6.1 Neurotransmission
Neurotransmission is the process by which signaling molecules (neurotransmitters) are released by neurons to affect target cells. Understanding neurotransmitter systems is fundamental to CNS pharmacology.
Glutamate - Excitatory Neurotransmission
Glutamate Receptors
Ionotropic: NMDA, AMPA, Kainate receptors (ligand-gated ion channels)
Metabotropic: mGluR1-8 (G-protein coupled receptors)
NMDA Receptor
Requires glycine co-agonist and membrane depolarization to relieve Mg²⁺ block
Permeable to Ca²⁺—critical for synaptic plasticity and learning
Excitotoxicity
Excessive glutamate → Ca²⁺ overload → neuronal death
Occurs in stroke, trauma, neurodegenerative diseases
GABA - Inhibitory Neurotransmission
GABAA Receptor
Cl⁻ ionotropic channel, pentameric structure (α, β, γ subunits)
Target for benzodiazepines, barbiturates, anesthetics, alcohol
GABAB Receptor
Gi/o-coupled GPCR, activates K⁺ channels, inhibits Ca²⁺ channels
Baclofen (muscle relaxant) is selective agonist
GABA Synthesis & Degradation
Synthesis: Glutamate → GABA (via glutamic acid decarboxylase, GAD)
Degradation: GABA → Succinate (via GABA transaminase)
Dopamine
D1-like Receptors (D1, D5)
Gs-coupled → ↑ cAMP
Postsynaptic, excitatory effects
D2-like Receptors (D2, D3, D4)
Gi/o-coupled → ↓ cAMP
Pre- and postsynaptic, inhibitory
Dopaminergic Pathways
Nigrostriatal: Motor control (Parkinson's)
Mesolimbic: Reward, addiction
Mesocortical: Cognition, executive function
Tuberoinfundibular: Prolactin regulation
Metabolism
MAO (monoamine oxidase) → DOPAC
COMT (catechol-O-methyltransferase) → 3-MT
Both → HVA (homovanillic acid)
Serotonin (5-HT)
Serotonin Receptors
14 subtypes (5-HT1–5-HT7), mostly GPCRs
Exception: 5-HT3 is ligand-gated Na⁺/K⁺ channel
Key Subtypes
5-HT1A: Anxiolytic effects (buspirone target)
5-HT2A: Psychedelic effects, antipsychotic target
5-HT3: Antiemetic target (ondansetron)
Synthesis & Reuptake
Tryptophan → 5-HTP → 5-HT (via tryptophan hydroxylase)
SERT (serotonin transporter): SSRI target
Norepinephrine (Noradrenaline)
α-Adrenergic Receptors
α₁: Gq-coupled → vasoconstriction
α₂: Gi-coupled → presynaptic inhibition
β-Adrenergic Receptors
β₁: Heart (↑ HR, contractility)
β₂: Bronchodilation, vasodilation
All Gs-coupled → ↑ cAMP
Locus Coeruleus
Major NE source in CNS
Regulates arousal, attention, stress response
Metabolism
MAO and COMT degrade NE
NET (norepinephrine transporter): reuptake