The cell membrane potential is hyperpolarized (becomes more negative).
  • Hyperpolarization takes the voltage further from threshold (-55mV), decreasing the likelihood of an action potential.

Neurotransmitter Characteristics

• Over 200 neurotransmitters exist.
• Act as chemical messengers between neurons.
• Differ in chemical structure.
• Can be excitatory or inhibitory.
• Act either fast (directly) or more slowly (indirectly).

Direct vs. Indirect Neurotransmitter Action

Direct Action

• Neurotransmitter binds directly to a receptor that is also an ion channel.
• The receptor channel opens, allowing ions to flow into or out of the cell.
• Ion flow is blocked when the ion channel is closed.

Indirect Action

• Neurotransmitter binds to a receptor on the cell surface.
• The receptor does not have a channel to open or close.
• Triggers a series of events mediated by proteins and enzymes inside the cell.
• Involves a second messenger (e.g., cAMP).
• Steps:
  1. The neurotransmitter (1st messenger) binds to and activates the receptor.
  2. The receptor activates a G protein.
  3. The G protein activates adenylate cyclase.
  4. Adenylate cyclase converts ATP to cAMP (2nd messenger).
  5. cAMP can:
     • Open or close ion channels, changing membrane permeability and the RMP of the cell.
     • Activate enzymes in the cytoplasm.
     • Stimulate specific genes in the nucleus to produce proteins.

Why Direct and Indirect Actions?

• Direct action: fast and short-acting effects (e.g., turning on skeletal muscle quickly).
• Indirect action: slower to start and longer-lasting effects (e.g., smooth and cardiac muscle contraction).

Major Neurotransmitter Groups

• Acetylcholine (ACh)
• Biogenic amines
• Amino acids
• Peptides
• Purines

Acetylcholine (ACh)

• The only neurotransmitter in its class.
• Binds to skeletal, smooth, and cardiac muscle, but acts differently at each location.
• Can be excitatory or inhibitory, direct or indirect.
• Function depends on the receptor it binds to.

Actions at Different Receptors

• Skeletal muscle and brain cells:
  • Excitatory by opening chemical-gated Na^+ channels.
  • Fast-acting because it directly opens Na^+ channels.
  • Designed for quick muscle start.
• Heart muscle:
  • Inhibitory by opening K^+ channels, inhibiting the cell and reducing contraction.
  • Slow-acting because it opens K^+ channels indirectly.
  • Cardiac muscle slowly squeezes blood to the body.
• Smooth muscle:
  • Excitatory by opening Ca^{++} channels.
  • Slow-acting because it opens Ca^{++} channels indirectly.
  • Smooth muscle slowly propels food through the small intestine.

*The same NT can have different actions by binding to different receptors, and opening different channels. Actions can be direct or indirect depending on the receptors.

Biogenic Amines

• Norepinephrine
• Serotonin
• Dopamine
• Histamine

Dopamine

• Excitatory neurotransmitter.
• Brain dopamine causes a positive mood.
• Lack of brain dopamine may lead to depression.

Serotonin

• Inhibitory neurotransmitter.
• A decrease in brain serotonin may cause anxiety.
• Maintains a calm and level mood.

Norepinephrine (NE, Adrenaline)

• Helps overcome emergencies.
• Can be excitatory and inhibitory at different receptors.
  1. Increases heart rate for more blood to muscle and brain.
  2. Opens airways for more oxygen.
  3. Closes blood vessels to the skin to redirect blood to the brain and skeletal muscles.

Amino Acid Neurotransmitters

• Glutamate: Excitatory neurotransmitter that increases the activity of neurons in the brain, keeping you awake.
• GABA (gamma-amino-butyric acid): Inhibitory neurotransmitter that calms activity of neurons in the brain, making you relaxed and sleepy.

Peptide Neurotransmitters

• Part of the pain pathway.
• Substance P: Excitatory peptide neurotransmitter that transmits pain information to the brain.
• Endorphins: Inhibitory peptide neurotransmitters that help turn off pain feelings.

Drugs and Their Interactions with Neurotransmitters

How Drugs Affect Neurotransmitter Function

• Neurotransmitters are internal chemical messengers.
• Drugs are external chemical messengers.
• Drugs bind to neurotransmitter binding sites.
• Drugs can either help or stop a neurotransmitter from working.

Agonist vs. Antagonist Drugs

• Agonist: enhance or help the action of a neurotransmitter.
  • If an agonist drug helps excitatory NT action, more excitement occurs
  • If an agonist drug helps inhibitory NT action, less excitement occurs
• Antagonist: block (stop) the action of a neurotransmitter.
  • If an antagonist drug blocks excitatory NT action, less excitement occurs
  • If an antagonist drug blocks inhibitory NT action, more excitement occurs

Examples of Drugs

Anti-depressant Drugs: Dopamine Agonists

• Dopamine (DA) is an excitatory neurotransmitter that keeps your mood up.
• Theory: A decrease in dopamine at the synapse may cause depression.
• Anti-depressant drugs are dopamine agonists, increasing the amount of dopamine available in the synapse.
• Wellbutrin is a Selective Dopamine Re-uptake Inhibitor (SDRI) that stops dopamine removal, allowing dopamine to stay in the synapse and elevate your mood.

Anti-anxiety Meds: Serotonin Agonists

• Serotonin (SE) is an inhibitory neurotransmitter that keeps you calm.
• A decrease in serotonin may cause anxiety.
• Prozac is a serotonin agonist (helper) that blocks the removal of serotonin, keeping more serotonin in the synapse and making you feel less anxious.
• Prozac is a selective serotonin re-uptake inhibitor (SSRI).

Pain Meds: Endorphin Agonists

• Endorphins naturally turn off pain feelings.
• Morphine acts as an endorphin agonist, helping endorphins reduce pain.

BOTOX: ACh Antagonist

• Botox prevents ACh from working.
• Stress causes ACh release onto skeletal muscles, leading to muscle contraction and frown lines.
• Botox prevents the release of ACh from vesicles, preventing it from reaching muscle cells and relaxing facial muscles.

Local Anesthetics: Lidocaine

• Injected near neurons carrying pain signals to the brain.
• Cause shut down of voltage-gated Na^+ ion channels in the axon preventing action potentials to occur.
• If the action potential does not carry pain information to the brain, you do not feel pain.

General Anesthetics

• Interfere with the function of receptors and channels in the cell membrane to make you "sleep" during an operation.
• Inhibit (turn off) excitatory (glutamate) receptors in the brain.
• Excite (turn on) inhibitory (GABA) receptors.