NEUR 5300 - Action Potentials and Synaptic Transmission

History and Principles of Neural Signaling

• Neuron Doctrine:

  • Developed following histological studies by Santiago Ramón y Cajal and Camillo Golgi, who shared the 1906 Nobel Prize in Physiology or Medicine.
  • Established that the nervous system is composed of discrete individual functional cells (neurons) rather than a continuous anatomical syncytium.

• Discovery of Bioelectricity:

  • Luigi Galvani ($1737\text{--}1798$) demonstrated "animal electricity" through experiments involving electrical stimulation of frog leg neuromuscular preparations.

• Experimental Models in Electrophysiology:

  • The giant axon of the squid (e.g., Loligo) served as the foundational preparation for modern electrophysiology.
  • The squid giant axon measures approximately $800\,\mu\text{m}$ in diameter, compared to a mammalian axon diameter of approximately $2\,\mu\text{m}$.
  • This massive diameter allowed for the direct insertion of intracellular recording electrodes into the axon extending from the stellate ganglion to record transmembrane potentials directly.

Structural Organization and Morphological Types of Neurons

• Canonical Anatomy of a Neuron:

  • Dendrites: Branching receptive processes that receive input signals from upstream neurons or environmental stimuli.
  • Cell Body (Soma): Synthesizes proteins and metabolic components; integrates incoming synaptic signals. Houses the nucleus, rough endoplasmic reticulum, and Golgi apparatus.
  • Axon Hillock and Initial Segment: The specialized junction between the cell body and axon where voltage-gated ion channel density is high and action potentials are initiated.
  • Axon: The extended conductile process responsible for transmitting action potentials over long distances.
  • Presynaptic Axon Terminal (Bouton): The output terminal that converts electrical signals into chemical messages via neurotransmitter release across the synaptic cleft.

• Functional Classification of Neurons:

  • Sensory Neurons: Unipolar or pseudounipolar neurons. Possess a peripheral process extending to sensory receptors in skin or tissues (mediating modalities such as pain or touch) and a central process entering a spinal cord segment.
  • Motor Neurons: Multipolar neurons with cell bodies located in the ventral horn of the spinal cord that extend myelinated axons to innervate effector targets such as skeletal muscle fibers.
  • Local Interneurons: Form localized circuits within specific regions of the central nervous system (CNS); characterized by short, unmyelinated or sparsely myelinated axons.
  • Projection Interneurons: Possess long axons that convey information between distinct brain regions or spinal cord segments.
  • Neuroendocrine Cells: Specialized neurons that secrete neurohormones directly into adjacent capillary beds for systemic circulation.

• Morphological Variants:

  • Bipolar Neurons: Feature two distinct processes (one axon and one dendrite) extending from opposite poles of the cell body. Present in special sensory pathways:
  • Retina: Connecting photoreceptors (rods and cones) to ganglion cells.
  • Olfactory Mucosa: Olfactory receptor cells projecting to the olfactory bulb.
  • Inner Ear: Vestibular branch (balance) and cochlear branch (hearing).
  • Multipolar Neurons: Possess a single axon and multiple dendritic trees. Examples include:
  • Pyramidal Cells: Found in the cerebral cortex.
  • Purkinje Cells: Found in the cerebellum, featuring extraordinarily elaborate dendritic arbors.

Transmembrane Solute Transport and Ionic Distribution

• Quantitative Ionic and Molecular Composition (Extracellular Fluid [ECF] vs. Intracellular Fluid [ICF]):

