1. CNS 5 & 6 Neurotransmitters & Neuromodulators

What is the difference between a neurotransmitter & a neuromodulator?

• Neurotransmitter = endogenous chemical that transmits signals across a synapse to another neurone, muscle, or effector cell

• Neuromodulator = endogenous chemical affecting groups of neurones or cells with the right receptor, often not released at synapses

  • Acts via second messengers

  • Produces longer-lasting effects

Endogenous = made naturally within the body

What are the major types of neurotransmitters & neuromodulators?

• Acetylcholine – NT

• Monoamines – NT & NM

  • Catecholamines: dopamine, noradrenaline, adrenaline

  • Indolamines: serotonin

• Amino acids – NT & NM

  • Glutamate, GABA, glycine

• Peptides – NT & NM

  • Endorphins, enkephalins

• Lipid-like substances – NT

  • Anandamide, leptin

• Nucleosides – NM

  • Adenosine

• Soluble gases – NM

  • Nitric oxide, carbon monoxide

What are the key features of acetylcholine (ACh) as a neurotransmitter?

• Found in PNS – causes skeletal muscle contraction

• In ANS & brain – involved in plasticity, arousal & reward

• Synthesised from choline + acetyl-CoA in presynaptic terminals

• Stored in vesicles & released via exocytosis

• Binds to cholinergic receptors = excitatory or inhibitory effects

• Removed by acetylcholinesterase (AChE)

• Choline is reuptaken by a specific transporter

What are the major acetylcholine pathways in the brain & their functions?

• Nucleus Basalis of Meynert

  • Neocortex = memory (via M1 receptors)

  • Frontal cortex = memory (via M1 receptors)

  • Hippocampus = spatial memory

  • Amygdala = emotions

• Dorsolateral Tegmental Nucleus

  • Cerebellum = balance & movement

  • Thalamus = sensory processing

  • Striatum (basal ganglia) = motor control via cholinergic interneurons

• ACh neurons are localised but project widely to modulate multiple brain functions

What are the types of acetylcholine (ACh) receptors, their agonists & antagonists?

• Nicotinic ACh receptors

  • Stimulated by: nicotine

  • Blocked by: curare

• Muscarinic ACh receptors

  • Stimulated by: muscarine

  • Blocked by: atropine

• ACh receptors are widely distributed & regulate many central & peripheral functions

What are the key features of nicotinic ACh receptors in the brain?

• Ligand-gated ion channels on neurones

• Activated by ACh = Na⁺ influx

• Causes depolarisation (EPSP) = ↑ excitability

What are the roles and signaling mechanisms of muscarinic ACh receptors?

• M1, M3, M5:

  • Activate G_q/11 proteins = excitation

  • Phospholipase activation = ↑ intracellular Ca²+ = depolarization

  • Slow EPSP, regulate K+ channels

• M2, M4:

  • Activate G_i/O proteins = inhibition

  • Inhibit adenylyl cyclase = ↓ cAMP

  • ↓ Protein kinase A activity = reduced phosphorylation of channels

  • Inhibit voltage-gated Ca²⁺ channels

• Effect: Dependent on receptor type and brain location, leading to either excitatory or inhibitory responses.

What are the types and examples of ACh receptor agonists and antagonists?

• Acetylcholinesterase inhibitors:

  • Reversible: e.g., neostigmine (treatment for Myasthenia gravis)

  • Irreversible: e.g., parathion (chemical weapon)

• Nicotinic receptor agonists:

  • Stimulate memory (e.g., nicotine)

  • Drug candidates for Alzheimer's disease, schizophrenia, ADHD (e.g., Galantamine)

• Nicotinic receptor antagonists:

  • Mild sedative & cough suppressant (e.g., DXM)

• Muscarinic receptor agonists:

  • Treatments for Alzheimer's disease (e.g., M1 receptor agonists)

  • Treatment for glaucoma (e.g., pilocarpine, M3 receptor agonists)

• Muscarinic receptor antagonists:

  • Atropine & scopolamine (toxins)

What are the types & key features of dopamine as a neurotransmitter?

• Type: Catecholamine

• Synthesised from: Tyrosine in dopaminergic neurones

• Stored in: Large dense core vesicles

• Released by: Vesicle exocytosis (AP-triggered)

• Receptor action: Binds dopamine receptors → excitatory or inhibitory (receptor-dependent)

• Removed by: Dopamine transporters (DAT)

• Degraded by: Monoamine oxidase (MAO)

• Functions:

  • Movement control (via basal ganglia)

  • Emotional response (via limbic system)

  • Pleasure & pain control (via nucleus accumbens)

What are the major dopamine pathways in the brain & their functions?