  • Sodium ($\text{Na}^+$): $142\,\text{mEq/L}$ (ECF) vs. $10\,\text{mEq/L}$ (ICF).
  • Potassium ($\text{K}^+$): $4\,\text{mEq/L}$ (ECF) vs. $140\,\text{mEq/L}$ (ICF).
  • Calcium ($\text{Ca}^{2+}$): $2.4\,\text{mEq/L}$ (ECF) vs. $0.0001\,\text{mEq/L}$ (ICF).
  • Magnesium ($\text{Mg}^{2+}$): $1.2\,\text{mEq/L}$ (ECF) vs. $58\,\text{mEq/L}$ (ICF).
  • Chloride ($\text{Cl}^-$): $103\,\text{mEq/L}$ (ECF) vs. $4\,\text{mEq/L}$ (ICF).
  • Bicarbonate ($\text{HCO}_3^-$): $28\,\text{mEq/L}$ (ECF) vs. $10\,\text{mEq/L}$ (ICF).
  • Inorganic Phosphates: $4\,\text{mEq/L}$ (ECF) vs. $75\,\text{mEq/L}$ (ICF).
  • Sulfate ($\text{SO}_4^{2-}$): $1\,\text{mEq/L}$ (ECF) vs. $2\,\text{mEq/L}$ (ICF).
  • Glucose: $90\,\text{mg/dl}$ (ECF) vs. $0\text{ to }20\,\text{mg/dl}$ (ICF).
  • Amino Acids: $30\,\text{mg/dl}$ (ECF) vs. $200\,\text{mg/dl}$ (ICF).
  • Lipids (Cholesterol, Phospholipids, Neutral Fat): $0.5\,\text{g/dl}$ (ECF) vs. $2\text{ to }95\,\text{g/dl}$ (ICF).
  • Oxygen Partial Pressure ($\text{PO}_2$): $35\,\text{mm Hg}$ (ECF) vs. $20\,\text{mm Hg}$ (ICF).
  • Carbon Dioxide Partial Pressure ($\text{PCO}_2$): $46\,\text{mm Hg}$ (ECF) vs. $50\,\text{mm Hg}$ (ICF).
  • $\text{pH}$: $7.4$ (ECF) vs. $7.0$ (ICF).
  • Proteins: $2\,\text{g/dl}$ ($5\,\text{mEq/L}$) (ECF) vs. $16\,\text{g/dl}$ ($40\,\text{mEq/L}$) (ICF).

• Mechanisms of Transmembrane Transport:

  • Simple Diffusion: Passive net movement of solutes down concentration, electrical, or pressure gradients without interaction with carrier proteins.
  • Passive Transport (Facilitated Diffusion): Passive solute flux down an electrochemical gradient mediated by channel proteins or carrier proteins.
  • Active Transport: Solute flux against an electrochemical gradient. Requires coupling to metabolic energy, such as ATP hydrolysis.
  • $\text{Na}^+/\text{K}^+$ ATPase Pump: Primary active transporter that hydrolyzes ATP to pump $3\,\text{Na}^+$ ions out of the cell and $2\,\text{K}^+$ ions into the cell per cycle. Maintains resting ionic gradients and contributes electrogenically to resting potential.
  • Leak Channels: Non-gated membrane channels. Resting neuronal membranes exhibit significantly higher permeability to $\text{K}^+$ than to $\text{Na}^+$ due to a greater density of open $\text{K}^+$ leak channels.

Electrophysiology and Action Potential Dynamics

• Resting Membrane Potential (RMP):
  • All excitable cells maintain a baseline electrical potential difference across their membrane, typically $-70\,\text{mV}$ (or $-90\,\text{mV}$ depending on neuronal subtype and theoretical model).
  • Established by fixed intracellular organic anions (proteins, nucleic acids) and the selective permeability/concentration gradients of $\text{K}^+$ and $\text{Na}^+$.
  • Measured experimentally by placing one microelectrode inside the cytoplasm and a second reference electrode in the extracellular fluid.

• Phases of Membrane Potential Alteration:

  • Depolarization: Membrane potential becomes less negative / more positive relative to RMP (excitatory stimulus).
  • Repolarization: Membrane potential returns toward RMP following depolarization.
  • Hyperpolarization: Membrane potential becomes more negative than RMP (inhibitory potential).

• Gating Mechanics of Voltage-Gated (VG) Ion Channels:

  • Voltage-Gated $\text{Na}^+$ Channels:
  • Contain two distinct gates: an activation gate (extracellular) and an inactivation gate (intracellular).
  • At resting potential ($-70\,\text{mV}$ to $-90\,\text{mV}$), the activation gate is closed.
  • Depolarization to threshold ($-50\,\text{mV}$ to $-55\,\text{mV}$) rapidly opens the activation gate, initiating inward $\text{Na}^+$ influx.
  • At peak positive potential ($+30\,\text{mV}$ to $+35\,\text{mV}$), the channel inactivates as the inactivation gate closes, halting $\text{Na}^+$ influx.
  • Voltage-Gated $\text{K}^+$ Channels:
  • Closed at resting membrane potential.
  • Undergo slow activation in response to depolarization, opening fully near peak positive potential ($+30\,\text{mV}$) to allow outward $\text{K}^+$ efflux.

• Sequential Steps of an Action Potential (AP):
  1. A depolarizing stimulus brings the membrane potential to threshold ($-50\,\text{mV}$ to $-55\,\text{mV}$).
  2. Voltage-gated $\text{Na}^+$ channels open rapidly, creating a steep inward electrochemical gradient for $\text{Na}^+$.
  3. $\text{Na}^+$ influx further depolarizes the cell, opening more VG $\text{Na}^+$ channels in a positive feedback loop.
  4. Membrane potential rapidly reverses from $-70\,\text{mV}$ to a peak overshoot of $+30\,\text{mV}$ to $+35\,\text{mV}$.
  5. VG $\text{Na}^+$ channels become inactivated (inactivation gates close).
  6. VG $\text{K}^+$ channels open fully; an outward electrochemical gradient drives $\text{K}^+$ efflux in a negative feedback loop to restore negativity.
  7. Persistent outward $\text{K}^+$ flux generates a transient after-hyperpolarization (undershoot, approaching $-80\,\text{mV}$ to $-90\,\text{mV}$).
  8. VG $\text{K}^+$ channels close, and membrane potential returns to RMP.
  • Both depolarizing rising phase and repolarizing falling phase occur via passive diffusion down electrochemical gradients; the $\text{Na}^+/\text{K}^+$ ATPase pump re-establishes basal ion concentrations over time.

• Properties of Action Potentials:

  • All-or-None Law: If threshold is attained, a full-amplitude action potential fires; if threshold is not attained, no action potential occurs.
  • Constant Amplitude and Duration: Amplitude does not exceed approx. $+30\,\text{mV}$ because VG $\text{Na}^+$ channels rapidly inactivate and VG $\text{K}^+$ channels open.
  • Frequency Coding: Stimulus strength is encoded by action potential frequency, not by changes in action potential amplitude.
  • Recruitment: Stronger stimuli activate a larger population of axons possessing higher activation thresholds.

• Refractory Periods:

  • Absolute Refractory Period: Period during which another action potential cannot be generated, regardless of stimulus strength. Caused by inactivated VG $\text{Na}^+$ channels whose inactivation gates are closed. Membrane excitability is zero.
  • Relative Refractory Period: Period following the absolute refractory period during which a second action potential can be triggered, but requires a stronger-than-normal depolarizing stimulus. Caused by open VG $\text{K}^+$ channels (hyperpolarizing outward current) and recovering $\text{Na}^+$ channels. Excitability gradually recovers to baseline.

Cable Properties and Impulse Propagation

• Neuronal Cable Properties:

  • Cable properties refer to the ability of a neuron to transmit electrical charge passively through its cytoplasm.
  • Passive cable properties of axons are poor due to high internal cytoplasmic resistance and significant charge loss leaking through non-insulated membrane leak channels.
  • Passive electrotonic potentials decay rapidly over short distances; an action potential cannot travel down an axon purely by passive conduction.