• Nigrostriatal (Substantia Nigra → Striatum):

  • Motor control (↓ dopamine here = Parkinson’s motor symptoms)

• Mesolimbic (VTA → Nucleus Accumbens):

  • Mood, reward, addiction

• Mesocortical (VTA → Prefrontal Cortex):

  • Attention, working memory, cognition

• Tuberoinfundibular (Hypothalamus → Pituitary):

  • Regulates hormone secretion

What are the mechanisms of D₁-like & D₂-like dopamine receptors?

• D₁-like receptors (D₁, D₅)
  • Coupled to Gₛ = ↑ adenylyl cyclase = ↑ cAMP = ↑ PKA = excitatory

• D₂-like receptors (D₂, D₃, D₄)
  • Coupled to Gᵢ/ₒ = ↓ adenylyl cyclase = ↓ cAMP = ↓ PKA = inhibitory

• Balance is key in regions like basal ganglia
  • Imbalance = motor disorders (e.g. Parkinson’s)

How is dopamine action terminated at the synapse?

• Re-uptake into presynaptic neuron via dopamine transporter (DAT)

• Driven by Na⁺/K⁺ gradients maintained by Na⁺/K⁺-ATPase (via ATP hydrolysis)

• Co-transport of dopamine with Na⁺ & Cl⁻ into the neuron

• K⁺ binding resets transporter to outward position; release into synaptic cleft restores ionic gradient

What are the roles of dopamine agonists & antagonists?

• Agonists/mimetics:

  • DA transporter inhibitors (↑ synaptic DA) — e.g. amphetamine, cocaine

  • DA precursor (↑ DA synthesis) — L-DOPA for Parkinson’s

• Antagonists:

  • D₂ antagonists — typical antipsychotics for schizophrenia

  • Can cause Parkinson-like symptoms

  • ↑ prolactin release

  • Tranquillizing/sedative effects

What is the role of noradrenaline (NA) in the brain and body, and how is it synthesized, released, and removed from the synaptic cleft?

• Neurotransmitter of the catecholamine family

• Roles: autonomic control (sympathetic nervous system), alertness, rest cycles, attention, & memory in the CNS

• Synthesized from tyrosine in presynaptic terminals of adrenergic neurones

• Stored in large dense-core vesicles

• Released by vesicle exocytosis

• Binds to adrenergic receptors, causing excitatory or inhibitory postsynaptic effects

• Removed from synaptic cleft by adrenergic transporters

• Degraded by monoamine oxidase (MAO) & catechol-O-methyltransferase (COMT)

Where are the main pathways of noradrenaline (NA) in the brain, and what functions do they regulate in different regions?

• Locus coeruleus: Cell bodies of adrenergic neurones located in the pons; axons project to multiple brain areas.

• Neocortex (α2 receptors): Regulates attention, concentration, and cognitive function.

• Frontal cortex (β1 receptors): Regulates mood.

• Limbic areas: Regulates emotions.

• Cerebellum: Regulates tremor and movement coordination.

• Brainstem (Cardiovascular centres): Regulates cardiovascular functions.

Associated neurological disorders:

• Affective disorders

• Depression

• Autonomic failure

• Pain

How does noradrenaline exert its effects on the brain, and how do the different receptors (α1, α2, β) contribute to excitatory and inhibitory functions?

Receptors: Noradrenaline acts on different receptors in the brain, similar to peripheral receptors.

• α1 receptors: Coupled to the phospholipid pathway via Gq proteins, leading to excitatory effects.

• α2 receptors: Coupled to Gi proteins, inhibiting adenylate cyclase, leading to inhibitory effects.

• β receptors: Coupled to Gs proteins, stimulating adenylate cyclase, resulting in excitatory effects.

Neuronal activity: These receptors are expressed by neurons in the brain and regulate various functions depending on the type of receptor activated.

Excitatory and inhibitory effects:

• α1 and β receptors are excitatory.

• α2 receptors are inhibitory.

How is noradrenaline re-uptake terminated at the synapse?

• Re-uptake occurs via an energy-dependent process across the presynaptic membrane.