• Conduction in Unmyelinated Axons:

  • Inward $\text{Na}^+$ influx during an action potential generates local circuit currents that passively depolarize adjacent membrane regions to threshold.
  • Voltage-gated channels in the adjacent uninsulated region open, regenerating a fresh action potential.
  • Conduction velocity is slow ($0.5\text{--}2.0\,\text{m/s}$) because an action potential must be generated at every fraction of a micrometer along the axon.
  • Conduction is strictly unidirectional (orthodromic) because the upstream membrane segment remains in its refractory period.

• Conduction in Myelinated Axons (Saltatory Conduction):

  • Myelin sheaths (formed by Schwann cells in the PNS and Oligodendrocytes in the CNS) act as electrical insulators, preventing ion movement across insulated internodal membranes.
  • Interruptions in myelin called Nodes of Ranvier contain concentrated clusters of VG $\text{Na}^+$ and $\text{K}^+$ channels.
  • Inward current generated at one node spreads passively down the low-resistance interior axoplasm to the next node.
  • Depolarization rapidly brings the next Node of Ranvier to threshold, causing the action potential to "leap" from node to node (saltatory conduction).
  • Conduction velocity is rapid (up to $100\text{--}120\,\text{m/s}$) and conserves metabolic energy because ion flux occurs exclusively at nodal regions.

Structural and Functional Mechanisms of Synaptic Transmission

• Synapse Definition: Functional junction between a presynaptic neuron and a postsynaptic target cell (neuron, muscle fiber, or gland cell). Transmission occurs unidirectionally.

• Electrical Synapses:

  • Characterized by direct physical and electrical continuity between adjacent cells via gap junctions.
  • A gap junction channel consists of two hemichannels (connexons), each composed of $6$ connexin protein subunits (total of $12$ connexin proteins per functional junction across a $2\text{--}4\,\text{nm}$ gap cleft).
  • Allows passive ionic current flow and small second messengers to pass directly without synaptic delay.
  • Examples include smooth muscle, cardiac muscle, glial cells, and specialized central neural networks requiring synchronized firing.

• Chemical Synapses:

  • Presynaptic terminal boutons are separated from postsynaptic cells by a fluid-filled space called the synaptic cleft (approx. $20\text{--}50\,\text{nm}$ wide).
  • Transmission depends on exocytotic release of chemical neurotransmitters stored in membrane-bound synaptic vesicles.

• Step-by-Step Excitation-Secretion Coupling at Chemical Synapses:

  1. Action potential propagates down the presynaptic axon to the terminal bouton.
  2. Depolarization opens voltage-gated $\text{Ca}^{2+}$ channels located at active zones.
  3. Extracellular $\text{Ca}^{2+}$ enters the bouton down its steep concentration gradient ($2.4\,\text{mEq/L}$ ECF vs. $0.0001\,\text{mEq/L}$ ICF).
  4. Intracellular $\text{Ca}^{2+}$ binds to calmodulin.
  5. Active calmodulin activates protein kinase enzymes.
  6. Protein kinase phosphorylates synapsin proteins, releasing synaptic vesicles from cytoskeletal attachments.
  7. Vesicles migrate to docking sites and form fusion complexes at the presynaptic membrane.
  8. Synaptic vesicles undergo rapid exocytosis, releasing neurotransmitter into the synaptic cleft. The volume of neurotransmitter released is directly proportional to action potential firing frequency.
  9. Neurotransmitter diffuses across the cleft and binds to specific receptor proteins on the postsynaptic membrane.

Postsynaptic Potentials and Synaptic Integration

• Postsynaptic Potentials:

  • Excitatory Postsynaptic Potential (EPSP): Graded depolarizing potential caused by net inward positive current (e.g., $\text{Na}^+$ influx). Shifts membrane potential closer to action potential threshold.
  • Inhibitory Postsynaptic Potential (IPSP): Graded hyperpolarizing potential caused by inward negative current (e.g., $\text{Cl}^-$ influx) or outward positive current (e.g., $\text{K}^+$ efflux). Shifts membrane potential further away from threshold.

• Key Differences Between Action Potentials and Synaptic Potentials (EPSPs/IPSPs):

  • Threshold: Action potentials require reaching threshold voltage; EPSPs/IPSPs have no threshold.
  • Magnitude: Action potentials are all-or-none with fixed magnitude; EPSPs/IPSPs are graded in magnitude relative to neurotransmitter amount.
  • Refractory Period: Action potentials exhibit absolute and relative refractory periods; EPSPs/IPSPs have no refractory period.
  • Summation: Action potentials cannot summate; EPSPs and IPSPs summate algebraically.

• Mechanisms of Synaptic Summation:

  • Spatial Summation: Algebraic integration of simultaneous postsynaptic potentials originating from multiple presynaptic boutons located at different spatial points across the postsynaptic neuron.
  • Temporal Summation: Algebraic integration of successive postsynaptic potentials elicited in rapid succession by high-frequency firing of a single presynaptic terminal over time.

• Integration at the Axon Hillock:

  • EPSPs decay electrotonically as they travel along dendrites toward the soma.
  • The algebraic sum of all spatial and temporal EPSPs and IPSPs reaching the initial segment/axon hillock determines whether the local potential reaches threshold to fire an all-or-none action potential.

• Long-Term Potentiation (LTP):

  • Prolonged enhancement of synaptic efficacy following high-frequency repetitive (tetanic) stimulation along specific neural pathways.
  • Neural pathways in the hippocampus utilize glutamate acting on NMDA (N-methyl-D-aspartate) receptors to trigger LTP, forming a fundamental mechanism for learning and memory storage.

• Presynaptic vs. Postsynaptic Inhibition:

  • Presynaptic Inhibition: An axo-axonic synapse reduces the amount of neurotransmitter released by the target presynaptic bouton, selectively inhibiting a single specific input pathway without altering overall postsynaptic cell responsiveness.
  • Postsynaptic Inhibition: Direct generation of IPSPs on the postsynaptic soma or dendrites, decreasing the responsiveness of the postsynaptic neuron to all incoming excitatory inputs.

Circuit Organization, Reflexes, and Signal Processing

• Neuronal Circuit Topology:

  • Divergence: A single presynaptic input neuron branches to form synapses with multiple downstream postsynaptic neurons. Can occur within a single pathway to cause signal amplification, or diverge into multiple separate tracts to transmit signals to distinct functional areas.
  • Convergence: Multiple presynaptic input fibers converge to synapse upon a single postsynaptic target neuron. Inputs may originate from multiple terminal branches of a single source neuron or from multiple separate anatomical sources.
  • Reverberatory (Oscillatory) Circuits: Feedback neural loops where axon collaterals from downstream neurons loop back to re-stimulate upstream neurons in the chain. Produces prolonged signal discharge after the initial input stimulus ceases; modulated by facilitating or inhibiting inputs.

• Reflex Arc and Inhibitory Circuitry:

  • Feed-Forward Inhibition: An incoming sensory signal directly excites a motor neuron innervating an agonist muscle (e.g., extensor motor neuron) while simultaneously exciting an inhibitory interneuron that inhibits the motor neuron innervating the antagonist muscle (e.g., flexor motor neuron). Guarantees reciprocal inhibition during movement.
  • Feedback Inhibition: A motor neuron gives off a recurrent axon collateral that excites an inhibitory interneuron (such as a Renshaw cell), which loops back to inhibit the same motor neuron and neighboring motor neurons, limiting motor firing rates.
  • Stretch Reflex Mechanism (Patellar Reflex):
  1. Mechanical tap on the patellar tendon stretches the quadriceps muscle spindle.
  2. Primary sensory neurons fire action potentials that enter the dorsal horn of the spinal cord segment.
  3. Sensory axon synapses directly and excitatorily on alpha motor neurons innervating the quadriceps (extensor) muscle, causing contraction.
  4. Simultaneously, a sensory axon collateral synapses on an inhibitory interneuron in the spinal gray matter.
  5. The inhibitory interneuron releases inhibitory neurotransmitter onto alpha motor neurons innervating the hamstring (flexor) muscle, preventing flexor contraction.