• Sodium/potassium ATPases use ATP hydrolysis to create an ion gradient.

• This gradient drives transporter opening, co-transporting Na+, Cl-, and DA.

• Potassium ions bind to the transporter, enabling it to return to the outward position.

What are the agonists and antagonists of noradrenaline?

• Agonists & Mimetics:

  • NA transporter inhibitors: amphetamine, cocaine (increase wakefulness, alertness, reduce fatigue; drugs of abuse)

  • Tricyclic antidepressants: imipramine (uptake inhibitors for NA & 5-HT)

  • MAO inhibitors: impair cognitive processes, cause euphoria, insomnia, hallucinations, delusions

• Antagonists:

  • Beta blockers: anxiolytic effects

What is serotonin and its role in the brain and body?

• Serotonin (5-HT): A neurotransmitter of the indolamine category.

• Functions:

  • Controls mood, appetite, sleep

  • Regulates cognitive functions like memory and learning

• Synthesis: Made in presynaptic terminals from tryptophan, stored in large dense core vesicles.

• Release: Released via exocytosis from vesicles.

• Receptors: Binds to 5-HT receptors, producing excitatory or inhibitory effects.

• Termination: Removed from the synaptic cleft by specific transporters and degraded by monoamine oxidase (MAO).

What are the serotonin pathways in the brain and their functions?

• Raphe Nucleus: Located at the border between the pons and midbrain, it is the source of serotonergic neurons.

• Frontal Cortex: Mood regulation.

• Limbic Areas: Involved in anxiety and panic.

• Basal Ganglia: Regulates movement, obsessions, and compulsions.

• Spinal Cord: Regulates nociception and sexual dysfunction.

• Hypothalamus: Involved in appetite regulation.

• Sleep Centers: Found in the reticular formation, involved in vomiting.

• Associated Disorders: Depression, anxiety, migraine.

What are the effects of different serotonin (5-HT) receptor families in the brain?

• 5-HT1 & 5-HT5 receptors: Coupled to Gi/o proteins, leading to inhibition and a decrease in excitation.

• 5-HT2 family receptors: Coupled to Gq proteins, leading to excitation.

• 5-HT3 receptors: Ligand-gated ion channels, leading to depolarization.

• 5-HT4, 6, 7 receptors: Coupled to Gs proteins, leading to excitation.

How is serotonin re-uptake terminated at the synapse?

• The action of serotonin is terminated by re-uptake across the presynaptic membrane, similar to dopamine and noradrenaline.

• This is an energy-dependent process.

• Sodium/potassium ATPases use ATP to create a concentration gradient of ions across the presynaptic membrane.

• The gradient drives the transporter to co-transport Na+, Cl-, and DA from the synaptic cleft.

• K+ binding to the transporter allows it to return to the outward position.

• The release of K+ ions into the synaptic cleft equilibrates the ionic gradient across the presynaptic membrane.

What are some drugs that affect serotonin reuptake and serotonergic transmission?

• Fluoxetine (Prozac) inhibits serotonin reuptake and is used to treat:

  • Depression

  • Some anxiety disorders

  • Obsessive-compulsive disorder

• Hallucinogenic drugs, like LSD, interact with serotonergic transmission:

  • LSD stimulates 5-HT2A receptors in the forebrain, producing visual perception distortions.

• Neurotransmitter precursors: Drugs can increase (e.g., L-dopa for dopamine) or inhibit synthesis.

• Neurotransmitter storage: Drugs can inhibit vesicle storage, disrupting release.

• Neurotransmitter release: Drugs can stimulate or block release, but both are toxic (e.g., black widow spider venom).

• Receptors:

  • Serotonin receptors: Specific subtypes are good targets.

  • GABA receptors: Multiple subtypes offer specific drug targeting.

  • Nicotinic receptors: Affects both CNS and periphery.

  • Post-synaptic & auto-receptors: Can inhibit or enhance neurotransmitter release.

• Reuptake mechanisms:

  • Fluoxetine (Prozac) blocks serotonin reuptake.

  • Cocaine inhibits dopamine, serotonin, and norepinephrine reuptake.

• Acetylcholinesterase inhibition: Specific to acetylcholine transmission.

What are the main challenges in CNS drug development?

• Limited understanding of CNS diseases & brain function → hinders rational drug design

• Drug specificity is difficult = ↑ risk of CNS side effects

• Blood-brain barrier blocks most drugs = many fail to reach brain cells