Biochemical Classification and Mechanisms of Neurotransmitters

• Criteria for Establishing a Neurotransmitter:

  1. The substance must be present within the presynaptic terminal.
  2. The substance must be released in response to presynaptic depolarization in a $\text{Ca}^{2+}$-dependent manner.
  3. Specific functional receptors for the substance must be present on the postsynaptic membrane.

• Major Functional and Structural Classes:

  • Small-Molecule Neurotransmitters: Acetylcholine; Amino acids (Glutamate, Aspartate, GABA, Glycine); Biogenic amines (Catecholamines: Dopamine, Norepinephrine, Epinephrine; Indoleamine: Serotonin/5-HT; Imidazoleamine: Histamine); Purines (ATP, Adenosine).
  • Neuropeptides ($3\text{--}30+$ amino acids): Opioid peptides ($\beta$-endorphin, Met-enkephalin, Leu-enkephalin, Endomorphins, Nociceptin), Substance P, Cholecystokinin (CCK), Neuropeptide Y.
  • Gaseous Neurotransmitters: Nitric oxide (NO), Carbon monoxide (CO).

• Synthesis and Axonal Transport Dynamics:
  • Small-Molecule Neurotransmitters: Synthetic enzymes are synthesized in the soma (RER and Golgi) and transported via slow axonal transport to the terminal. Neurotransmitters are synthesized locally in the presynaptic cytoplasm and loaded into small clear-core vesicles via vesicular transporters.
  • Neuropeptides: Propeptides and processing enzymes are synthesized in the soma (RER) and packaged into large dense-core vesicles in the Golgi apparatus. Vesicles are transported down the axon along microtubules via fast axonal transport. Propeptides are cleaved into active peptide neurotransmitters inside vesicles during transport.

• Receptors and Transduction Mechanisms:
  • Ionotropic Receptors (Ligand-Gated Ion Channels): Multimeric channel complexes where neurotransmitter binding directly opens the pore.
  • Example: Nicotinic Acetylcholine Receptor (nAChR). Composed of $5$ polypeptide subunits enclosing an ion channel. Contains $2$ binding sites for ACh. Binding of two ACh molecules opens the channel, permitting rapid $\text{Na}^+$ influx and $\text{K}^+$ efflux (dominated by inward $\text{Na}^+$ flux, generating an EPSP). Found in autonomic ganglia, skeletal muscle neuromuscular junctions, and CNS.

• Metabotropic Receptors (G-Protein-Coupled Receptors): Single monomeric receptors linked to heterotrimeric G-proteins ($\alpha$, $\beta$, $\gamma$ subunits).
  • Example: Muscarinic Acetylcholine Receptor (mAChR). Binding of ACh activates the receptor, causing the G-protein $\alpha$ subunit or $\beta\gamma$ complex to dissociate and diffuse along the membrane to open or close separate ion channel proteins (e.g., opening $\text{K}^+$ channels to cause hyperpolarization/IPSP in cardiac muscle).

* **Second Messenger Cascades (cAMP Path)**: Binding of monoamine neurotransmitters (e.g., Norepinephrine) induces G-protein $\alpha$ subunit dissociation. The $\alpha$ subunit activates adenylate cyclase, converting ATP to cyclic AMP (cAMP). cAMP activates protein kinase, which phosphorylates ion channels or cellular proteins, opening channels or modulating gene transcription.

Specific Neurotransmitter Systems and Central Pathways

• Acetylcholine (ACh):
  • Synthesis: Synthesized in axon terminals from Choline and Acetyl CoA by Choline Acetyltransferase (ChAT). Loaded into synaptic vesicles.
  • Degradation: Hydrolyzed in the synaptic cleft by Acetylcholinesterase (AChE) into Choline and Acetate. Choline is re-absorbed into the presynaptic terminal via choline transporters.
  • Neuromuscular Junction (NMJ): Somatic motor neurons release ACh onto muscle end-plates, eliciting end-plate potentials (EPPs) that depolarize adjacent VG channels to trigger contraction.
  • Central Pathways: Basal forebrain constellation (including the Basal Nucleus of Meynert) projects to the neocortex, hippocampus, and amygdala (involved in memory and arousal). Dorsolateral pontine tegmental constellation projects to the cerebellum, thalamus, and brainstem.

• Serotonin (5-Hydroxytryptamine / 5-HT):

  • Biochemical Origin: Derived from L-tryptophan.
  • Inactivation: Presynaptic reuptake via serotonin transporters, followed by enzymatic degradation by Monoamine Oxidase (MAO). Selective Serotonin Reuptake Inhibitors (SSRIs) inhibit reuptake, prolonging cleft action; used to treat depression, anxiety, migraines, and appetite disorders.
  • Central Pathways: Cell bodies are clustered in the Raphe Nuclei. Rostral raphe nuclei project to the cerebral cortex, thalamus, basal ganglia, limbic cortex, temporal lobe, and hippocampus. Caudal raphe nuclei project to the cerebellum and spinal cord.

• Dopamine (DA):

  • Synthetic Pathway: Tyrosine --(Tyrosine Hydroxylase)--> L-DOPA --(Dopa Decarboxylase)--> Dopamine.
  • Inactivation: Presynaptic reuptake via dopamine transporters (DAT). Degradation occurs presynaptically via MAO (mitochondrial) and postsynaptically/peripherally via Catechol-O-Methyltransferase (COMT) and MAO (liver).
  • Projections and Systems:
  • Nigrostriatal System: Substantia Nigra neurons project to the Corpus Striatum (caudate and putamen). Controls voluntary motor initiation. Degeneration of substantia nigra neurons causes Parkinson's disease.
  • Mesolimbic System: Ventral Tegmental Area (VTA) neurons project to the limbic system (Nucleus Accumbens, Amygdala, Hippocampus). Mediates reward and reinforcement. Addictive drugs promote dopaminergic activity in the nucleus accumbens.
  • Mesocortical System: VTA neurons project to the Frontal Cortex and Cingulate Gyrus (cognition and executive function).

• Norepinephrine (NE):

  • Synthetic Pathway: Tyrosine -> L-DOPA -> Dopamine --(Dopamine $\beta$-Hydroxylase inside vesicles)--> Norepinephrine.
  • PNS Functions: Major neurotransmitter of postganglionic sympathetic neurons innervating smooth muscle, cardiac muscle, and glands; increases blood pressure and induces vasoconstriction.
  • CNS Projections: Originates predominantly in the Locus Coeruleus, projecting widely to the cerebral cortex, thalamus, amygdala, olfactory bulb, and cerebellum; regulates vigilance and arousal. Caudal raphe/brainstem neurons project to the spinal cord.

• Amino Acid Neurotransmitters:

  • Glutamate and Aspartate: Primary excitatory neurotransmitters in the CNS. Glutamate is synthesized from glutamine by glutaminase. Extracellular glutamate is cleared by astrocyte transporters, converted to glutamine by glutamine synthetase, and shuttled back to neurons. Activates AMPA, Kainate, and NMDA receptors (NMDA receptors mediate $\text{Ca}^{2+}$ influx required for learning and memory).
  • Glycine: Inhibitory neurotransmitter primary in the spinal cord and brainstem. Opens ligand-gated $\text{Cl}^-$ channels, producing hyperpolarizing IPSPs that control somatic motor reflexes.
  • GABA ($\gamma$-Aminobutyric Acid): Primary inhibitory neurotransmitter in the brain. Synthesized from glutamate by cytosolic Glutamic Acid Decarboxylase (GAD). Metabolized by GABA-transaminase (GABA-T). Opens $\text{Cl}^-$ channels to hyperpolarize postsynaptic membranes; critical for motor control in the cerebellum.

• Polypeptides, Gases, and Unconventional Signal Molecules:

  • Cholecystokinin (CCK): Promotes satiety following meals.
  • Substance P: Key neurotransmitter mediating spinal pain pathways.
  • Endogenous Opioids: Includes $\beta$-endorphin, Met-enkephalin, Leu-enkephalin, Endomorphins, and Nociceptin. Function as analgesics by blocking presynaptic Substance P release.
  • Neuropeptide Y (NPY): Most abundant neuropeptide in the brain; inhibits glutamate release in the hippocampus and acts as a powerful appetite stimulator.
  • Nitric Oxide (NO): Gas synthesized on demand; stimulates cGMP production. Functions in memory, smooth muscle relaxation, and macrophage bactericidal action.
  • Endocannabinoids: Lipid-derived retrograde messengers that bind to cannabinoid receptors (CB1/CB2). Inhibit presynaptic neurotransmitter release and mediate analgesia.
  • Carbon Monoxide (CO): Stimulates cGMP production; regulates odor adaptation in olfactory neurons and neuroendocrine function in the hypothalamus.

Neuropharmacology and Synaptic Modulation

• Pharmacological Mechanisms at the Synapse (Agonists vs. Antagonists):
  1. Precursor Drug (Agonist): Serves as a metabolic precursor to increase NT synthesis (e.g., L-DOPA for Dopamine).
  2. Inactivates Synthetic Enzyme (Antagonist): Inhibits synthetic enzymes to decrease NT synthesis (e.g., PCPA inhibits Serotonin synthesis).
  3. Vesicle Storage Blockade (Antagonist): Prevents NT packaging into vesicles (e.g., Reserpine blocks vesicular monoamine transporters).
  4. Stimulation of NT Release (Agonist): Promotes exocytosis of NT (e.g., Black widow spider venom triggers ACh release).
  5. Inhibition of NT Release (Antagonist): Blocks exocytosis of NT (e.g., Botulinum toxin cleaves SNARE proteins to block ACh release).
  6. Postsynaptic Receptor Activation (Agonist): Mimics NT at postsynaptic receptors (e.g., Nicotine and Muscarine activate ACh receptors).
  7. Postsynaptic Receptor Blockade (Antagonist): Competitively or non-competitively blocks postsynaptic receptors (e.g., Curare and Atropine block nicotinic and muscarinic ACh receptors).
  8. Autoreceptor Activation (Antagonist): Stimulates presynaptic autoreceptors, inhibiting NT synthesis/release via negative feedback (e.g., Apomorphine activates dopamine autoreceptors).
  9. Autoreceptor Blockade (Agonist): Blocks presynaptic autoreceptors, increasing NT synthesis/release (e.g., Clonidine blocks $\alpha_2$-adrenergic autoreceptors for Norepinephrine).
  10. Reuptake Blockade (Agonist): Inhibits presynaptic transporters, prolonging NT presence in the cleft (e.g., Cocaine blocks dopamine reuptake).
  11. Enzymatic Degradation Inactivation (Agonist): Inhibits degradative enzymes in the cleft (e.g., Physostigmine inhibits Acetylcholinesterase, elevating ACh levels).

Autonomic Nervous System Functions and Physiological Stress Responses

• Sympathetic Panic Response in Phobias / Stress:
  • Central activation originating in the Hypothalamus and Brainstem projects down upper and lower spinal cord segments to drive sympathetic activation.
  • Peripheral Effector Responses:
  • Ocular: Pupil dilation (mydriasis).
  • Vascular: Vasoconstriction of non-essential blood vessels, elevating blood pressure.
  • Respiratory: Tracheal and lung hyperventilation.
  • Cardiovascular: Increased heart rate (tachycardia).
  • Gastrointestinal: Altered stomach secretions, increased defecation (bowel stimulation).
  • Renal/Urinary: Altered kidney function and increased urination reflex activity.
  • Integumentary: Piloerection (goosebumps) and profuse sweating (diaphoresis).